| 1 |
35255429 |
10.1016/j.anndiagpath.2021.151886 |
De Novo CD5-positive diffuse large B-cell lymphoma: A genomic profiling study and prognostic analysis of 46 patients. |
We reported 46 cases of Diffuse Large B-cell lymphoma which abnormally expressed CD5 protein (De Novo CD5-positive DLBCL), which had attracted researcher's attention for a period of time for its poor prognosis. However, there were few studies on its molecular change. In the present article, we summarized the genetic alterations using a lymphopanel detection method by Next Generation Sequencing(NGS). The most frequently mutated genes were MYD88<sup>L265P</sup> (20/46, 43.5%), followed by PIMI (19/46, 41.3%), IGLL5 (13/46, 28.3%)and CD79B (11/46, 23.9%). We further investigated the relationship between gene alterations and prognosis using OS(Overall survival) and PFS(Progression-free survival). MYD88, CREBBP, and ACTB mutation were significantly associated with inferior OS (P = 0.032, 0.000, 0.001), PIMI, CREBBP, ACTB and CXCR4 mutation were significantly associated with inferior PFS (P = 0.016, 0.001, 0.045, 0.024). Meanwhile, we found that De Novo CD5-positive DLBCL had BCL-6(9/46,19.6%), C-MYC (4/46, 8.7%) and IRF4 (2/19, 10.5%) rearrangement, but without BCL-2 rearrangement, there were no significantly associations with prognosis. In summary, our research explored the gene alterations of De Novo CD5-positive DLBCL in a relatively large scale for the first time, the most common gene mutation was MYD88<sup>L265P</sup> which was also a potential prognostic factor, providing a potential therapeutic target for the patients of De Novo CD5-positive DLBCL. |
2022 |
05 |
23 |
Ann Diagn Pathol |
Fan |
Yue |
| 2 |
35344115 |
10.1007/s11033-022-07337-w |
Identification and validation of suitable housekeeping genes for gene expression studies in BCR-ABL1 positive B-lineage acute lymphoblastic leukemia. |
The stability of the housekeeping gene (HKG) expression is an absolute prerequisite for accurate normalization of target gene expression in a quantitative real-time polymerase chain reaction (RQ-PCR). In RQ-PCR, the widely used normalization approach involves the standardization of target genes to the most stable HKG control genes. According to the recent literature, in different experimental conditions the HKGs exhibit either up or down-regulation and thus affecting the gene expression profiles of target genes which leads to erroneous results. This implies that it is very important to select the appropriate HKG and verify the expression stability of the HKG before quantification of the target gene. The present study aims to analyze six different HKGs for their expression profiles and stability in BCR-ABL1 negative cases and validate them in BCR-ABL1 positive cases, detected by multiplex reverse transcribed polymerase chain reaction (RT-PCR). Six commonly used reference genes (GAPDH, ABL1, RNA18S, ACTB, GUSB, and EEF2) were selected in this study. RQ-PCR was performed on 24 BCR-ABL1 negative cases and the outcomes were validated on 24 BCR-ABL1 positive cases. RefFinder™, a web-based composite software was used to check the stability of HKG genes by different algorithms and comprehensive ranking of each HKG gene in BCR-ABL1 negative cases and finally validated in BCR-ABL1 positive cases. It was found that RNA18S, ABL1 and GUSB are good stable HKG genes, which showed minimum variability in gene expression compared to GAPDH, EEF2, and ACTB, the most commonly used HKG. |
2022 |
07 |
12 |
Mol Biol Rep |
Gupta |
Dikshat Gopal |
| 3 |
35765478 |
10.14202/vetworld.2022.1333-1340 |
Investigation of proteomic profiles in canine lymphoma using tandem mass tag-based quantitative proteomics approach. |
Specific tumor biomarkers are useful for the early diagnosis of cancer or can predict the recurrence of neoplastic disease in humans and animals. Lymphoma in dogs could be classified into B-, T-, and NK-cell origins. T-cell lymphoma has the worst prognosis with a shorter survival time and disease-free interval. This study aimed to identify the differential serum protein expressions of canine B- and T-cell lymphomas compared with healthy dogs using a tandem mass tag (TMT)-based quantitative proteomics. Serum samples were collected from 20 untreated canine lymphomas (14 B-cells and 6 T-cells) and four healthy control dogs. Sera peptides from each sample were processed for TMT 10-plex tagging and analyzed using liquid chromatography-mass spectrometry (MS). Differential proteome profiling was then compared between lymphoma and control. We discovered 20 elevated and 14 decreased serum proteins in the lymphoma group relative to the healthy group. Six candidate increased proteins in canine lymphomas were beta-actin cytoplasmic 1 (ACTB, p=0.04), haptoglobin (p=0.002), beta-2 microglobulin (aaaaaaaa2M, p=0.007), beta-2 glycoprotein 1 (APOH, p=0.03), metalloproteinase inhibitor 1 (TIMP-1, p=0.03), and CD44 antigen (p=0.02). When compared between B- and T-cell lymphomas, B-cell phenotypes had upregulated immunoglobulin (Ig) heavy chain V region GOM (p=0.02), clusterin (p=0.01), apolipoprotein C1 (APOC1, p=0.05), and plasminogen (p=0.02). These findings were investigated quantitative serum proteomes between B- and T-cell lymphomas using TMT-based MS. ACTB, aaaaaaaa2M, APOH, TIMP-1, CD44 antigen, Ig heavy chain V region GOM, and APOC1 are novel candidate proteins and might serve as a lymphoma biomarker in dogs. However, evaluation with an increased sample size is needed to confirm their diagnostic and prognostic ability. |
2022 |
07 |
16 |
Vet World |
Fonghem |
Piyanoot |
| 4 |
33404293 |
10.1080/15548627.2020.1871204 |
BNIP3L-mediated mitophagy is required for mitochondrial remodeling during the differentiation of optic nerve oligodendrocytes. |
Retinal ganglion cell axons are heavily myelinated (98%) and myelin damage in the optic nerve (ON) severely affects vision. Understanding the molecular mechanism of oligodendrocyte progenitor cell (OPC) differentiation into mature oligodendrocytes will be essential for developing new therapeutic approaches for ON demyelinating diseases. To this end, we developed a new method for isolation and culture of ON-derived oligodendrocyte lineage cells and used it to study OPC differentiation. A critical aspect of cellular differentiation is macroautophagy/autophagy, a catabolic process that allows for cell remodeling by degradation of excess or damaged cellular molecules and organelles. Knockdown of ATG9A and BECN1 (pro-autophagic proteins involved in the early stages of autophagosome formation) led to a significant reduction in proliferation and survival of OPCs. We also found that autophagy flux (a measure of autophagic degradation activity) is significantly increased during progression of oligodendrocyte differentiation. Additionally, we demonstrate a significant change in mitochondrial dynamics during oligodendrocyte differentiation, which is associated with a significant increase in programmed mitophagy (selective autophagic clearance of mitochondria). This process is mediated by the mitophagy receptor BNIP3L (BCL2/adenovirus E1B interacting protein 3-like). BNIP3L-mediated mitophagy plays a crucial role in the regulation of mitochondrial network formation, mitochondrial function and the viability of newly differentiated oligodendrocytes. Our studies provide novel evidence that proper mitochondrial dynamics is required for establishment of functional mitochondria in mature oligodendrocytes. These findings are significant because targeting BNIP3L-mediated programmed mitophagy may provide a novel therapeutic approach for stimulating myelin repair in ON demyelinating diseases.<b>Abbreviations:</b> A2B5: a surface antigen of oligodendrocytes precursor cells, A2B5 clone 105; ACTB: actin, beta; APC: an antibody to label mature oligodendrocytes, anti-adenomatous polyposis coli clone CC1; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG9A: autophagy related 9A; AU: arbitrary units; BafA1: bafilomycin A1; BCL2: B cell leukemia/lymphoma 2; BECN1: beclin 1, autophagy related; BNIP3: BCL2/adenovirus E1B interacting protein 3; BNIP3L/NIX: BCL2/adenovirus E1B interacting protein 3-like; CASP3: caspase 3; CNP: 2',3'-cyclic nucleotide 3'-phosphodiesterase; Ctl: control; COX8: cytochrome c oxidase subunit; CSPG4/NG2: chondroitin sulfate proteoglycan 4; DAPI: 4'6-diamino-2-phenylindole; DNM1L: dynamin 1-like; EGFP: enhanced green fluorescent protein; FACS: fluorescence-activated cell sorting; FIS1: fission, mitochondrial 1; FUNDC1: FUN14 domain containing 1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFAP: glial fibrillary growth factor; GFP: green fluorescent protein; HsESC: human embryonic stem cell; IEM: immunoelectron microscopy; LAMP1: lysosomal-associated membrane protein 1; LC3B: microtubule-associated protein 1 light chain 3; MBP: myelin basic protein; MFN2: mitofusin 2; Mito-Keima: mitochondria-targeted monomeric keima-red; Mito-GFP: mitochondria-green fluorescent protein; Mito-RFP: mitochondria-red fluorescent protein; MitoSOX: red mitochondrial superoxide probe; MKI67: antigen identified by monoclonal antibody Ki 67; MMP: mitochondrial membrane potential; O4: oligodendrocyte marker O4; OLIG2: oligodendrocyte transcription factor 2; ON: optic nerve; OPA1: OPA1, mitochondrial dynamin like GTPase; OPC: oligodendrocyte progenitor cell; PDL: poly-D-lysine; PINK1: PTEN induced putative kinase 1; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; RFP: red fluorescent protein; RGC: retinal ganglion cell; ROS: reactive oxygen species; RT-PCR: real time polymerase chain reaction; SEM: standard error of the mean; SOD2: superoxide dismutase 2, mitochondrial; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TMRM: tetramethylrhodamine methyl ester; TOMM20: translocase of outer mitochondrial membrane 20; TUBB: tubulin, beta; TUBB3: tubulin, beta 3 class III. |
2022 |
04 |
07 |
Autophagy |
Yazdankhah |
Meysam |
| 5 |
33952317 |
10.1186/s13148-021-01091-9 |
Methylated markers accurately distinguish primary central nervous system lymphomas (PCNSL) from other CNS tumors. |
Definitive diagnosis of primary central nervous system lymphoma (PCNSL) requires invasive surgical brain biopsy, causing treatment delays. In this paper, we identified and validated tumor-specific markers that can distinguish PCNSL from other CNS tumors in tissues. In a pilot study, we tested these newly identified markers in plasma. The Methylation Outlier Detector program was used to identify markers in TCGA dataset of 48 diffuse large B-cell lymphoma (DLBCL) and 656 glioblastomas and lower-grade gliomas. Eight methylated markers clearly distinguished DLBCL from gliomas. Marker performance was verified (ROC-AUC of ≥ 0.989) in samples from several GEO datasets (95 PCNSL; 2112 other primary CNS tumors of 11 types). Next, we developed a novel, efficient assay called Tailed Amplicon Multiplexed-Methylation-Specific PCR (TAM-MSP), which uses two of the methylation markers, cg0504 and SCG3 triplexed with ACTB. FFPE tissue sections (25 cases each) of PCNSL and eight types of other primary CNS tumors were analyzed using TAM-MSP. TAM-MSP distinguished PCNSL from the other primary CNS tumors with 100% accuracy (AUC = 1.00, 95% CI 0.95-1.00, P < 0.001). The TAM-MSP assay also detected as few as 5 copies of fully methylated plasma DNA spiked into 0.5 ml of healthy plasma. In a pilot study of plasma from 15 PCNSL, 5 other CNS tumors and 6 healthy individuals, methylation in cg0504 and SCG3 was detectable in 3/15 PCNSL samples (20%). The Methylation Outlier Detector program identified methylated markers that distinguish PCNSL from other CNS tumors with accuracy. The high level of accuracy achieved by these markers was validated in tissues by a novel method, TAM-MSP. These studies lay a strong foundation for a liquid biopsy-based test to detect PCNSL-specific circulating tumor DNA. |
2022 |
01 |
24 |
Clin Epigenetics |
Downs |
Bradley M |
| 6 |
34598060 |
10.1016/j.ctarc.2021.100465 |
Prioritising breast cancer theranostics: A current medical longing in oncology. |
The Theranostics approach has full potential to completely transform the contemporary medicine system to a patient-centric approach, as it is emerging in quite efficient manner, over the past few years. The primary impetus of this review is to analyse the patent growth in the domain of breast cancer theranostics. This wholesome analysis provides an insight into the current technological and R & D advancement over the years, in breast cancer theranostics. Thus, guide the end-users in getting the conclusion for policymaking and other public recommendations. This patent assessment also foretells about the future trends to carry out further achievements. Due to their easy availability, information richness, & versatility, patent's role in R&D policy has been emphasized by stake holders of innovation including scientists time to time. Graphical Abstract: The figure illustrates the applied technologies used for breast cancer theranostics by top three forward cited patents (A) The oligonucleotides with specific sequences (comprised of at least one of DNA, RNA, PNA. LNA, UNA or combination)<sup>1</sup> are capable of binding a targeted tumor protein (PARP1, HISTIHIB, HISTIHID, NCL, FBL, SFPQ, RPL12, ACTB, HIST1H4A, SSBP1, NONO, H2AFJ, and DDX21, forming a tumor protein complex or subunit or their fragments and might block the tumoral activity. These are also capable of binding to Ramos cells (Derived from Human Burkitt's lymphoma that is negative for Epstein Barr virus). These can also bind cell surface nucleolin and may inhibit cell proliferation. These molecules with detection agent detect the presence or level of disease specific protein. (B) These aptamers with chemical functionalization can be conjugated to an amine linker or high molecular weight non-immunogenic compound or a drug or cytotoxic moiety or labelled with fluorescent agent. These chemically modified aptamers can also bind disease - specific biomarkers e.g., circulating biomarkers, micro- vesicle surface antigens or their functional fragments and can be subsequently used for early diagnosis, prognosis or therapeutic purposes. <sup>1</sup>PNA: Peptide Nucleic Acid. LNA: Locked Nucleic Acid. UNA: Unlocked Nucleic Acid. |
2022 |
03 |
10 |
Cancer Treat Res Commun |
Pandey |
Prem N |
| 7 |
34925435 |
10.3389/fgene.2021.677650 |
Genetic Landscape of Relapsed and Refractory Diffuse Large B-Cell Lymphoma: A Systemic Review and Association Analysis With Next-Generation Sequencing. |
In our research, we screened 1,495 documents, compiled the whole-exome sequencing data of several studies, formed a data set including 92 observations of RRDLBCL (Relapsed and refractory diffuse large B-cell lymphoma), and performed association analysis on the high-frequency mutations among them. The most common mutations in the data set include TTN, KMT2D, TP53, IGLL5, CREBBP, BCL2, MYD88, and SOCS1 etc. Among these, CREBBP, KMT2D, and BCL2 have a strong association with each other, and SOCS1 has a strong association with genes such as STAT6, ACTB, CIITA, ITPKB, and GNA13. TP53 lacks significant associations with most genes. Through SOM clustering, expression-level analysis and protein interaction analysis of common gene mutations, we believe that RRDLBCL can be divided into five main types. We tested the function of the model and described the clinical characteristics of each subtype through a targeted sequencing RRDLBCL cohort of 96 patients. The classification is stated as follows: 1) JAK-STAT-related type: including STAT6, SOCS1, CIITA, etc. The genetic lineage is similar to PMBL and cHL. Retrospective analysis suggests that this subtype responds poorly to induction therapy (R-CHOP, <i>p</i> < 0.05). 2) BCL-CREBBP type: Epigenetic mutations such as KMT2D and CREBBP are more common in this type, and are often accompanied by BCL2 and EZH2 mutations. 3) MCD type: including MYD88 and CD79B, PIM1 is more common in this subtype. 4) TP53 mutation: TP53 mutant patients, which suggests the worst prognosis (<i>p</i> < 0.05) and worst response to CART treatment. 5) Undefined type (Sparse item type): Major Genetic Change Lacking Type, which has a better prognosis and better response to CART treatment. We also reviewed the literature from recent years concerning the previously mentioned common gene mutations. |
2021 |
12 |
21 |
Front Genet |
Gao |
Fan |
| 8 |
31242129 |
10.1080/15548627.2019.1635380 |
<i>MIR145-3p</i> promotes autophagy and enhances bortezomib sensitivity in multiple myeloma by targeting <i>HDAC4</i>. |
Multiple myeloma (MM) is an incurable plasma cell malignancy with poor survival. Autophagy, a stress-responsive catabolic process mediated by lysosomal activity, plays a crucial role in the pathophysiology of MM. Growing evidence has indicated that dysregulated microRNAs (miRNAs) are associated with the aberrant autophagy in various human cancers. However, to date, few miRNAs have been reported to directly modulate autophagy in the pathobiology of MM. In this study, we investigated the role of <i>MIR145-3p</i> (microRNA 145-3p) in MM, with focus on cellular processes autophagy and cell death. Our results provided evidence that downregulation of <i>MIR145-3p</i> expression was associated with disease progression in human MM. <i>MIR145-3p</i> triggered autophagic flux through direct targeting of <i>HDAC4</i> (histone deacetylase 4) in MM cells, leading to enhanced apoptosis. Silencing <i>HDAC4</i> recapitulated the effects of <i>MIR145-3p</i>, whereas enforced expression of <i>HDAC4</i> abrogated the effects of <i>MIR145-3p</i>. Furthermore, we showed that suppression of <i>HDAC4</i> by <i>MIR145-3p</i> resulted in upregulation of the pro-apoptotic protein BCL2L11 and caused MTORC1 inactivation, which in turn led to enhanced autophagy and cell death. Importantly, we demonstrated that <i>MIR145-3p</i> mimic could potentiate the anti-MM activity of bortezomib in both <i>in vitro</i> and <i>in vivo</i> experiments. Overall, our findings indicate that <i>MIR145-3p</i> exerted a tumor suppression function in MM by inducing autophagic cell death and suggest that <i>MIR145-3p</i>-based targeted therapy would represent a novel strategy for MM treatment.<b>Abbreviations:</b> 3-MA: 3-methyladenine; 3'-UTR: 3'-untranslated region; 7-AAD: 7-aminoactinomycin D; ACTB: actin beta; ANXA5: annexin A5; ATG5: autophagy related 5; ATG7: autophagy related 7; B2M: beta-2-microglobulin; BAF: bafilomycin A<sub>1</sub>; BCL2L11: BCL2 like 11; Bort: bortezomib; CASP3: caspase 3; CCK-8: Cell Counting Kit-8; CQ: chloroquine; Ct: threshold cycle; ctrl: control; DAPI: 4',6-diamidino-2-phenylindole; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; HDAC4: histone deacetylase 4; ISS: International Staging System; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; miRNAs: microRNAs; <i>MIR145-3p</i>: microRNA 145-3p; MM: multiple myeloma; mRNA: messenger RNA; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; PCs: plasma cells; PFS: progression-free survival; qRT-PCR: quantitative reverse transcription PCR; RPS6KB1: ribosomal protein S6 kinase B1; SD: standard deviation; siRNA: small interfering RNA; SQSTM1: sequestosome 1; STV: starvation; TUBB: tubulin beta class I. |
2021 |
06 |
07 |
Autophagy |
Wu |
Hongkun |
| 9 |
32349449 |
10.3390/ijms21093093 |
Prevalence of Cytoplasmic Actin Mutations in Diffuse Large B-Cell Lymphoma and Multiple Myeloma: A Functional Assessment Based on Actin Three-Dimensional Structures. |
Mutations in actins have been linked to several developmental diseases. Their occurrence across different cancers has, however, not been investigated. Using the cBioPortal database we show that human actins are infrequently mutated in patient samples of various cancers types. Nevertheless, ranking these studies by mutational frequency suggest that some have a higher percentage of patients with <i>ACTB</i> and <i>ACTG1</i> mutations. Within studies on hematological cancers, mutations in <i>ACTB</i> and <i>ACTG1</i> are associated with lymphoid cancers since none have currently been reported in myeloid cancers. Within the different types of lymphoid cancers <i>ACTB</i> mutations are most frequent in diffuse large B-cell lymphoma (DLBCL) and <i>ACTG1</i> mutations in multiple myeloma. We mapped the ACTB and ACTG1 mutations found in these two cancer types on the 3D-structure of actin showing they are in regions important for actin polymer formation or binding to myosin. The potential effects of the mutations on actin properties imply that mutations in cytoplasmic actins deserve dedicated research in DLBCL and multiple myeloma. |
2021 |
02 |
01 |
Int J Mol Sci |
Witjes |
Laura |
| 10 |
32565964 |
10.3892/ol.2020.11552 |
Comprehensive characterization of driver genes in diffuse large B cell lymphoma. |
Diffuse large B cell lymphoma (DLBCL) is the most common hematological malignancy and is one of the most frequent non-Hodgkin lymphomas. Large-scale genomic studies have defined genetic drivers of DLBCL and their association with functional and clinical outcomes. However, the lymphomagenesis of DLBCL is yet to be fully understood. In the present study, four computational tools OncodriveFM, OncodriveCLUST, integrated Cancer Genome Score and Driver Genes and Pathways were used to detect driver genes and driver pathways involved in DLBCL. The aforementioned tools were also used to perform an integrative investigation of driver genes, including co-expression network, protein-protein interaction, copy number variation and survival analyses. The present study identified 208 driver genes and 31 driver pathways in DLBCL. <i>IGLL5, MLL2, BTG2, B2M, PIM1, CARD11</i> were the top five frequently mutated genes in DLBCL. <i>NOTCH3, LAMC1, COL4A1, PDGFRB</i> and <i>KDR</i> were the 5 hub genes in the blue module that were associated with patient age. <i>TP53, MYC, EGFR, PTEN, IL6, STAT3, MAPK8, TNF</i> and <i>CDH1</i> were at the core of the protein-protein interaction network. <i>PRDM1, CDKN2A, CDKN2B, TNFAIP3, RSPO3</i> were the top five frequently deleted driver genes in DLBCL, while <i>ACTB, BTG2, PLET1, CARD11, DIXDC1</i> were the top five frequently amplified driver genes in DLBCL. High <i>EIF3B, MLH1, PPP1CA</i> and <i>RECQL4</i> expression was associated with decreased overall survival rate of patients with DLBCL. High <i>XPO1</i> and <i>LYN</i> expression were associated with increased overall survival rate of patients with DLBCL. The present study improves the understanding of the biological processes and pathways involved in lymphomagenesis. The driver genes, <i>EIF3B, MLH1, PPP1CA, RECQL4, XPO1</i> and <i>LYN</i>, pave the way for developing prognostic biomarkers and new therapeutic strategies for DLBCL. |
2020 |
09 |
28 |
Oncol Lett |
Fan |
Zheng |
| 11 |
31108950 |
10.3390/genes10050376 |
Identification and Validation of Novel Reference Genes in Acute Lymphoblastic Leukemia for Droplet Digital PCR. |
Droplet digital PCR is the most robust method for absolute nucleic acid quantification. However, RNA is a very versatile molecule and its abundance is tissue-dependent. RNA quantification is dependent on a reference control to estimate the abundance. Additionally, in cancer, many cellular processes are deregulated which consequently affects the gene expression profiles. In this work, we performed microarray data mining of different childhood cancers and healthy controls. We selected four genes that showed no gene expression variations (<i>PSMB6</i>, <i>PGGT1B</i>, <i>UBQLN2</i> and <i>UQCR2</i>) and four classical reference genes (<i>ACTB</i>, <i>GAPDH</i>, <i>RPL4</i> and RPS18). Gene expression was validated in 40 acute lymphoblastic leukemia samples by means of droplet digital PCR. We observed that <i>PSMB6</i>, <i>PGGT1B</i>, <i>UBQLN2</i> and <i>UQCR2</i> were expressed ~100 times less than <i>ACTB</i>, <i>GAPDH</i>, <i>RPL4</i> and <i>RPS18</i>. However, we observed excellent correlations among the new reference genes (<i>p</i> < 0.0001). We propose that <i>PSMB6</i>, <i>PGGT1B</i>, <i>UBQLN2</i> and <i>UQCR2</i> are housekeeping genes with low expression in childhood cancer. |
2020 |
02 |
14 |
Genes (Basel) |
Villegas-Ruíz |
Vanessa |
| 12 |
29433359 |
10.1080/15548627.2017.1390636 |
Piperlongumine restores the balance of autophagy and apoptosis by increasing BCL2 phosphorylation in rotenone-induced Parkinson disease models. |
Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease and is caused by genetics, environmental factors and aging, with few treatments currently available. Apoptosis and macroautophagy/autophagy play critical roles in PD pathogenesis; as such, modulating their balance is a potential treatment strategy. BCL2 (B cell leukemia/lymphoma 2) is a key molecule regulating this balance. Piperlongumine (PLG) is an alkaloid extracted from Piper longum L. that has antiinflammatory and anticancer effects. The present study investigated the protective effects of PLG in rotenone-induced PD cell and mouse models. We found that PLG administration (2 and 4 mg/kg) for 4 wk attenuated motor deficits in mice and prevented the loss of dopaminergic neurons in the substantia nigra induced by oral administration of rotenone (10 mg/kg) for 6 wk. PLG improved cell viability and enhanced mitochondrial function in primary neurons and SK-N-SH cells. These protective effects were exerted via inhibition of apoptosis and induction of autophagy through enhancement of BCL2 phosphorylation at Ser70. These results demonstrate that PLG exerts therapeutic effects in a rotenone-induced PD models by restoring the balance between apoptosis and autophagy. 6-OHDA, 6-hydroxydopamine; ACTB, actin, beta; BafA1, bafilomycin A<sub>1</sub>; BAK1, BCL2-antagonist/killer 1; BAX, BCL2-associated X protein; BCL2, B cell leukemia/lymphoma2; BECN1, Beclin 1, autophagy related; CoQ10, coenzyme Q<sub>10</sub>; COX4I1/COX IV, cytochrome c oxidase subunit 4I1; CsA, cyclosporine A; ED50, 50% effective dose; FITC, fluorescein isothiocyanate; GFP, green fluorescent protein; HPLC, high-performance liquid chromatography; JC-1, tetraethylbenz-imidazolylcarbocyanine iodide; LC3, microtubule-associated protein 1 light chain3; LC-MS/MS, liquid chromatography-tandem mass spectrometry; LDH, lactate dehydrogenase; l-dopa, 3, 4-dihydroxyphenyl-l-alanine; MAPK8/JNK1, mitogen-activated protein kinase 8; MMP, mitochondrial membrane potential; mPTP, mitochondrial permeability transition pore; mRFP, monomeric red fluorescent protein; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NFE2L2/NRF2, nuclear factor, erythroid derived 2, like 2; PD, Parkinson disease; PLG, piperlongumine; pNA, p-nitroanilide; PI, propidium iodide; PtdIns3K, phosphatidylinositol 3-kinase; PtdIns3P, phosphatidylinositol-3-phosphate; PTX, paclitaxel; Rap, rapamycin; SQSTM1/p62, sequestosome 1; TH, tyrosine hydroxylase; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling; WIPI2, WD repeat domain, phosphoinositide interacting 2; ZFYVE1/DFCP1, zinc finger, FYVE domain containing 1. |
2019 |
10 |
03 |
Autophagy |
Liu |
Jia |
| 13 |
27868373 |
10.1002/ajmg.a.38057 |
Acute myeloid leukemia in Baraitser-Winter cerebrofrontofacial syndrome. |
Baraitser-Winter malformation syndrome (BWMS), Fryns-Aftimos syndrome (FA), and craniofrontofacial syndromes (CFFs) have all been recently proposed to be part of the same phenotypic spectrum of Baraitser-Winter cerebrofrontofacial syndrome (BWCFF), which is characterized by facial dysmorphism, ocular coloboma, brain malformations, and intellectual disabilities. In addition to that, the recent discovery of missense mutations in one of the two ubiquitously expressed cytoplasmic β- and γ-acting-encoding genes ACTB (7p22.1) and ACTG1 (17q25.3) in patients carrying a clinical diagnosis of BWSM, FA, or CCF has provided further evidence that these clinical conditions do indeed belong to the same entity at the molecular level. Two cases of BWCFF patients presenting with malignancies (i.e., acute lymphocytic leukemia and cutaneous lymphoma) have been published thus far. Here, we report a 21-year-old female with molecularly confirmed FA, who developed acute myeloid leukemia (AML). The present finding may indicate that actinopathies could be cancer-predisposing syndromes although small numbers and publication bias should be taken into account. © 2016 Wiley Periodicals, Inc. |
2017 |
10 |
24 |
Am J Med Genet A |
Cianci |
Paola |
| 14 |
28807016 |
10.1186/s12885-017-3536-6 |
Endogenous controls of gene expression in N-methyl-N-nitrosourea-induced T-cell lymphoma in p53-deficient mice. |
Real-time polymerase chain reaction (PCR) has become an increasingly important technique for gene expression profiling because it can provide insights into complex biological and pathological processes and be used to predict disease or treatment outcomes. Although normalized data are necessary for an accurate estimation of mRNA expression levels, several pieces of evidence suggest that the expression of so-called housekeeping genes is not stable. This study aimed to validate reference genes for the normalization of real-time PCR in an N-methyl-N-nitrosourea (MNU)-induced T-cell lymphoma mouse model. T-cell lymphomas were generated in p53-deficient mice by treatment with 37.5 mg/kg MNU. Thymus and spleen were identified as the primary target organs with the highest incidences of lymphomas. We analyzed the RNA expression levels of eight potential endogenous reference genes (Gapdh, Rn18s, Actb, Hprt, B2M, Rplp0, Gusb, Ctbp1). The expression stabilities of these reference genes were tested at different time points after MNU treatment using geNorm and NormFinder algorithms. A total of 65% of MNU-treated mice developed T-cell lymphomas, with the spleen and thymus as the major target organs. All candidate reference genes were amplified efficiently by quantitative reverse-transcription polymerase chain reaction (RT-qPCR). Gene stability evaluation after MNU treatment and during lymphomagenesis revealed that Ctbp1 and Rplp0 were the most stably expressed genes in the thymus and spleen, respectively. RT-PCR of thymus RNA using two additional sets of primer confirmed that Ctbp1 was the most stable of all the candidate reference genes. We provided suitable endogenous controls for gene expression studies in the T-cell lymphoma model. |
2018 |
05 |
03 |
BMC Cancer |
Wu |
Xi |
| 15 |
26852652 |
10.1016/j.bcmd.2015.11.006 |
ETV6/RUNX1 transcript is a target of RNA-binding protein IGF2BP1 in t(12;21)(p13;q22)-positive acute lymphoblastic leukemia. |
The oncofetal RNA-binding protein IGF2BP1 (IGF2 mRNA binding protein 1) is overexpressed in a subset of cancers and promotes cell cycle, migration and aggressive phenotype by regulating post-transcriptionally a number of key mRNAs (e. g, ACTB, CD44, CTNNB1, KRAS, MAPK4, MYC, PTEN and others). IGF2BP1 is also overexpressed in t(12;21)(p13;q22)-positive acute lymphoblastic leukemia (ALL), but the biological significance of this phenomenon has not been addressed so far. We have identified leukemia fusion gene ETV6/RUNX1 mRNA to be highly enriched in immunoprecipitated fraction of endogenous IGF2BP1 from a model cell line REH and t(12;21)(p13;q22)-positive ALL samples. Furthermore, downregulation of IGF2BP1 by two-fold has resulted in a corresponding decrease of ETV6/RUNX1 mRNA validating this transcript as a target of IGF2BP1 protein in t(12;21)(p13;q22)-positive ALL. These data infer that IGF2BP1 is a potent regulator of ETV6/RUNX1 mRNA stability and potentially link this evolutionary-highly conserved protein to cell transformation events in ETV6/RUNX1-mediated leukemogenesis of t(12;21)(p13;q22)-positive ALL. |
2016 |
10 |
25 |
Blood Cells Mol Dis |
Stoskus |
Mindaugas |
| 16 |
25052316 |
10.1038/ejhg.2014.95 |
Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases. |
Baraitser-Winter, Fryns-Aftimos and cerebrofrontofacial syndrome types 1 and 3 have recently been associated with heterozygous gain-of-function mutations in one of the two ubiquitous cytoplasmic actin-encoding genes ACTB and ACTG1 that encode β- and γ-actins. We present detailed phenotypic descriptions and neuroimaging on 36 patients analyzed by our group and six cases from the literature with a molecularly proven actinopathy (9 ACTG1 and 33 ACTB). The major clinical anomalies are striking dysmorphic facial features with hypertelorism, broad nose with large tip and prominent root, congenital non-myopathic ptosis, ridged metopic suture and arched eyebrows. Iris or retinal coloboma is present in many cases, as is sensorineural deafness. Cleft lip and palate, hallux duplex, congenital heart defects and renal tract anomalies are seen in some cases. Microcephaly may develop with time. Nearly all patients with ACTG1 mutations, and around 60% of those with ACTB mutations have some degree of pachygyria with anteroposterior severity gradient, rarely lissencephaly or neuronal heterotopia. Reduction of shoulder girdle muscle bulk and progressive joint stiffness is common. Early muscular involvement, occasionally with congenital arthrogryposis, may be present. Progressive, severe dystonia was seen in one family. Intellectual disability and epilepsy are variable in severity and largely correlate with CNS anomalies. One patient developed acute lymphocytic leukemia, and another a cutaneous lymphoma, indicating that actinopathies may be cancer-predisposing disorders. Considering the multifaceted role of actins in cell physiology, we hypothesize that some clinical manifestations may be partially mutation specific. Baraitser-Winter cerebrofrontofacial syndrome is our suggested designation for this clinical entity. |
2015 |
10 |
22 |
Eur J Hum Genet |
Verloes |
Alain |
| 17 |
25696013 |
|
Selection of superior reference genes' combination for quantitative real-time PCR in B-cell lymphomas. |
Normalization of real-time quantitative PCR data to appropriate reference genes is crucial to accurately interpret results. Many genes commonly used as reference standards do not perform as expected, depending on cell type and experimental design. In our previous work, we addressed the issue of suitable reference genes for lymphoid tissue and successfully applied the normalization factor-based approach to discriminate lymphoid malignancies according to their cyclin D1 mRNA level. Here, we addressed the problem of reference gene selection and sufficient number on an enlarged sample set with seven candidate genes. The experimental set included 165 samples of spleens, lymph nodes, and peripheral blood mononuclear cells from patients with different types of non-Hodgkin lymphomas along with non-neoplastic lymphoid specimens. For the first time, we compared all major stability ranking algorithms of Visual Basic for Applications (VBA) applets geNorm, BestKeeper, and NormFinder and tested candidate reference genes on a large and heterogeneous set of fresh clinical lymphoid samples. We concluded that a normalization-based approach using three reference genes (YWHAZ, UBC and ACTB) allows for robust reduction of the variance in real-time PCR results and that the further addition of reference genes does not improve data normalization. This creates a clinically applicable tool for PCR-based lymphoma diagnostics. |
2015 |
12 |
15 |
Ann Clin Lab Sci |
Potashnikova |
Daria |
| 18 |
25715028 |
10.1080/15548627.2015.1017191 |
BAX and BAK1 are dispensable for ABT-737-induced dissociation of the BCL2-BECN1 complex and autophagy. |
Disruption of the complex of BECN1 with BCL2 or BCL2L1/BCL-XL is an essential switch that turns on cellular autophagy in response to environmental stress or treatment with BH3 peptidomimetics. Recently, it has been proposed that BCL2 and BCL2L1/BCL-XL may inhibit autophagy indirectly through a mechanism dependent on the proapoptotic BCL2 family members, BAX and BAK1. Here we report that the BH3 mimetic, ABT-737, induces autophagy in parallel with disruption of BCL2-BECN1 binding in 2 different apoptosis-deficient cell types lacking BAX and BAK1, namely in mouse embryonic fibroblasts cells and in human colon cancer HCT116 cells. We conclude that the BH3 mimetic ABT-737 induces autophagy through a BAX and BAK1-independent mechanism that likely involves disruption of BECN1 binding to antiapoptotic BCL2 family members. |
2016 |
03 |
07 |
Autophagy |
Pedro |
Jose Manuel Bravo-San |
| 19 |
25984893 |
10.1080/15548627.2015.1034402 |
The GST-BHMT assay reveals a distinct mechanism underlying proteasome inhibition-induced macroautophagy in mammalian cells. |
By monitoring the fragmentation of a GST-BHMT (a protein fusion of glutathionine S-transferase N-terminal to betaine-homocysteine S-methyltransferase) reporter in lysosomes, the GST-BHMT assay has previously been established as an endpoint, cargo-based assay for starvation-induced autophagy that is largely nonselective. Here, we demonstrate that under nutrient-rich conditions, proteasome inhibition by either pharmaceutical or genetic manipulations induces similar autophagy-dependent GST-BHMT processing. However, mechanistically this proteasome inhibition-induced autophagy is different from that induced by starvation as it does not rely on regulation by MTOR (mechanistic target of rapamycin [serine/threonine kinase]) and PRKAA/AMPK (protein kinase, AMP-activated, α catalytic subunit), the upstream central sensors of cellular nutrition and energy status, but requires the presence of the cargo receptors SQSTM1/p62 (sequestosome 1) and NBR1 (neighbor of BRCA1 gene 1) that are normally involved in the selective autophagy pathway. Further, it depends on ER (endoplasmic reticulum) stress signaling, in particular ERN1/IRE1 (endoplasmic reticulum to nucleus signaling 1) and its main downstream effector MAPK8/JNK1 (mitogen-activated protein kinase 8), but not XBP1 (X-box binding protein 1), by regulating the phosphorylation-dependent disassociation of BCL2 (B-cell CLL/lymphoma 2) from BECN1 (Beclin 1, autophagy related). Moreover, the multimerization domain of GST-BHMT is required for its processing in response to proteasome inhibition, in contrast to its dispensable role in starvation-induced processing. Together, these findings support a model in which under nutrient-rich conditions, proteasome inactivation induces autophagy-dependent processing of the GST-BHMT reporter through a distinct mechanism that bears notable similarity with the yeast Cvt (cytoplasm-to-vacuole targeting) pathway, and suggest the GST-BHMT reporter might be employed as a convenient assay to study selective macroautophagy in mammalian cells. |
2016 |
02 |
23 |
Autophagy |
Rui |
Yan-Ning |
| 20 |
26043155 |
10.1080/15548627.2015.1055439 |
TNFAIP3 promotes survival of CD4 T cells by restricting MTOR and promoting autophagy. |
Autophagy plays important roles in metabolism, differentiation, and survival in T cells. TNFAIP3/A20 is a ubiquitin-editing enzyme that is thought to be a negative regulator of autophagy in cell lines. However, the role of TNFAIP3 in autophagy remains unclear. To determine whether TNFAIP3 regulates autophagy in CD4 T cells, we first analyzed Tnfaip3-deficient naïve CD4 T cells in vitro. We demonstrated that Tnfaip3-deficient CD4 T cells exhibited reduced MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) puncta formation, increased mitochondrial content, and exaggerated reactive oxygen species (ROS) production. These results indicate that TNFAIP3 promotes autophagy after T cell receptor (TCR) stimulation in CD4 T cells. We then investigated the mechanism by which TNFAIP3 promotes autophagy signaling. We found that TNFAIP3 bound to the MTOR (mechanistic target of rapamycin) complex and that Tnfaip3-deficient cells displayed enhanced ubiquitination of the MTOR complex and MTOR activity. To confirm the effects of enhanced MTOR activity in Tnfaip3-deficient cells, we analyzed cell survival following treatment with Torin1, an MTOR inhibitor. Tnfaip3-deficient CD4 T cells exhibited fewer cell numbers than the control cells in vitro and in vivo. In addition, the impaired survival of Tnfaip3-deficient cells was ameliorated with Torin1 treatment in vitro and in vivo. The effect of Torin1 was abolished by Atg5 deficiency. Thus, enhanced MTOR activity regulates the survival of Tnfaip3-deficient CD4 T cells. Taken together, our findings illustrate that TNFAIP3 restricts MTOR signaling and promotes autophagy, providing new insight into the manner in which MTOR and autophagy regulate survival in CD4 T cells. |
2016 |
04 |
18 |
Autophagy |
Matsuzawa |
Yu |
| 21 |
24275555 |
10.1016/j.bbadis.2013.11.021 |
Peri-conceptional obesogenic exposure induces sex-specific programming of disease susceptibilities in adult mouse offspring. |
Vulnerability of the fetus upon maternal obesity can potentially occur during all developmental phases. We aimed at elaborating longer-term health outcomes of fetal overnutrition during the earliest stages of development. We utilized Naval Medical Research Institute (NMRI) mice to induce pre-conceptional and gestational obesity and followed offspring outcomes in the absence of any postnatal obesogenic influences. Male adult offspring developed overweight, insulin resistance, hyperleptinemia, hyperuricemia and hepatic steatosis; all these features were not observed in females. Instead, they showed impaired fasting glucose and a reduced fat mass and adipocyte size. Influences of the interaction of maternal diet∗sex concerned offspring genes involved in fatty liver disease, lipid droplet size regulation and fat mass expansion. These data suggest that a peri-conceptional obesogenic exposure is sufficient to shape offspring gene expression patterns and health outcomes in a sex- and organ-specific manner, indicating varying developmental vulnerabilities between sexes towards metabolic disease in response to maternal overnutrition. |
2014 |
04 |
16 |
Biochim Biophys Acta |
Dahlhoff |
M |
| 22 |
24418552 |
10.1016/j.virol.2013.11.022 |
HTLV-1 infects human mesenchymal stromal cell in vitro and modifies their phenotypic characteristics. |
The typical characteristics of mesenchymal stem cells (MSCs) can be affected by inflammatory microenvironment; however, the exact contribution of HTLV-1 to MSC dysfunction remains to be elucidated. In this study, we demonstrated that MSC cell surface molecules VCAM-1 and ICAM-1 are upregulated by contact with HTLV-1, and HLA-DR was most highly expressed in MSCs co-cultured with MT2 cells. The expression levels of VCAM-1 and HLA-DR were increased in MSCs cultured in the presence of PBMCs isolated from HTLV-1-infected symptomatic individuals compared with those cultured with cells from asymptomatic infected individuals or healthy subjects. HTLV-1 does not impair the MSC differentiation process into osteocytes and adipocytes. In addition, MSCs were efficiently infected with HTLV-1 in vitro through direct contact with HTLV-1-infected cells; however, cell-free virus particles were not capable of causing infection. In summary, HTLV-1 can alter MSC function, and this mechanism may contribute to the pathogenesis of this viral infection. |
2014 |
04 |
07 |
Virology |
Rodrigues |
Evandra Strazza |
| 23 |
23266771 |
10.1016/j.cca.2012.12.012 |
ACTB in cancer. |
Beta-actin (ACTB) has traditionally been regarded as an endogenous housekeeping gene and has been widely used as a reference gene/protein in quantifying expression levels in tumors. However, ACTB is closely associated with a variety of cancers and accumulating evidence indicates that ACTB is de-regulated in liver, melanoma, renal, colorectal, gastric, pancreatic, esophageal, lung, breast, prostate, ovarian cancers, leukemia and lymphoma. ACTB is generally found to be up-regulated in the majority of tumor cells and tissues. The abnormal expression and polymerization of ACTB and the resulting changes to the cytoskeleton are revealed to be associated with the invasiveness and metastasis of cancers. The current review explores relevant mechanisms, integrates current understandings, and provides suggestions for future studies of the roles of ACTB in tumors. |
2013 |
08 |
27 |
Clin Chim Acta |
Guo |
Chunmei |
| 24 |
23326330 |
10.1371/journal.pone.0052384 |
Activated ERM protein plays a critical role in drug resistance of MOLT4 cells induced by CCL25. |
We have previously demonstrated that the CCR9/CCL25 signaling pathway plays an important role in drug resistance in human acute T-lymphocytic leukemia (T-ALL) by inducing activation of ERM protein with polarized distribution in T-ALL cell line MOLT4. However, the mechanism of action of the activated ERM protein in the drug resistance of MOLT4 cells induced by CCL25 remains uncharacterized. Here we investigated the mechanism of CCR9/CCL25-initiated drug resistance in CCR9-high-expressing T-ALL cells. Our results showed that 1) the function of P-gp was increased after treatment with CCL25; 2) P-gp colocalized and co-immunoprecipitated with p-ERM and F-actin in CCL25 treated cells; and 3) ERM-shRNA conferred drug sensitivity coincident with release of ERM interactions with P-gp and F-actin after treatment with CCL25. These data suggest it is pivotal that P-gp associate with the F-actin cytoskeleton through p-ERM in CCR9/CCL25 induced multidrug resistance of T-ALL cells. Strategies aimed at inhibiting P-gp-F-actin cytoskeleton association may be helpful in increasing the efficiency of therapies in T-ALL. |
2013 |
07 |
05 |
PLoS One |
Zhang |
Li |
| 25 |
23849470 |
10.1186/1756-8722-6-52 |
Protein biomarkers distinguish between high- and low-risk pediatric acute lymphoblastic leukemia in a tissue specific manner. |
The current study evaluated the differential expression detected in the proteomic profiles of low risk- and high risk- ALL pediatric patients to characterize candidate biomarkers related to diagnosis, prognosis and patient targeted therapy. Bone marrow and peripheral blood plasma and cell lysates samples were obtained from pediatric patients with low- (LR) and high-risk (HR) ALL at diagnosis. As controls, non-leukemic pediatric patients were studied. Cytogenetic analysis was carried out by G- banding and interphase fluorescent in situ hybridization. Differential proteomic analysis was performed using two-dimensional gel electrophoresis and protein identification by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. The differential expression of certain proteins was confirmed by Western blot analysis. The obtained data revealed that CLUS, CERU, APOE, APOA4, APOA1, GELS, S10A9, AMBP, ACTB, CATA and AFAM proteins play a significant role in leukemia prognosis, potentially serving as distinctive biomarkers for leukemia aggressiveness, or as suppressor proteins in HR-ALL cases. In addition, vitronectin and plasminogen probably contributed to leukemogenesis, whilst bicaudal D-related protein 1 could afford a significant biomarker for pediatric ALL therapeutics. |
2014 |
05 |
05 |
J Hematol Oncol |
Braoudaki |
Maria |
| 26 |
22343534 |
10.1073/pnas.1121343109 |
Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. |
To gain insight into the genomic basis of diffuse large B-cell lymphoma (DLBCL), we performed massively parallel whole-exome sequencing of 55 primary tumor samples from patients with DLBCL and matched normal tissue. We identified recurrent mutations in genes that are well known to be functionally relevant in DLBCL, including MYD88, CARD11, EZH2, and CREBBP. We also identified somatic mutations in genes for which a functional role in DLBCL has not been previously suspected. These genes include MEF2B, MLL2, BTG1, GNA13, ACTB, P2RY8, PCLO, and TNFRSF14. Further, we show that BCL2 mutations commonly occur in patients with BCL2/IgH rearrangements as a result of somatic hypermutation normally occurring at the IgH locus. The BCL2 point mutations are primarily synonymous, and likely caused by activation-induced cytidine deaminase-mediated somatic hypermutation, as shown by comprehensive analysis of enrichment of mutations in WRCY target motifs. Those nonsynonymous mutations that are observed tend to be found outside of the functionally important BH domains of the protein, suggesting that strong negative selection against BCL2 loss-of-function mutations is at play. Last, by using an algorithm designed to identify likely functionally relevant but infrequent mutations, we identify KRAS, BRAF, and NOTCH1 as likely drivers of DLBCL pathogenesis in some patients. Our data provide an unbiased view of the landscape of mutations in DLBCL, and this in turn may point toward new therapeutic strategies for the disease. |
2012 |
05 |
04 |
Proc Natl Acad Sci U S A |
Lohr |
Jens G |
| 27 |
19309015 |
10.1002/elps.200800508 |
2-D PAGE-based comparison of proteasome inhibitor bortezomib in sensitive and resistant mantle cell lymphoma. |
Although gene expression following bortezomib treatment has been previously explored, direct effects of bortezomib-induced proteasome inhibition on protein level has not been analyzed so far. Using 2-D PAGE in five mantle cell lymphoma cell lines, we screened for cellular protein level alterations following treatment with 25 nM bortezomib for up to 4 h. Using MS, we identified 38 of the 41 most prominent reliably detected protein spots. Twenty-one were affected in all cell lines, whereas the remaining 20 protein spots were exclusively altered in sensitive cell lines. Western blot analysis was performed for 17 of the 38 identified proteins and 70.6% of the observed protein level alterations in 2-D gels was verified. All cell lines exhibited alterations of the cellular protein levels of heat shock-induced protein species (HSPA9, HSP7C, HSPA5, HSPD1), whereas sensitive cell lines also displayed altered cellular protein levels of energy metabolism (ATP5B, AK5, TPI1, ENO-1, ALDOC, GAPDH), RNA and transcriptional regulation (HNRPL, SFRS12) and cell division (NEBL, ACTB, SMC1A, C20orf23) as well as tumor suppressor genes (ENO-1, FH). These proteins clustered in a tight interaction network centered on the major cellular checkpoints TP53. The results were confirmed in primary mantle cell lymphoma, thus confirming the critical role of these candidate proteins of proteasome inhibition. |
2009 |
08 |
18 |
Electrophoresis |
Weinkauf |
Marc |
| 28 |
20031021 |
10.1016/j.rbmo.2009.09.024 |
Apoptosis in normal ovaries of women with and without endometriosis. |
The aim of this study was to evaluate the factors predisposing to implants of endometriotic lesions in normal ovarian cortexes of women with and without endometriosis by assessing the expression of pro-apoptotic and anti-apoptotic factors and follicular density. Ovarian biopsies were performed during laparoscopy in 18 patients with endometrioma and in 10 healthy women. Detection of apoptosis was performed with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling assay. p53 and BCL2 proteins were assessed by immunohistochemistry. Quantitative real-time polymerase chain reaction was performed to evaluate BAX , BAK , BCL2 , BCL-XL , survivin and beta-actin ( ACTB ) expression. The p53 protein was positive in a significantly higher number of secondary follicles, whereas the B-cell chronic lymphocytic leukaemia/lymphoma 2 (BCL2) protein was positive in all follicles in unaffected tissue of endometriotic women, compared with the controls. Overexpression of the BCL2 and survivin genes and a decreased BAX and BAK gene expression were observed in the endometriotic group although only the difference in survivin expression was significant (P = 0.016). The BCL2 / BAX ratio showed an increased value in the ovarian cortex in controls compared with endometriosis patients. In conclusion, the reduction of apoptosis in unaffected tissue in women with endometriosis suggests that they may be predisposed to develop endometriosis. |
2010 |
02 |
25 |
Reprod Biomed Online |
Depalo |
Raffaella |
| 29 |
17823310 |
10.1182/blood-2007-04-087775 |
HGAL, a lymphoma prognostic biomarker, interacts with the cytoskeleton and mediates the effects of IL-6 on cell migration. |
HGAL is a newly identified germinal center (GC)-specific gene whose expression by the tumor cells correlates with a favorable prognosis in patients with diffuse large B-cell and classical Hodgkin lymphomas. The function of HGAL is unknown. Previous studies demonstrated that HGAL is dispensable for GC formation, immunoglobulin gene class-switch recombination, and somatic hypermutation. Herein, we identify a role for HGAL in the regulation of cell motility. We demonstrate that IL-6 induces the phosphorylation of the C-terminal tyrosine residue of the HGAL protein via the Lyn kinase, and promotes its relocalization from the cytoplasm to podosome-like structures. Further, IL-6-induced HGAL phosphorylation increases its interaction with myosin II and is associated with inhibition of cell migration. Knockdown of endogenous HGAL ameliorates IL-6-induced inhibition of cell migration, whereas overexpression of HGAL imparts inhibitory effects of IL-6 on cell migration. Taken together, our results suggest that HGAL is involved in negative regulation of lymphocyte migration, thus constraining lymphocytes to the GC. Inhibition of lymphocyte migration might contribute to the less aggressive clinical behavior of HGAL-expressing lymphomas. |
2008 |
02 |
26 |
Blood |
Lu |
Xiaoqing |
| 30 |
16105984 |
10.1182/blood-2005-03-1204 |
p130Cas mediates the transforming properties of the anaplastic lymphoma kinase. |
Translocations of the anaplastic lymphoma kinase (ALK) gene have been described in anaplastic large-cell lymphomas (ALCLs) and in stromal tumors. The most frequent translocation, t(2;5), generates the fusion protein nucleophosmin (NPM)-ALK with intrinsic tyrosine kinase activity. Along with transformation, NPM-ALK induces morphologic changes in fibroblasts and lymphoid cells, suggesting a direct role of ALK in cell shaping. In this study, we used a mass-spectrometry-based proteomic approach to search for proteins involved in cytoskeleton remodeling and identified p130Cas (p130 Crk-associated substrate) as a novel interactor of NPM-ALK. In 293 cells and in fibroblasts as well as in human ALK-positive lymphoma cell lines, NPM-ALK was able to bind p130Cas and to induce its phosphorylation. Both of the effects were dependent on ALK kinase activity and on the adaptor protein growth factor receptor-bound protein 2 (Grb2), since no binding or phosphorylation was found with the kinase-dead mutant NPM-ALK(K210R) or in the presence of a Grb2 dominant-negative protein. Phosphorylation of p130Cas by NPM-ALK was partially independent from Src (tyrosine kinase pp60c-src) kinase activity, as it was still detectable in Syf-/- cells. Finally, p130Cas-/- (also known as Bcar1-/-) fibroblasts expressing NPM-ALK showed impaired actin filament depolymerization and were no longer transformed compared with wild-type cells, indicating an essential role of p130Cas activation in ALK-mediated transformation. |
2006 |
01 |
18 |
Blood |
Ambrogio |
Chiara |
| 31 |
1505215 |
10.1159/000133336 |
Sublocalization of an invasion-inducing locus and other genes on human chromosome 7. |
By somatic cell fusion studies between noninvasive mouse T-lymphoma cells and invasive human activated normal T-cells we have previously shown that the genetic information responsible for the induction of invasive and metastatic potential in interspecies T-cell hybrids is located on human chromosome 7. Apparently, genes derived from normal activated T-cells are dominantly expressed in the hybrids and control the invasive and, as a consequence, metastatic potential of these T-lymphoma cells. To sublocalize the invasion-inducing locus on chromosome 7 we have generated hybrids that harbor only specific regions of human chromosome 7 with or without a small fragment of human chromosome 21. Analysis of these hybrids revealed that the invasion-inducing locus maps to 7p12----cen. The human DNA complement of the hybrids was confirmed by Southern blot analysis using a large panel of chromosome 7-specific DNA probes. Several of these genes could be further sublocalized. These included: ARAF2 to 7p12----cen, D7S21 to 7pter----p12, ACTB to 7p15----p12, EGFR to 7p12, MDH2 to 7cen----q22, and PDGFA to 7pter----p15. |
1992 |
09 |
22 |
Cytogenet Cell Genet |
Habets |
G G |
| 32 |
34265801 |
10.1097/PAS.0000000000001780 |
Plasticity of Mature B Cells Between Follicular and Classic Hodgkin Lymphomas: A Series of 22 Cases Expanding the Spectrum of Transdifferentiation. |
Follicular lymphoma and classic Hodgkin lymphoma can be associated in composite and/or sequential lymphomas. Common IGH and BCL2 rearrangements have already been identified between both contingents of these entities, but mutation profiles have not yet been investigated. The main objective of this study was to analyze the transdifferentiation process that may occur between Hodgkin and follicular contingents in sequential and composite lymphomas to better characterize these entities. From 2004 to 2020, a retrospective multicentric study was performed, including 9 composite and 13 sequential lymphomas. Clinical data were retrospectively collected. Fluorescent in situ hybridization of BCL2 and BCL6 rearrangements, polymerase chain reaction of IGH and IGK rearrangements, next-generation sequencing of IGK rearrangement, and targeted next-generation sequencing (TNGS) on a panel of genes frequently mutated in lymphomas were performed on each contingent of composite and sequential lymphomas. For TNGS, each contingent was isolated by laser capture microdissection. Clinical presentation and evolution were more aggressive in sequential than composite lymphomas. By fluorescent in situ hybridization, common rearrangements of BCL6 and BCL2 were identified between both contingents. Similarly, a common clonal relationship was established by evaluating IGH and IGK rearrangement by polymerase chain reaction or next-generation sequencing. By TNGS, the same pathogenic variants were identified in both contingents in the following genes: CREBBP, KMT2D, BCL2, EP300, SF3B1, SOCS1, ARID1A, and BCOR. Specific pathogenic variants for each contingent were also identified: XPO1 for Hodgkin lymphoma contingent and FOXO1, TNFRSF14 for follicular lymphoma contingent. This study reinforces the hypothesis of a transdifferentiation process between Hodgkin and follicular contingent of sequential/composite lymphomas. |
2022 |
02 |
14 |
Am J Surg Pathol |
Trecourt |
Alexis |
| 33 |
34560683 |
10.1097/PAS.0000000000001813 |
A Comprehensive Clinicopathologic and Molecular Study of 19 Primary Effusion Lymphomas in HIV-infected Patients. |
Primary effusion lymphoma (PEL) is associated with human herpesvirus 8 and frequently with Epstein-Barr virus (EBV). We report here a single-center series of 19 human immunodeficiency virus-associated PELs, including 14 EBV+ and 5 EBV- PELs. The objectives were to describe the clinicopathologic features of PELs, with a focus on programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) expression, to search for genetic alterations by targeted deep sequencing analysis, and to compare the features between EBV+ and EBV- cases. All the patients were male, and the median age at diagnosis was 47 years old (interquartile range: 40 to 56 y). Reflecting the terminal B-cell differentiation, immunophenotypic profiles showed low expression levels of B-cell markers, including CD19 (0/19), CD20 (1/19), CD79a (0/19), PAX5 (1/19), BOB1 (3/19), and OCT2 (4/19), contrasting with a common expression of CD38 (10/19), CD138 (7/19), and IRF4/MUM1 (18/19). We observed a frequent aberrant expression of T-cell markers, especially CD3 (10/19), and less frequently CD2 (2/19), CD4 (3/19), CD5 (1/19), and CD8 (0/19). Only 2 cases were PD-L1 positive on tumor cells and none PD-1 positive. With respect to immune cells, 3 samples tested positive for PD-L1 and 5 for PD-1. Our 36-gene lymphopanel revealed 7 distinct variants in 5/10 PELs, with either a single or 2 mutations per sample: B2M (n=2), CD58 (n=1), EP300 (n=1), TNFAIP3 (n=1), ARID1A (n=1), and TP53 (n=1). Finally, we did not observe any major clinical, pathologic, or immunohistochemical differences between EBV+ and EBV- PELs and the outcome was similar (2-y overall survival probability of 61.9% [95% confidence interval, 31.2-82.1] vs. 60.0% [95% confidence interval, 12.6-88.2], respectively, P=0.62). |
2022 |
03 |
07 |
Am J Surg Pathol |
Calvani |
Julien |
| 34 |
34649275 |
10.1182/bloodadvances.2021005316 |
Worse outcome and distinct mutational pattern in follicular lymphoma with anti-HBc positivity. |
Epidemiological studies have demonstrated the association between hepatitis B virus (HBV) infection and B-cell non-Hodgkin lymphoma (NHL), mainly for diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). We studied a cohort of 121 patients with FL for HBV infection status, clinical features, and gene mutational profile. Anti-HBc was detectable in 16 patients (13.2%), although all had undetectable HBV DNA. Anti-HBcore+ (anti-HBc+) cases presented with older age at diagnosis than anti-HBc- cases (68.1 vs 57.2 years; P = .007) and higher β2-microglobulin (56.3% vs 28.9%; P = .04). All patients included in the study fulfilled criteria for treatment and received therapy with rituximab or rituximab-containing chemotherapy. There were no episodes of HBV reactivation or HBV hepatitis during treatment and/or maintenance. Remarkably, anti-HBc+ patients had significantly lower 10-year progression-free survival (PFS; 12.9% vs 58.3%; P < .0001) and overall survival (OS; 22.0% vs 86.2%; P < .0001), that remained at multivariate analysis. Gene mutational profiling of all cases showed that anti-HBc+ cases had higher incidence of ARID1A mutations and absence of EP300 mutations, 2 key epigenetic regulators in FL. Overall, our study shows that FL patients with resolved HBV infection have a worse outcome independently of other well-known clinical risk factors and a distinct gene mutational profile. |
2022 |
03 |
10 |
Blood Adv |
Fernández-Rodríguez |
Concepción |
| 35 |
34791836 |
10.1002/cam4.4422 |
Identification of a genetic signature enriching for response to ibrutinib in relapsed/refractory follicular lymphoma in the DAWN phase 2 trial. |
The single-arm DAWN trial (NCT01779791) of ibrutinib monotherapy in patients with relapsed/refractory follicular lymphoma (FL) showed an overall response rate (ORR) of 20.9% and a median response duration of 19.4 months. This biomarker analysis of the DAWN dataset sought to determine genetic classifiers for prediction of response to ibrutinib treatment. Whole exome sequencing was performed on baseline tumor samples. Potential germline variants were excluded; a custom set of 1216 cancer-related genes was examined. Responder- versus nonresponder-associated variants were identified using Fisher's exact test. Classifiers with increasing numbers of genes were created using a greedy algorithm that repeatedly selected genes, adding the most nonresponders to the existing ""predicted nonresponders"" set and were evaluated with 10-fold cross-validation. Exome data were generated from 88 patient samples and 13,554 somatic mutation variants were inferred. Response data were available for 83 patients (17 responders, 66 nonresponders). Each sample showed 100 to >500 mutated genes, with greater variance across nonresponders. The overall variant pattern was consistent with previous FL studies; 75 genes had mutations in >10% of patients, including genes previously reported as associated with FL. Univariate analysis yielded responder-associated genes FANCA, HISTH1B, ANXA6, BTG1, and PARP10, highlighting the importance of functions outside of B-cell receptor signaling, including epigenetic processes, DNA damage repair, cell cycle/proliferation, and cell motility/invasiveness. While nonresponder-associated genes included well-known TP53 and CARD11, genetic classifiers developed using nonresponder-associated genes included ATP6AP1, EP400, ARID1A, SOCS1, and TBL1XR1, suggesting resistance to ibrutinib may be related to broad biological functions connected to epigenetic modification, telomere maintenance, and cancer-associated signaling pathways (mTOR, JAK/STAT, NF-κB). The results from univariate and genetic classifier analyses provide insights into genes associated with response or resistance to ibrutinib in FL and identify a classifier developed using nonresponder-associated genes, which warrants further investigation. NCT01779791. |
2022 |
03 |
21 |
Cancer Med |
Balasubramanian |
Sriram |
| 36 |
35038193 |
10.1111/his.14617 |
Incidence, clinicopathological features and genetics of in-situ follicular neoplasia: a comprehensive screening study in a Japanese cohort. |
In-situ follicular neoplasia (ISFN) is a histologically recognizable neoplastic proliferation of follicular lymphoma (FL)-like B cells confined to the germinal centres. While some ISFNs are associated with overt FL, others are incidentally identified as isolated or pure forms in individuals without evidence of overt FL. The prevalence of incidentally found isolated ISFN is approximately 3% in Europe; however, no screening study has been conducted in Asia. To investigate the incidence and clinicopathological characteristics of ISFNs in the Japanese population, we conducted histopathological screening of the lymph nodes (LNs) resected for solid tumours or inflammatory conditions. We screened for ISFN in 5700 LNs from 340 individuals using immunohistochemistry for BCL2 and identified seven ISFNs, with an incidence of 2.1%. The median age of the individuals with ISFN was 67 years, none of whom developed overt FL, with a median follow-up of 59 months. Next-generation sequencing was performed in five ISFNs, and 10 variants in seven FL-associated genes were identified. The identified variants included HIST1H1E (n = 2), ARID1A (n = 2), KMT2D (n = 1), CARD11 (n = 1), BCL7A (n = 1), CREBBP (n = 1) and TNFRSF14 (n = 1). The incidence of isolated ISFN in the Japanese population is not significantly different from that in Europe, presumably reflecting the recent increase in FL in Japan. These incidentally found ISFNs have a low potential to transform into overt FL. Although mutations of FL-associated genes are already present in ISFNs, further molecular studies are needed to identify driver genes leading to the transformation of ISFN to overt FL. |
2022 |
03 |
30 |
Histopathology |
Oishi |
Naoki |
| 37 |
35054466 |
10.3390/life12010073 |
The Pathologic and Genetic Characteristics of Extranodal NK/T-Cell Lymphoma. |
Extranodal NK/T-cell lymphoma is a neoplasm of NK cells or cytotoxic T cells presenting in extranodal sites, most often in the nasal cavity. The typical immunophenotypes are cCD3+, sCD3-, CD4-, CD5-, CD8-, CD16-, and CD56+ with the expression of cytotoxic molecules. Tumor subsets express NK cell receptors, CD95/CD95L, CD30, MYC, and PDL1. Virtually all the tumor cells harbor the EBV genome, which plays a key role in lymphomagenesis as an epigenetic driver. EBV-encoded oncoproteins modulate the host-cell epigenetic machinery, reprogramming the viral and host epigenomes using host epigenetic modifiers. NGS analysis revealed the mutational landscape of ENKTL, predominantly involving the JAK-STAT pathway, epigenetic modifications, the RNA helicase family, the RAS/MAP kinase pathway, and tumor suppressors, which indicate an important role of these pathways and this group of genes in the lymphomagenesis of ENKTL. Recently, three molecular subtypes were proposed, the tumor-suppressor/immune-modulator (TSIM), MGA-BRDT (MB), and HDAC9-EP300-ARID1A (HEA) subtypes, and they are well-correlated with the cell of origin, EBV pattern, genomic alterations, and clinical outcomes. A future investigation into the function and interaction of discovered genes would be very helpful for better understanding the molecular pathogenesis of ENKTL and establishing better treatment strategies. |
2022 |
01 |
28 |
Life (Basel) |
Kim |
Hyunsung |
| 38 |
35172382 |
10.1002/JLB.5A0721-361R |
Genomic heterogeneity contributed to different prognosis between adult and pediatric acute lymphoblastic. |
The prognosis of acute lymphoblastic leukemia (ALL) in adults is inferior to that in children. Hence, ALL remains challenging to cure in the adult population. Aberrant genetic alterations have been observed in ALL, although the patterns of differential gene alterations in adult and pediatric ALL have not been comprehensively determined on a genome-wide scale. We investigated the biologic differences in genomic profiles between adults (n = 64) and children (n = 54) with ALL and relationship between genomic heterogeneity and prognosis. The 2 populations showed similar common mutation types but an increased prevalence of genetic alterations in adult ALL. The median numbers of gene mutations were 17 (range: 1-53) and 4.5 (range: 1-19) per sample in adult and pediatric ALL, respectively (p < 0.001). An increased number of gene mutations and age were significantly correlated (R<sup>2</sup> = 0.5853, p < 0.001). We identified 122 and 53 driver genes in adult and pediatric ALL samples, respectively. IKZF1, IDH1, and TTN mutations were significantly enriched in adult patients with ALL. KRAS, ARID1A, and CREBBP mutations were significantly enriched in pediatric patients with ALL (p < 0.05). The incidence of relapse was 40.0% and 9.6% in adult and pediatric patients with ALL, respectively (p = 0.003). The overall survival and relapse-free survival of adult patients with ALL were poorer than those of pediatric patients with ALL (p = 0.002 and p < 0.001, respectively). This genomic landscape enhances the understanding of the biologic differences in ALL between the 2 populations and provides insight for developing therapeutic approaches. |
2022 |
08 |
26 |
J Leukoc Biol |
Chen |
Yanxin |
| 39 |
35317330 |
10.14740/wjon1436 |
Non-GCB Diffuse Large B-Cell Lymphoma With an Atypical Disease Course: A Case Report and Clinical Exome Analysis. |
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid tumor among other non-Hodgkin lymphomas (30-40% of all cases). This type of lymphoma is characterized by significant differences in treatment response and the heterogeneity of clinical traits. Approximately 60% of patients are cured using standard chemotherapy (CT), while in 10-15% of cases, the tumor is characterized by an extremely aggressive course and resistance to even the most high-dose programs with autologous stem cell transplantation (auto-SCT). The activated B-cell (ABC) subtype of DLBCL is characterized by poor prognosis. Here, we describe a clinical case of diffuse ABC-DLBCL with an atypical disease course. Complete remission was achieved after four courses of CT, followed by autologous hematopoietic stem cell transplantation (auto-HSCT). However, early relapse occurred 2 months after the completion of treatment. According to the results of cytogenetic studies, significant chromosome breakdowns were observed. Exome sequencing allowed for the detection of several novel mutations that affect components of the NOTCH2 and NF-κB signaling pathways, a number of epigenetic regulators (<i>KMT2D</i>, <i>CREBBP</i>, <i>EP300</i>, <i>ARID1A</i>, <i>MEF2B</i>), as well as members of the immunoglobulin superfamily (<i>CD58</i> and <i>CD70</i>). Whether these mutations were the result of therapy or were originally present in the lymphoid tumor remains unclear. Nevertheless, the introduction of genomic technologies into clinical practice is important for making a diagnosis and developing a DLBCL treatment regimen with the use of targeted drugs. |
2022 |
03 |
24 |
World J Oncol |
Tsygankova |
Svetlana |
| 40 |
35454811 |
10.3390/cancers14081904 |
Deciphering Genetic Alterations of Hairy Cell Leukemia and Hairy Cell Leukemia-like Disorders in 98 Patients. |
Hairy cell leukemia (cHCL) patients have, in most cases, a specific clinical and biological presentation with splenomegaly, anemia, leukopenia, neutropenia, monocytopenia and/or thrombocytopenia, identification of hairy cells that express CD103, CD123, CD25, CD11c and identification of the V600E mutation in the B-Raf proto-oncogene (<i>BRAF</i>) in 90% of cases. Monocytopenia is absent in vHCL and SDRPL patients and the abnormal cells do not express CD25 or CD123 and do not present the <i>BRAF<sup>V600E</sup></i> mutation. Ten percent of cHCL patients are BRAF<sup>WT</sup> and the distinction between cHCL and HCL-like disorders including the variant form of HCL (vHCL) and splenic diffuse red pulp lymphoma (SDRPL) can be challenging. We performed deep sequencing in a large cohort of 84 cHCL and 16 HCL-like disorders to improve insights into the pathogenesis of the diseases. <i>BRAF</i> mutations were detected in 76/82 patients of cHCL (93%) and additional mutations were identified in Krüppel-like Factor 2 (<i>KLF2</i>) in 19 patients (23%) or <i>CDKN1B</i> in 6 patients (7.5%). Some <i>KLF2</i> genetic alterations were localized on the cytidine deaminase (AID) consensus motif, suggesting AID-induced mutations. When analyzing sequential samples, a clonal evolution was identified in half of the cHCL patients (6/12 pts). Among the 16 patients with HCL-like disorders, we observed an enrichment of <i>MAP2K1</i> mutations in vHCL/SDRPL (3/5 pts) and genes involved in the epigenetic regulation (<i>KDM6A, EZH2, CREBBP, ARID1A</i>) (3/5 pts). Furthermore, <i>MAP2K1</i> mutations were associated with a bad prognosis and a shorter time to next treatment (TTNT) and progression-free survival (PFS), independently of the HCL classification. |
2022 |
07 |
16 |
Cancers (Basel) |
Maitre |
Elsa |
| 41 |
35727053 |
10.1002/cncr.34348 |
Differential prognostic effect of systemic inflammation in patients with non-small cell lung cancer treated with immunotherapy or chemotherapy: A post hoc analysis of the phase 3 OAK trial. |
A proinflammatory diathesis, as measured by the neutrophil to lymphocyte ratio (NLR), heralds an adverse disease course for non-small cell lung cancer (NSCLC). This post hoc analysis used data from the phase 3 OAK trial (NCT02008227), which randomized previously treated patients with NSCLC to atezolizumab or docetaxel. The main objective was assessing the differential impact of the pretreatment NLR on overall survival according to the treatment modality. In addition, patients' genomic characteristics were assessed according to their inflammatory status with a circulating free DNA (cfDNA) next-generation sequencing (NGS) analysis. In all, 600 and 575 patients with NLR data were included in the atezolizumab and docetaxel cohorts, respectively, with a median NLR of 4 (interquartile range, 2.6-6.7) for the pooled population. An NLR ≥4 was associated with a positive smoking status (88.6% vs. 78.1%; p < .01), male sex (66.4% vs. 57.6%; p = .01), a worse performance status (71.3% vs. 55.2%; p < .01), a higher number of metastatic sites (63.2% vs. 51.6%; p = .01), squamous histology (32.1% vs. 21.4%; p < .01), and tissue KRAS mutations (30% vs. 18.7%; p = .02) but not with programmed death ligand 1 (PD-L1) expression or the tissue epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) status. A pretreatment NLR ≥4 was more strongly associated with mortality after atezolizumab (adjusted hazard ratio [HR], 1.64; 95% confidence interval [CI], 1.35-2.01) versus docetaxel (HR, 1.32; 95% CI, 1.08-1.60; multivariable [MVA] interaction p = .08). The HR for an increased risk of death for PD-L1-negative/NLR ≥4 patients (compared with PD-L1-positive/NLR <4 patients) was significantly higher in the atezolizumab cohort (MVA interaction p = .01). The exclusion of EGFR/ALK-positive patients further increased the prognostic ability of the baseline NLR in favor of atezolizumab (MVA interaction p = .02). Pretreatment cfDNA data from NGS showed that patients with a high blood tumor mutation burden (cutoff, 16 mut/Mb) had a higher median NLR (4.6 vs. 3.7; p = .01). After adjustments for multiple comparisons, none of the selected variants of interest (EGFR, KRAS, TP53, KEAP1, STK11, SMARCA4, ARID1A, and targeted DNA damage response and repair genes) were significantly associated with the NLR. A low baseline NLR identified patients with NSCLC who derived a greater survival benefit from atezolizumab in comparison with those identified in the docetaxel cohort. The NLR could complement PD-L1 expression in tailoring treatment in this setting. |
2022 |
08 |
08 |
Cancer |
Cortellini |
Alessio |
| 42 |
35794096 |
10.1038/s41467-022-31355-8 |
Clinical relevance of molecular characteristics in Burkitt lymphoma differs according to age. |
While survival has improved for Burkitt lymphoma patients, potential differences in outcome between pediatric and adult patients remain unclear. In both age groups, survival remains poor at relapse. Therefore, we conducted a comparative study in a large pediatric cohort, including 191 cases and 97 samples from adults. While TP53 and CCND3 mutation frequencies are not age related, samples from pediatric patients showed a higher frequency of mutations in ID3, DDX3X, ARID1A and SMARCA4, while several genes such as BCL2 and YY1AP1 are almost exclusively mutated in adult patients. An unbiased analysis reveals a transition of the mutational profile between 25 and 40 years of age. Survival analysis in the pediatric cohort confirms that TP53 mutations are significantly associated with higher incidence of relapse (25 ± 4% versus 6 ± 2%, p-value 0.0002). This identifies a promising molecular marker for relapse incidence in pediatric BL which will be used in future clinical trials. |
2022 |
07 |
08 |
Nat Commun |
Burkhardt |
Birgit |
| 43 |
35879731 |
10.1186/s40364-022-00401-4 |
Dynamic change of soluble interleukin-2 receptor distinguished molecular heterogeneity and microenvironment alterations in diffuse large B-cell lymphoma. |
Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma with variable clinical outcomes and prediction of prognosis remains important for long-term remission. We performed serial serum soluble interleukin-2 receptor (sIL-2R) measurement pretreatment and before each cycle of the treatment in 599 patients with de novo DLBCL. Genomic and transcriptomic features were analyzed by 223 DNA- and 227 RNA-sequencing, respectively. Applying the cut-off value to sIL-2R pretreatment and cycle 2 (C2) level, patients were classified into FINE subtype (pretreatment low level) with good prognosis, RES subtype (pretreatment high level and C2 low level) with intermediate prognosis, and RET subtype (pretreatment high level and C2 high level) with poor prognosis, independent of International Prognostic Index. In ""others"" genetic subtype, dynamic change of sIL-2R showed prognostic significance and genetic features. Compared with FINE subtype, RES subtype had increased ARID1A and MYD88 mutations, and RET subtype had increased KMT2D, LYN and SOCS1 mutations. RES and RET subtypes showed significant enrichment in oncogenic pathways, such as ERK, NF-κB, JAK-STAT, and immune-associated pathways. As for tumor microenvironment, RES subtype exhibited increased recruiting activity of CD8 + T, T helper 1, and natural killer cells, and RET subtype with increased recruiting activity of CD4 + T and regulatory T cells in silico. There was a positive correlation between transcripts of IL-2R and immune checkpoint expressions including PD-1 and CTLA-4. Our findings identified that dynamic change of sIL-2R, with this simple and easy detection method in peripheral blood, had long-term prognostic effect and specific relation to microenvironment alterations in DLBCL. |
2022 |
07 |
29 |
Biomark Res |
Huo |
Yu-Jia |
| 44 |
36001451 |
10.1097/PAS.0000000000001956 |
Targeted Mutational Profiling Reveals Clonal Relationships in Metachronous Occurrence of Classic Hodgkin and Mediastinal Large B-Cell Lymphomas. |
Classic Hodgkin lymphoma (CHL) patients may infrequently present with a prior or recurrent disease with discordant histology resembling non-Hodgkin lymphomas. These include primary mediastinal large B-cell lymphoma (PMBL), diffuse large B-cell lymphoma (DLBCL), or mediastinal gray-zone lymphoma (MGZL). Such patients are often refractory to standard therapy and their diagnosis is hampered by significant morphologic and immunophenotypic overlap and insufficient molecular data. Among 509 CHL patients seen at an academic medical center, 6 patients had a prior or subsequent diagnosis different from CHL. Paired tissue samples were evaluated by targeted mutational analysis using a 164-gene panel. Our findings show multiple shared variants indicative of a clonal relationship between the CHL and the PMBL, DLBCL, or MGZL diagnoses. Most frequent mutated genes included TNFAIP3 (4 of 6, 66.7%), STAT6 (3 or 6, 50%), ARID1A (3 of 6, 50%), and XPO1 (3 of 5, 60%). Three patients showed the same oncogenic variant within the XPO1 gene (E571K), and mutations in TNFAIP3 and B2M were observed in 2 of the 5 patients with shared variants. In addition, differences in the mutation profile between the lymphoma pairs were also observed, which could represent clonal evolution. Mutational profiling could be of benefit in patients with recurrent/refractory disease with discordant histology, where the clonal relationship could be helpful to inform and guide therapeutic decisions. These findings provide further evidence of a true biological continuum surrounding CHL, PMBL, DLBCL, and MGZL and shed light on underlying genetic events and their clinical impact. |
2022 |
08 |
24 |
Am J Surg Pathol |
Singh |
Kunwar |
| 45 |
33431788 |
10.1038/s41392-020-00437-8 |
CREBBP/EP300 mutations promoted tumor progression in diffuse large B-cell lymphoma through altering tumor-associated macrophage polarization via FBXW7-NOTCH-CCL2/CSF1 axis. |
Epigenetic alterations play an important role in tumor progression of diffuse large B-cell lymphoma (DLBCL). However, the biological relevance of epigenetic gene mutations on tumor microenvironment remains to be determined. The core set of genes relating to histone methylation (KMT2D, KMT2C, EZH2), histone acetylation (CREBBP, EP300), DNA methylation (TET2), and chromatin remodeling (ARID1A) were detected in the training cohort of 316 patients by whole-genome/exome sequencing (WGS/WES) and in the validation cohort of 303 patients with newly diagnosed DLBCL by targeted sequencing. Their correlation with peripheral blood immune cells and clinical outcomes were assessed. Underlying mechanisms on tumor microenvironment were investigated both in vitro and in vivo. Among all 619 DLBCL patients, somatic mutations in KMT2D (19.5%) were most frequently observed, followed by mutations in ARID1A (8.7%), CREBBP (8.4%), KMT2C (8.2%), TET2 (7.8%), EP300 (6.8%), and EZH2 (2.9%). Among them, CREBBP/EP300 mutations were significantly associated with decreased peripheral blood absolute lymphocyte-to-monocyte ratios, as well as inferior progression-free and overall survival. In B-lymphoma cells, the mutation or knockdown of CREBBP or EP300 inhibited H3K27 acetylation, downregulated FBXW7 expression, activated the NOTCH pathway, and downstream CCL2/CSF1 expression, resulting in tumor-associated macrophage polarization to M2 phenotype and tumor cell proliferation. In B-lymphoma murine models, xenografted tumors bearing CREBBP/EP300 mutation presented lower H3K27 acetylation, higher M2 macrophage recruitment, and more rapid tumor growth than those with CREBBP/EP300 wild-type control via FBXW7-NOTCH-CCL2/CSF1 axis. Our work thus contributed to the understanding of aberrant histone acetylation regulation on tumor microenvironment as an alternative mechanism of tumor progression in DLBCL. |
2022 |
03 |
04 |
Signal Transduct Target Ther |
Huang |
Yao-Hui |
| 46 |
33829512 |
10.1111/his.14378 |
Bcl-2-negative IGH-BCL2 translocation-negative follicular lymphoma of the thyroid differs genetically and epigenetically from Bcl-2-positive IGH-BCL2 translocation-positive follicular lymphoma. |
Follicular lymphoma (FL), comprising a minor subset of primary thyroid lymphomas, is divided into two groups based on Bcl-2 expression and IGH-BCL2 translocation. The clinicopathological features exhibited by Bcl-2-negative IGH-BCL2 translocation-negative FL of the thyroid (Bcl-2<sup>-</sup> /IGH-BCL2<sup>-</sup> tFL) are different from those of conventional FL; however, its lymphomagenesis remains unclear. Here, we collected samples from seven patients with Bcl-2<sup>-</sup> /IGH-BCL2<sup>-</sup> tFL to investigate their epigenetic and genetic aberrations. The immunohistochemical profiles of epigenetic modifiers and the methylation status of histones were examined, including EZH2, MLL2/KMT2D, CBP/CREBBP, EP300, H3K27me3 and H3K4me3, in Bcl-2<sup>-</sup> /IGH-BCL2<sup>-</sup> tFL and Bcl-2-positive IGH-BCL2 translocation-positive FL of the thyroid (Bcl-2<sup>+</sup> /IGH-BCL2<sup>+</sup> tFL). Most Bcl-2<sup>-</sup> /IGH-BCL2<sup>-</sup> tFLs retained the positivity of epigenetic modifiers and lower expression of H3K27me3, although Bcl-2<sup>+</sup> /IGH-BCL2<sup>+</sup> tFLs exhibited aberrant immunohistochemical patterns of EZH2 and CBP/CREBBP and overexpression of H3K27me3. Samples from seven cases were further analysed using targeted sequencing, focusing on the exons of 409 key tumour suppressor genes and oncogenes. Bcl-2<sup>-</sup> /IGH-BCL2<sup>-</sup> tFLs do not have pathogenic mutations of epigenetic modifiers, such as EZH2, MLL2/KMT2D, MLL3/KMT2C, EP300 and ARID1A, which have been reported in FLs in the literature, whereas Bcl-2<sup>+</sup> /IGH-BCL2<sup>+</sup> tFLs are probably pathogenic/pathogenic missense mutations or frameshift mutations of these genes. Additionally, novel mutations in TET2 and EP400 were detected in Bcl-2<sup>-</sup> /IGH-BCL2<sup>-</sup> tFLs. Different genetic and epigenetic abnormalities might be involved in the oncogenesis of Bcl-2<sup>-</sup> /IGH-BCL2<sup>-</sup> tFLs from Bcl-2<sup>+</sup> /IGH-BCL2<sup>+</sup> tFLs and other FLs. |
2022 |
01 |
28 |
Histopathology |
Hamamoto |
Yuichiro |
| 47 |
34039950 |
10.1038/s41408-021-00493-5 |
Genomic insights into the pathogenesis of Epstein-Barr virus-associated diffuse large B-cell lymphoma by whole-genome and targeted amplicon sequencing. |
Epstein-Barr virus (EBV)-associated diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS) constitute a distinct clinicopathological entity in the current World Health Organization (WHO) classification. However, its genomic features remain sparsely characterized. Here, we combine whole-genome sequencing (WGS), targeted amplicon sequencing (tNGS), and fluorescence in situ hybridization (FISH) from 47 EBV + DLBCL (NOS) cases to delineate the genomic landscape of this rare disease. Integrated WGS and tNGS analysis clearly distinguished this tumor type from EBV-negative DLBCL due to frequent mutations in ARID1A (45%), KMT2A/KMT2D (32/30%), ANKRD11 (32%), or NOTCH2 (32%). WGS uncovered structural aberrations including 6q deletions (5/8 patients), which were subsequently validated by FISH (14/32 cases). Expanding on previous reports, we identified recurrent alterations in CCR6 (15%), DAPK1 (15%), TNFRSF21 (13%), CCR7 (11%), and YY1 (6%). Lastly, functional annotation of the mutational landscape by sequential gene set enrichment and network propagation predicted an effect on the nuclear factor κB (NFκB) pathway (CSNK2A2, CARD10), IL6/JAK/STAT (SOCS1/3, STAT3), and WNT signaling (FRAT1, SFRP5) alongside aberrations in immunological processes, such as interferon response. This first comprehensive description of EBV + DLBCL (NOS) tumors substantiates the evidence of its pathobiological independence and helps stratify the molecular taxonomy of aggressive lymphomas in the effort for future therapeutic strategies. |
2022 |
01 |
10 |
Blood Cancer J |
Gebauer |
Niklas |
| 48 |
34070951 |
10.3390/diagnostics11060999 |
Diagnostic and Prognostic Value of Circulating Cell-Free DNA for Cholangiocarcinoma. |
The analysis of cfDNA has been applied as a liquid biopsy in several malignancies. However, its value in the diagnosis and prognosis of cholangiocarcinoma (CCA) have not been well defined. We aimed to investigate the diagnostic and prognostic values of cfDNA level and tumor-specific mutation in circulating DNA (ctDNA) in CCA. The plasma cfDNA levels from 62 CCA patients, 33 benign biliary disease (BBD) patients and 30 normal controls were quantified by fluorescent assay. Targeted probe-based sequencing of 60 genes was applied for mutation profiling in 10 ctDNA samples and their corresponding treatment-naïve tissues. cfDNA levels in CCA were significantly higher than those in BBD and normal controls. We found that cfDNA levels at 0.2175 and 0.3388 ng/µL significantly discriminated CCA from healthy controls and BBD with 88.7 and 82.3% sensitivity and 96.7 and 57.6% specificity, respectively. cfDNA levels showed superior diagnostic efficacy in detecting CCA compared to CEA and CA19-9. <i>ARID1A</i> (30%), <i>PBRM1</i> (30%), <i>MTOR</i> (30%), and <i>FGFR3</i> (30%) mutations were the most common. Using nine frequently mutated genes in the ctDNA samples, the diagnostic accuracy of cfDNA sequencing was 90.8%, with 96.7% average sensitivity and 72.4% specificity. This study supports the use of cfDNA as a diagnosis and prognostic biomarker for CCA. |
2021 |
06 |
27 |
Diagnostics (Basel) |
Wintachai |
Preawwalee |
| 49 |
34348985 |
10.1136/jclinpath-2021-207441 |
Clinicopathological characteristics and genetic variations of uterine tumours resembling ovarian sex cord tumours. |
To investigate the clinicopathological and molecular characteristics of uterine tumours resembling ovarian sex cord tumours (UTROSCTs) and the value of molecular diversity in the clinical diagnosis and treatment. Five patients with UTROSCT were enrolled, and their clinical data, pathological morphologies, immunophenotypes and molecular features were analysed. Fluorescence in situ hybridisation for <i>NCOA1</i>, <i>NCOA2</i>, <i>NCOA3</i>, <i>JAZF1</i> and <i>PHF1</i> and next-generation sequencing for 27 homologous recombination/repair (HRR) pathway genes were performed on five and three UTROSCT specimens, respectively. All five patients were treated for abnormal uterine bleeding and grossly presented with intrauterine polyps. Under a microscope, tumour cells grew diffusely and presented a cordlike arrangement and glandular duct-like structures, with nuclei ranging from round to oval, vesicular chromatin and visible nucleoli in some cases. The mitotic count was less than 3/10 high-power fields. Immunohistochemistry showed sex cord, epithelial cell and smooth muscle cell biomarkers and diffuse, strong staining for B cell lymphoma-2 (BCL-2). <i>NCOA1</i> and <i>NCOA3</i> rearrangements were identified in 80% (4/5) of the cases. <i>JAZF1</i> and <i>PHF1</i> rearrangements were not detected in any of five patients. HRR pathway gene mutations were detected in all three patients, including <i>FANCE</i>, <i>ATR</i> and <i>ARID1A</i> mutations in one case each. UTROSCT is a rare mesenchymal tumour, and biopsy specimens are easily misdiagnosed. UTROSCT diagnosis requires the combined use of biomarkers and molecular detection. BCL-2 has potential diagnostic value as a marker. UTROSCT can have mutations related to the HRR pathway, suggesting that this tumour type may be sensitive to platinum/poly (ADP-ribose) polymerase inhibitors. |
2021 |
08 |
05 |
J Clin Pathol |
Ye |
Shan |
| 50 |
31423576 |
10.1111/bjh.16159 |
M7-FLIPI is not prognostic in follicular lymphoma patients with first-line rituximab chemo-free therapy. |
The clinical course of follicular lymphoma (FL) is highly variable. Recently the m7-FL international prognostic index (FLIPI) integrating performance status, FLIPI score and the mutational status of seven genes, was shown to stratify patients into ""low-risk"" and ""high-risk"" with respect to 5-year failure-free survival after first-line immunochemotherapy. Our aim was to evaluate the model after rituximab without chemotherapy. The Nordic Lymphoma Group performed two randomized clinical trials on indolent lymphoma patients receiving single rituximab and rituximab with interferon-α2a. In total, 95 FL patients had sufficient fresh-frozen diagnostic material for sequencing. A targeted panel for the genes EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP and CARD11 was utilized for m7-FLIPI score calculation. With a median follow-up of 10·6 years, 76% of patients were alive. No difference in time to treatment failure (TTF), defined as the interval between start of trial therapy and initiation of new therapy or death, nor overall survival (OS) was found between the m7-FLIPI risk groups (log-rank P = 0·94 and 0·99, respectively). EZH2 mutations were associated with longer TTF (log-rank P = 0·04) and in EP300 mutations were associated with shorter TTF (log-rank P = 0·01). We conclude that the prognostic value of the m7-FLIPI clinicogenetic model seems dependent on therapeutic regimen. |
2020 |
08 |
05 |
Br J Haematol |
Lockmer |
Sandra |
| 51 |
32083995 |
10.1200/JCO.19.02314 |
Genomic Landscape of Waldenström Macroglobulinemia and Its Impact on Treatment Strategies. |
Next-generation sequencing has revealed recurring somatic mutations in Waldenström macroglobulinemia (WM), including <i>MYD88</i> (95%-97%), <i>CXCR4</i> (30%-40%), <i>ARID1A</i> (17%), and <i>CD79B</i> (8%-15%). Deletions involving chromosome 6q are common in patients with mutated <i>MYD88</i> and include genes that modulate NFKB, BCL2, Bruton tyrosine kinase (BTK), and apoptosis. Patients with wild-type <i>MYD88</i> WM show an increased risk of transformation and death and exhibit many mutations found in diffuse large B-cell lymphoma. The discovery of <i>MYD88</i> and <i>CXCR4</i> mutations in WM has facilitated rational drug development, including the development of BTK and CXCR4 inhibitors. Responses to many agents commonly used to treat WM, including the BTK inhibitor ibrutinib, are affected by <i>MYD88</i> and/or <i>CXCR4</i> mutation status. The mutation status of both <i>MYD88</i> and <i>CXCR4</i> can be used for a precision-guided treatment approach to WM. |
2020 |
12 |
23 |
J Clin Oncol |
Treon |
Steven P |
| 52 |
32918521 |
10.1002/pbc.28704 |
Aggressive Langerhans cell histiocytosis following T-cell acute lymphoblastic leukemia. |
A 4-year-old female child developed cutaneous Langerhans cell histiocytosis 6 months following a diagnosis of T-cell acute lymphoblastic leukemia. Imaging revealed no evidence of systemic disease. Seven months later, the first systemic lesion was discovered on laryngoscopy. Restaging Positron Emission Tomography - Computed Tomography at that time revealed new 18-fluorodeoxyglucose-positive lesions in the left apical pleural margin, right lower peri-esophageal region, left ventricular myocardium, pancreas, upper pole of the left kidney, and inguinal and gluteal regions consistent with progressive systemic disease. Genomic testing revealed a low tumor mutational burden as well as mutations in KRAS G12A, ARID1A Q524, CDKN2A/B loss, and an alteration in NOTCH1. |
2021 |
01 |
25 |
Pediatr Blood Cancer |
Jansen |
Chandler |
| 53 |
32978169 |
10.1158/0008-5472.CAN-20-2147 |
EZH2-Targeted Therapies in Cancer: Hype or a Reality. |
Next-generation genomic sequencing has identified multiple novel molecular alterations in cancer. Since the identification of DNA methylation and histone modification, it has become evident that genes encoding epigenetic modifiers that locally and globally regulate gene expression play a crucial role in normal development and cancer progression. The histone methyltransferase enhancer of zeste homolog 2 (EZH2) is the enzymatic catalytic subunit of the polycomb-repressive complex 2 (PRC2) that can alter gene expression by trimethylating lysine 27 on histone 3 (H3K27). EZH2 is involved in global transcriptional repression, mainly targeting tumor-suppressor genes. EZH2 is commonly overexpressed in cancer and shows activating mutations in subtypes of lymphoma. Extensive studies have uncovered an important role for EZH2 in cancer progression and have suggested that it may be a useful therapeutic target. In addition, tumors harboring mutations in other epigenetic genes such as <i>ARID1A, KDM6</i>, and <i>BAP1</i> are highly sensitive to EZH2 inhibition, thus increasing its potential as a therapeutic target. Recent studies also suggest that inhibition of EZH2 enhances the response to tumor immunotherapy. Many small-molecule inhibitors have been developed to target EZH2 or the PRC2 complex, with some of these inhibitors now in early clinical trials reporting clinical responses with acceptable tolerability. In this review, we highlight the recent advances in targeting EZH2, its successes, and potential limitations, and we discuss the future directions of this therapeutic subclass. |
2021 |
03 |
29 |
Cancer Res |
Eich |
Marie-Lisa |
| 54 |
33252851 |
10.1002/ctm2.221 |
Influence of oncogenic mutations and tumor microenvironment alterations on extranodal invasion in diffuse large B-cell lymphoma. |
Diffuse large B-cell lymphoma (DLBCL) is an aggressive subtype of lymphoma, and multiple extranodal involvement (ENI) indicates adverse clinical outcomes. The aim of this study was to investigate the influence of oncogenic mutations and tumor microenvironment alterations on ENI in DLBCL. The clinical features of 1960 patients with newly diagnosed DLBCL were analyzed, and DNA and RNA sequencing was performed on 670 and 349 patients, respectively. Oncogenic mutations and tumor microenvironment alterations were compared according to ENI and evaluated in zebrafish patient-derived tumor xenograft models. Multiple ENI was significantly associated with poor performance status, advanced stage, elevated serum lactate dehydrogenase, low response rate, and inferior prognosis. Lymphoma invasion of the bones, spleen, bone marrow, liver, and central nervous system were independent unfavorable prognostic factors. MYD88 was frequently mutated in patients with multiple ENI, co-occurred with mutations in CD79B, PIM1, TBL1XR1, BTG1, MPEG1, and PRDM1, and correlated with invasion of the bones, kidney/adrenal glands, breasts, testes, skin, and uterus/ovaries. For tumor microenvironment alterations, patients with multiple ENI showed higher regulatory T-cell (Treg)-recruiting activity, but lower extracellular matrix-encoding gene expression, than those without ENI and with single ENI. Elevated Treg-recruiting activity was related to mutations in B2M, SGK1, FOXO1, HIST1H1E, and ARID1A, and correlated with invasion of the bone marrow and thyroid. Additionally, mutations in MYD88, PIM1, TBL1XR1, SGK1, FOXO1, HIST1H1E, and ARID1A were associated with decreased major histocompatibility complex class I expression. Zebrafish models further revealed relationships between MYD88 mutations and invasion of the kidneys and gonads, as well as B2M mutations and invasion of the bone marrow. Increased CXCR4 expression is linked to bone marrow invasion in an organotropic way. Our findings thus contribute to an improved understanding of the biological behavior of multiple ENI and provide a clinical rationale for targeting ENI in DLBCL. |
2020 |
12 |
07 |
Clin Transl Med |
Shen |
Rong |
| 55 |
33376237 |
10.1038/s41392-020-00331-3 |
Combination of anti-PD-1 antibody with P-GEMOX as a potentially effective immunochemotherapy for advanced natural killer/T cell lymphoma. |
Advanced natural killer/T cell lymphoma (NKTL) has demonstrated poor prognosis with currently available therapies. Here, we report the efficacy of anti-programmed death 1 (PD-1) antibody with the P-GEMOX (pegaspargase, gemcitabine, and oxaliplatin) regimen in advanced NKTL. Nine patients underwent six 21-day cycles of anti-PD-1 antibody (day 1), pegaspargase 2000 U/m<sup>2</sup> (day 1), gemcitabine 1 g/m<sup>2</sup> (days 1 and 8) and oxaliplatin 130 mg/m<sup>2</sup> (day 1), followed by anti-PD-1 antibody maintenance every 3 weeks. Programmed death-ligand 1 (PD-L1) expression and genetic alterations were determined in paraffin-embedded pretreatment tissue samples using immunohistochemistry and next-generation sequencing (NGS) analysis. Responses were assessed using <sup>18</sup>F-fluorodeoxyglucose positron emission tomography (<sup>18</sup>FDG-PET) and computed tomography or magnetic resonance imaging. Eight patients exhibited significant responses, comprising of seven complete remissions and one partial remission (overall response rate: 88.9%). After a median follow-up of 10.6 months, 6/9 patients (66.7%) remained in complete remission. The most common grade 3/4 adverse events were anemia (33.3%), neutropenia (33.3%), and thrombocytopenia (33.3%); all of which were manageable and resolved. Immunochemotherapy produced a high response rate in patients with positive PD-L1 expression (5/6, 83.3%). NGS analysis suggested that STAT3/JAK3/PD-L1 alterations and ARID1A mutation were associated with immunochemotherapy efficacy. Mutation in DDX3X and alteration in epigenetic modifiers of KMT2D, TET2, and BCORL1 might indicate a poor response to immunochemotherapy. In conclusion, the anti-PD-1 antibody plus P-GEMOX regimen demonstrated promising efficacy in advanced NKTL. PD-L1 expression combined with specific genetic alterations could be used as potential biomarkers to predict therapeutic responses to immunochemotherapy. |
2021 |
10 |
13 |
Signal Transduct Target Ther |
Cai |
Jun |
| 56 |
30886885 |
10.1016/j.gore.2019.02.007 |
Endometrial cancer arising after complete remission of uterine malignant lymphoma: A case report and mutation analysis. |
Uterine malignant lymphoma is rare and its association with secondary cancer has not been fully described. Here, we report a rare case of endometrial cancer arising after 1 year of complete remission of uterine diffuse large B-cell lymphoma (DLBCL). An 88-year-old woman was referred to us for abnormal genital bleeding and was diagnosed with uterine DLBCL. She underwent chemotherapy comprising rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisolone followed by radiation therapy; subsequently, she achieved complete remission. One year later, she noticed genital bleeding recurrence, and endometrial biopsy revealed endometrial adenocarcinoma. Total hysterectomy and bilateral salpingo-oophorectomy were performed. Her pathological diagnosis was endometrial endometrioid carcinoma, grade 1 (pT1aN0). Adenocarcinoma was observed over foamy macrophages aggregates, indicating remission of DLBCL. Targeted sequencing of both DLBCL and endometrial cancer revealed 24 gene mutations including the truncation-type mutations of <i>ARID1A</i> and <i>PTEN</i> occurring only in endometrial cancer. These multiple somatic gene mutations accumulating within 1 year imply endometrial carcinogenesis induced by DNA damages caused by treatment for DLBCL. Although the epidemiological risk of secondary malignancies after uterine lymphoma remains unclear, the present case serves as a warning for secondary cancer and highlights the importance of early detection and treatment. |
2020 |
10 |
01 |
Gynecol Oncol Rep |
Kuno |
Ikumi |
| 57 |
31123138 |
10.1136/jclinpath-2019-205727 |
Intravascular NK/T-cell lymphoma: clinicopathological and integrated molecular analysis of two cases provides a clue to disease pathogenesis. |
To elucidate the clinicopathological and molecular features of intravascular NK/T-cell lymphoma (IVNKTCL). Two cases of IVNKTCL were retrieved from a single-centre cohort composed of 25 intravascular lymphomas. Whole-exome and RNA sequencing and immunohistochemistry were performed. We identified somatic mutations in the following epigenetic regulators: four histone genes (<i>HIST1H2AN</i>, <i>HIST1H2BE</i>, <i>HIST1H2BN</i> and <i>H3F3A),</i> histone deacetylase (<i>HDAC5</i>), two helicases (<i>WRN</i> and <i>DDX3X</i>), two methylation-related enzymes (<i>TET2</i> and <i>DNMT1</i>) and the SNI/SWF pathway (<i>ARID1A</i>). Copy number analysis identified driver gene alterations comprising the loss of <i>ARID1B</i>, <i>HACE1</i> and <i>SMAD4</i>, and the gain of <i>SOX2</i> and histone clusters. RNA sequencing analysis did not indicate the presence of any fusion gene. Both cases were positive for Epstein-Barr virus (EBV) and showed strong expression of programmed death-ligand 1 (PD-L1). This study raises the possibility that, at least for some patients, IVNKTCL may be considered an epigenetic disease with EBV infection-associated aetiopathogenesis. |
2019 |
09 |
03 |
J Clin Pathol |
Fujikura |
Kohei |
| 58 |
31300419 |
10.1182/bloodadvances.2018029546 |
Sporadic and endemic Burkitt lymphoma have frequent <i>FOXO1</i> mutations but distinct hotspots in the AKT recognition motif. |
FOXO1 has an oncogenic role in adult germinal center-derived lymphomas, in which mutations, predominately within the AKT recognition motif, cause nuclear retention of FOXO1, resulting in increased cell proliferation. To determine the prevalence and distribution of <i>FOXO1</i> mutations in pediatric Burkitt lymphoma (BL), we sequenced a large number of sporadic and endemic BL patient samples. We report a high frequency of <i>FOXO1</i> mutations in both sporadic and endemic BL at diagnosis, occurring in 23/78 (29%) and 48/89 (54%) samples, respectively, as well as 8/16 (50%) cases at relapse. Mutations of T24 were the most common in sporadic BL but were rare in endemic cases, in which mutations of residue S22, also within the AKT recognition motif, were the most frequent. <i>FOXO1</i> mutations were almost always present in the major tumor cell clone but were not associated with outcome. Analysis of other recurrent mutations reported in BL revealed that <i>FOXO1</i> mutations were associated with mutations of <i>DDX3X</i> and <i>ARID1A,</i> but not <i>MYC</i>, <i>TCF3</i>/<i>ID3,</i> or members of the phosphatidylinositol 3-kinase signaling pathway. We further show common nuclear retention of the FOXO1 protein, irrespective of mutation status, suggesting alternative unknown mechanisms for maintaining FOXO1 transcriptional activity in BL. CRISPR/Cas9 knockout of <i>FOXO1</i> in an endemic cell line produced a significant decrease in cell proliferation, supporting an oncogenic role for <i>FOXO1</i> in endemic BL. Thus, <i>FOXO1</i> is frequently mutated in both sporadic and endemic BL and may offer a potential therapeutic target for pediatric BL patients worldwide. |
2020 |
07 |
07 |
Blood Adv |
Zhou |
Peixun |
| 59 |
31747604 |
10.1016/j.celrep.2019.10.083 |
Targeting Excessive EZH1 and EZH2 Activities for Abnormal Histone Methylation and Transcription Network in Malignant Lymphomas. |
Although global H3K27me3 reprogramming is a hallmark of cancer, no effective therapeutic strategy for H3K27me3-high malignancies harboring EZH2<sup>WT/WT</sup> has yet been established. We explore epigenome and transcriptome in EZH2<sup>WT/WT</sup> and EZH2<sup>WT/Mu</sup> aggressive lymphomas and show that mutual interference and compensatory function of co-expressed EZH1 and EZH2 rearrange their own genome-wide distribution, thereby establishing restricted chromatin and gene expression signatures. Direct comparison of leading compounds introduces potency and a mechanism of action of the EZH1/2 dual inhibitor (valemetostat). The synthetic lethality is observed in all lymphoma models and primary adult T cell leukemia-lymphoma (ATL) cells. Opposing actions of EZH1/2-polycomb and SWI/SNF complexes are required for facultative heterochromatin formation. Inactivation of chromatin-associated genes (ARID1A, SMARCA4/BRG1, SMARCB1/SNF5, KDM6A/UTX, BAP1, KMT2D/MLL2) and oncovirus infection (HTLV-1, EBV) trigger EZH1/2 perturbation and H3K27me3 deposition. Our study provides the mechanism-based rationale for chemical dual targeting of EZH1/2 in cancer epigenome. |
2020 |
09 |
21 |
Cell Rep |
Yamagishi |
Makoto |
| 60 |
29307627 |
10.1016/j.humpath.2017.12.025 |
Dedifferentiated liposarcoma composed predominantly of rhabdoid/epithelioid cells: a frequently misdiagnosed highly aggressive variant. |
Dedifferentiated liposarcoma is one of the most common sarcoma types in adults with a predilection for the retroperitoneum. We have recently encountered 6 cases of DDL composed predominantly of rounded, rhabdoid or epithelioid cells mimicking rhabdoid melanoma, epithelioid rhabdomyosarcoma or undifferentiated carcinoma. Patients were 5 males and one female aged 64 to 81 years (median, 68). Tumors originated in the retroperitoneum (n=5; 3 in the psoas muscle) and deep soft tissue of the thigh (n=1). All 3 patients with follow-up died of metastatic disease within 4 to 8 months. Preoperative biopsy diagnoses never suggested dedifferentiated liposarcoma as a possibility; instead carcinoma, rhabdomyosarcoma and lymphoma were on top of suggestions. Five resected tumors were composed predominantly (70%-100%) of anaplastic rounded to oval rhabdoid cells with prominent central nucleoli and paranuclear rhabdoid inclusions. Bi- and multinucleation was a constant feature. The background stroma showed variable myxoid changes and minor mixed inflammatory cells. Two cases showed homologous dedifferentiation and another had sclerosing spindle cell nodule but a well-differentiated lipomatous component was not seen in any. One biopsied case showed solely monotonous small round blue cells with scattered rhabdoid cells. Immunohistochemistry showed expression of MDM2 (6/6), CDK4 (5/6), pancytokeratin AE/1AE3 (4/6) and diffusely desmin and myogenin (2/6). All cases showed high-level co-amplification of MDM2/CDK4 by in situ hybridization. The SWI/SNF complex components (SMARCB1, SMARCA2, SMARCA4, ARID1A and PBRM1) were intact in all cases. This highly aggressive liposarcoma variant needs to be distinguished from a variety of neoplasms including undifferentiated carcinoma, melanoma, lymphoma, rhabdomyosarcoma and others. |
2019 |
04 |
09 |
Hum Pathol |
Agaimy |
Abbas |
| 61 |
29486633 |
10.1177/1533034618754475 |
Loss of ARID1A Expression Correlates With Tumor Differentiation and Tumor Progression Stage in Pancreatic Ductal Adenocarcinoma. |
Mutations in the AT-rich interactive domain 1A gene, which encodes a subunit of the Switch/Sucrose nonfermentable chromatin remodeling complex, can result in loss of protein expression and are associated with different cancers. Here, we used immunohistochemistry to investigate the significance of AT-rich interactive domain 1A loss in 73 pancreatic ductal adenocarcinoma cases with paired paracancerous normal pancreatic tissues. The relationship between levels of the AT-rich interactive domain 1A protein product, BAF250a, and clinicopathological parameters in the 73 pancreatic cancer specimens was also analyzed. We found that the expression of AT-rich interactive domain 1A in normal pancreatic tissue was higher than that in tumor tissue. Loss of AT-rich interactive domain 1A expression in pancreatic tumors was associated with tumor differentiation ( P = .002) and tumor stage ( P = .048). Meanwhile, BAF250a protein levels were not related to lymph node metastasis, distant metastasis, sex, or age and were not associated with survival. Transfection of the pancreatic cancer cell lines AsPC-1 and PANC-1 with small-interfering RNA specific for AT-rich interactive domain 1A resulted in elevated messenger RNA and protein expression levels of B-cell lymphoma-2 (Bcl-2), CyclinD1, and Kirsten rat sarcoma viral oncogene (KRAS). The AT-rich interactive domain 1A expression level in the cells was increased following microRNA-31 (miR-31) inhibitor transfection. Our data provide additional evidence that AT-rich interactive domain 1A might function as a tumor suppressor gene in pancreatic carcinogenesis. |
2019 |
04 |
01 |
Technol Cancer Res Treat |
Zhang |
Li |
| 62 |
29669287 |
10.1016/j.celrep.2018.03.078 |
ZRANB1 Is an EZH2 Deubiquitinase and a Potential Therapeutic Target in Breast Cancer. |
Although EZH2 enzymatic inhibitors have shown antitumor effects in EZH2-mutated lymphoma and ARID1A-mutated ovarian cancer, many cancers do not respond because EZH2 can promote cancer independently of its histone methyltransferase activity. Here we identify ZRANB1 as the EZH2 deubiquitinase. ZRANB1 binds, deubiquitinates, and stabilizes EZH2. Depletion of ZRANB1 in breast cancer cells results in EZH2 destabilization and growth inhibition. Systemic delivery of ZRANB1 small interfering RNA (siRNA) leads to marked antitumor and antimetastatic effects in preclinical models of triple-negative breast cancer (TNBC). Intriguingly, a small-molecule inhibitor of ZRANB1 destabilizes EZH2 and inhibits the viability of TNBC cells. In patients with breast cancer, ZRANB1 levels correlate with EZH2 levels and poor survival. These findings suggest the therapeutic potential for targeting the EZH2 deubiquitinase ZRANB1. |
2019 |
09 |
17 |
Cell Rep |
Zhang |
Peijing |
| 63 |
29989027 |
10.18632/oncotarget.25601 |
New generation sequencing of targeted genes in the classical and the variant form of hairy cell leukemia highlights mutations in epigenetic regulation genes. |
Classical hairy cell leukemia (HCL-c) is a rare lymphoid neoplasm. <i>BRAF<sup>V600E</sup></i> mutation, detected in more than 80% of the cases, is described as a driver mutation, but additional genetic abnormalities appear to be necessary for the disease progression. For cases of HCL-c harboring a wild-type <i>BRAF</i> gene, the differential diagnosis of the variant form of HCL (HCL-v) or splenic diffuse red pulp lymphoma (SDRPL) is complex. We selected a panel of 21 relevant genes based on a literature review of whole exome sequencing studies (<i>BRAF</i>, <i>MAP2K1</i>, <i>DUSP2</i>, <i>MAPK15</i>, <i>ARID1A</i>, <i>ARID1B</i>, <i>EZH2</i>, <i>KDM6A</i>, <i>CREBBP</i>, <i>TP53</i>, <i>CDKN1B</i>, <i>XPO1</i>, <i>KLF2</i>, <i>CXCR4</i>, <i>NOTH1</i>, <i>NOTCH2</i>, <i>MYD88</i>, <i>ANXA1</i>, <i>U2AF1</i>, <i>BCOR</i>, and <i>ABCA8</i>). We analyzed 20 HCL-c and 4 HCL-v patients. The analysis of diagnostic samples mutations in <i>BRAF</i> (<i>n</i> = 18), <i>KLF2</i> (<i>n</i> = 4), <i>MAP2K1</i> (<i>n</i> = 3), <i>KDM6A</i> (<i>n</i> = 2), <i>CDKN1B</i> (<i>n</i> = 2), <i>ARID1A</i> (<i>n</i> = 2), <i>CREBBP</i> (<i>n</i> = 2) <i>NOTCH1</i> (<i>n</i> = 1) and <i>ARID1B</i> (<i>n</i> = 1). <i>BRAF<sup>V600E</sup></i> was found in 90% (18/20) of HCL-c patients. In HCL-c patients with <i>BRAF<sup>V600E</sup></i> , other mutations were found in 33% (6/18) of cases. All 4 HCL-v patients had mutations in epigenetic regulatory genes: <i>KDM6A</i> (<i>n</i> = 2), <i>CREBBP</i> (<i>n</i> = 1) or <i>ARID1A</i> (<i>n</i> = 1). The analysis of sequential samples (at diagnosis and relapse) from 5 patients (2 HCL-c and 3 HCL-v), showed the presence of 2 new subclonal mutations (<i>BCOR<sup>E1430X</sup></i> and <i>XPO1<sup>E571K</sup></i> ) in one patient and variations of the mutated allele frequency in 2 other cases. In the HCL-v disease, we described new mutations targeting <i>KDM6A</i> that encode a lysine demethylase protein. This opens new perspectives for personalized medicine for this group of patients. |
2019 |
11 |
20 |
Oncotarget |
Maitre |
Elsa |
| 64 |
30134235 |
10.1159/000492835 |
Frequent Mutations in Natural Killer/T Cell Lymphoma. |
Extranodal natural killer (NK)/T cell lymphoma (ENKTL-NT or NKTCL), with its aggressive nature and poor prognosis, has been widely studied to discover more effective treatment options. Various somatic gene alterations have been identified by traditional Sanger sequencing. However, recently, novel gene mutations in NKTCL have been revealed by next-generation sequencing (NGS) technology, suggesting the potential for novel targeted therapies. This review discusses recurrent aberrations in NKTCL detected by NGS, which can be categorized into three main groups, specifically, tumor suppressors (TP53, DDX3X, and MGA), the JAK/STAT cascade, and epigenetic modifiers (KMT2D, BCOR, ARID1A, and EP300). Some epigenetic dysregulation and DDX3X mutation, which have been rarely identified by traditional sequencing technology, were recently uncovered with high frequencies by NGS. In this review, we summarize the mutational frequencies of various genes in NKTCL. In general, based on our analysis, BCOR is the most frequently mutated gene (16.9%), followed by TP53 (14.7%), and DDX3X (13.6%). The characterization of such genes provides new insight into the pathogenesis of this disease and indicates new biomarkers or therapeutic targets. |
2018 |
09 |
18 |
Cell Physiol Biochem |
Zhang |
Yanjie |
| 65 |
30190015 |
10.1016/j.hoc.2018.05.007 |
Working Toward a Genomic Prognostic Classification of Waldenström Macroglobulinemia: C-X-C Chemokine Receptor Type 4 Mutation and Beyond. |
Waldenström macroglobulinemia is a rare indolent B-cell lymphoma. Whole-exome sequencing studies have improved our knowledge of the Waldenström macroglobulinemia mutational landscape. The MYD88 L265P mutation is present in nearly 90% of patients with Waldenström macroglobulinemia. CXCR4 mutations are identified in approximately 30% of MYD88L265P cases and have been associated with ibrutinib resistance in clinical trials. Mutations in CD79B, ARID1a, or TP53 were described at lower frequency. Deciphering the earliest initiating lesions and identifying the molecular alterations leading to disease progression currently represent important goals in the future to identify the most relevant targets for precision therapy in Waldenström macroglobulinemia. |
2019 |
02 |
28 |
Hematol Oncol Clin North Am |
Magierowicz |
Marion |
| 66 |
27872090 |
10.1158/0008-5472.CAN-16-1303 |
Mutational Landscape of Pediatric Acute Lymphoblastic Leukemia. |
Current standard of care for patients with pediatric acute lymphoblastic leukemia (ALL) is mainly effective, with high remission rates after treatment. However, the genetic perturbations that give rise to this disease remain largely undefined, limiting the ability to address resistant tumors or develop less toxic targeted therapies. Here, we report the use of next-generation sequencing to interrogate the genetic and pathogenic mechanisms of 240 pediatric ALL cases with their matched remission samples. Commonly mutated genes fell into several categories, including RAS/receptor tyrosine kinases, epigenetic regulators, transcription factors involved in lineage commitment, and the p53/cell-cycle pathway. Unique recurrent mutational hotspots were observed in epigenetic regulators CREBBP (R1446C/H), WHSC1 (E1099K), and the tyrosine kinase FLT3 (K663R, N676K). The mutant WHSC1 was established as a gain-of-function oncogene, while the epigenetic regulator ARID1A and transcription factor CTCF were functionally identified as potential tumor suppressors. Analysis of 28 diagnosis/relapse trio patients plus 10 relapse cases revealed four evolutionary paths and uncovered the ordering of acquisition of mutations in these patients. This study provides a detailed mutational portrait of pediatric ALL and gives insights into the molecular pathogenesis of this disease. Cancer Res; 77(2); 390-400. ©2016 AACR. |
2017 |
07 |
24 |
Cancer Res |
Ding |
Ling-Wen |
| 67 |
28401006 |
|
Genomic and proteomic characterization of ARID1A chromatin remodeller in ampullary tumors. |
<i>AT rich interactive domain 1A (ARID1A)</i> is one of the most commonly mutated genes in a broad variety of tumors. The mechanisms that involve <i>ARID1A</i> in ampullary cancer progression remains elusive. Here, we evaluated the frequency of <i>ARID1A</i> and <i>KRAS</i> mutations in ampullary adenomas and adenocarcinomas and in duodenal adenocarcinomas from two cohorts of patients from Singapore and Romania, correlated with clinical and pathological tumor features, and assessed the functional role of <i>ARID1A</i>. In the ampullary adenocarcinomas, the frequency of <i>KRAS</i> and <i>ARID1A</i> mutations was 34.7% and 8.2% respectively, with a loss or reduction of ARID1A protein in 17.2% of the cases. <i>ARID1A</i> mutational status was significantly correlated with ARID1A protein expression level (P=0.023). There was a significant difference in frequency of <i>ARID1A</i> mutation between Romania and Singapore (2.7% versus 25%, P=0.04), suggestive of different etiologies. One somatic mutation was detected in the ampullary adenoma group. <i>In vitro</i> studies indicated the tumor suppressive role of <i>ARID1A</i>. Our results warrant further investigation of this chromatin remodeller as a potential early biomarker of the disease, as well as identification of therapeutic targets in <i>ARID1A</i> mutated ampullary cancers. |
2020 |
09 |
30 |
Am J Cancer Res |
Nastase |
Anca |
| 68 |
29025291 |
10.1556/650.2017.30868 |
[Waldenström's macroglobulinemia and its individualized therapy options]. |
Waldenström's macroglobulinaemia is a form of lymphoplasmocytic lymphoma that preferentially localizes to the bone marrow and causes a special syndrome characterized by monoclonal IgM hypersecretion. Recent results point to the fact that this disease has at least three different pathobiological forms with different clinical presentation. While mutations of MYD88 occur in 95-97% of the cases, there are CXCR4 mutations in 30-40%, ARID1A mutations in 17% and CD79B mutations in approximately 10% of afflicted individuals. CXCR pathway signaling is able to transcriptionally silence tumor suppressors induced by MYD88 activation. Patients with mutated MYD88 and CXCR4 present with higher tumor burden, slower developing and less deep response upon therapy with more frequent resistance. In this review, based on the most recent data, a treatment selection advice is provided for the therapy of symptomatic patients. Orv Hetil. 2017; 158(41): 1604-1614. |
2017 |
12 |
14 |
Orv Hetil |
Szemlaky |
Zsuzsanna |
| 69 |
29222279 |
10.1182/asheducation-2017.1.358 |
Follicular lymphoma: are we ready for a risk-adapted approach? |
Follicular lymphoma is the most common indolent non-Hodgkin lymphoma in the Western hemisphere. The natural history of FL appears to have been favorably impacted by the introduction of rituximab after randomized clinical trials demonstrated that the addition of rituximab to standard chemotherapy induction has improved the overall survival. Yet, the disease is biologically and clinically heterogeneous with wide variations in outcomes for individual patients. The ability to accurately risk-stratify patients and then tailor therapy to the individual is an area of ongoing research. Historically, tumor grade, tumor burden, and the FL international prognostic index (version 1 and version 2) have been used to distinguish low-risk from high-risk patients. Biologic factors such as mutations in key genes can identify patients at high risk for poor outcomes to first-line therapy (mutational status of 7 genes [EZH2, ARID1A, MEF2B, EP300, FOX01, CREBBP, and CARD11] with Follicular Lymphoma International Prognostic Index). More recently, the quality of the response to initial therapy, as measured by either PET imaging or by remission duration, has been show to identify individuals at high risk. However, several unmet needs remain, including a better ability to identify high-risk patients at diagnosis, the development of predictive biomarkers for targeted agents, and strategies to reduce the risk of transformation. |
2018 |
07 |
18 |
Hematology Am Soc Hematol Educ Program |
Kahl |
Brad S |
| 70 |
26839360 |
10.1136/thoraxjnl-2015-207950 |
A patient with complex multiple genomic ALK alterations. |
NA |
2016 |
08 |
08 |
Thorax |
Liu |
Xin |
| 71 |
27102345 |
10.1038/modpathol.2016.79 |
Comprehensive genomic profiling of orbital and ocular adnexal lymphomas identifies frequent alterations in MYD88 and chromatin modifiers: new routes to targeted therapies. |
Non-Hodgkin lymphoma of the orbit and ocular adnexa is the most common primary orbital malignancy. Treatments for low- (extra-nodal marginal zone and follicular lymphomas) and high-grade (diffuse large B-cell lymphoma) are associated with local and vision-threatening toxicities. High-grade lymphomas relapse frequently and exhibit poor survival rates. Despite advances in genomic profiling and precision medicine, orbital and ocular adnexal lymphomas remain poorly characterized molecularly. We performed targeted next-generation sequencing (NGS) profiling of 38 formalin-fixed, paraffin-embedded orbital and ocular adnexal lymphomas obtained from a single-center using a panel targeting near-term, clinically relevant genes. Potentially actionable mutations and copy number alterations were prioritized based on gain- and loss-of-function analyses, and catalogued, approved, and investigational therapies. Of 36 informative samples, including marginal zone lymphomas (n=20), follicular lymphomas (n=9), and diffuse large B-cell lymphomas (n=7), 53% harbored a prioritized alteration (median=1, range 0-5/sample). MYD88 was the most frequently altered gene in our cohort, with potentially clinically relevant hotspot gain-of-function mutations identified in 71% of diffuse large B-cell lymphomas and 25% of marginal zone lymphomas. Prioritized alterations in epigenetic modulators were common and included gain-of-function EZH2 and loss-of-function ARID1A mutations (14% of diffuse large B-cell lymphomas and 22% of follicular lymphomas contained alterations in each of these two genes). Single prioritized alterations were also identified in the histone methyltransferases KMT2B (follicular lymphoma) and KMT3B (diffuse large B-cell lymphoma). Loss-of-function mutations and copy number alterations in the tumor suppressors TP53 (diffuse large B-cell and follicular lymphoma), CDKN2A (diffuse large B-cell and marginal zone lymphoma), PTEN (diffuse large B-cell lymphoma), ATM (diffuse large B-cell lymphoma), and NF1 (diffuse large B-cell lymphoma), and gain-of-function mutations in the oncogenes HRAS (follicular lymphoma) and NRAS (diffuse large B-cell lymphoma) were also observed. Together, our study demonstrates that NGS can be used to profile routine formalin-fixed, paraffin-embedded orbital and ocular adnexal lymphomas for identification of somatic-driving alterations and nomination of potential therapeutic strategies. |
2018 |
01 |
12 |
Mod Pathol |
Cani |
Andi K |
| 72 |
27590521 |
10.18632/oncotarget.11773 |
Deep targeted sequencing in pediatric acute lymphoblastic leukemia unveils distinct mutational patterns between genetic subtypes and novel relapse-associated genes. |
To characterize the mutational patterns of acute lymphoblastic leukemia (ALL) we performed deep next generation sequencing of 872 cancer genes in 172 diagnostic and 24 relapse samples from 172 pediatric ALL patients. We found an overall greater mutational burden and more driver mutations in T-cell ALL (T-ALL) patients compared to B-cell precursor ALL (BCP-ALL) patients. In addition, the majority of the mutations in T-ALL had occurred in the original leukemic clone, while most of the mutations in BCP-ALL were subclonal. BCP-ALL patients carrying any of the recurrent translocations ETV6-RUNX1, BCR-ABL or TCF3-PBX1 harbored few mutations in driver genes compared to other BCP-ALL patients. Specifically in BCP-ALL, we identified ATRX as a novel putative driver gene and uncovered an association between somatic mutations in the Notch signaling pathway at ALL diagnosis and increased risk of relapse. Furthermore, we identified EP300, ARID1A and SH2B3 as relapse-associated genes. The genes highlighted in our study were frequently involved in epigenetic regulation, associated with germline susceptibility to ALL, and present in minor subclones at diagnosis that became dominant at relapse. We observed a high degree of clonal heterogeneity and evolution between diagnosis and relapse in both BCP-ALL and T-ALL, which could have implications for the treatment efficiency. |
2018 |
05 |
22 |
Oncotarget |
Lindqvist |
C Mårten |
| 73 |
27729836 |
10.5808/GI.2016.14.3.78 |
Mutational Analysis of Extranodal NK/T-Cell Lymphoma Using Targeted Sequencing with a Comprehensive Cancer Panel. |
Extranodal natural killer (NK)/T-cell lymphoma, nasal type (NKTCL), is a malignant disorder of cytotoxic lymphocytes of NK or T cells. It is an aggressive neoplasm with a very poor prognosis. Although extranodal NKTCL reportedly has a strong association with Epstein-Barr virus, the molecular pathogenesis of NKTCL has been unexplored. The recent technological advancements in next-generation sequencing (NGS) have made DNA sequencing cost- and time-effective, with more reliable results. Using the Ion Proton Comprehensive Cancer Panel, we sequenced 409 cancer-related genes to identify somatic mutations in five NKTCL tissue samples. The sequencing analysis detected 25 mutations in 21 genes. Among them, <i>KMT2D</i>, a histone modification-related gene, was the most frequently mutated gene (four of the five cases). This result was consistent with recent NGS studies that have suggested <i>KMT2D</i> as a novel driver gene in NKTCL. Mutations were also found in <i>ARID1A</i>, a chromatin remodeling gene, and <i>TP53</i>, which also recurred in recent NGS studies. We also found mutations in 18 novel candidate genes, with molecular functions that were potentially implicated in cancer development. We suggest that these genes may result in multiple oncogenic events and may be used as potential bio-markers of NKTCL in the future. |
2020 |
09 |
30 |
Genomics Inform |
Choi |
Seungkyu |
| 74 |
25444907 |
10.1016/j.canlet.2014.11.024 |
Gene mutations in primary tumors and corresponding patient-derived xenografts derived from non-small cell lung cancer. |
Molecular annotated patient-derived xenograft (PDX) models are useful for the preclinical investigation of anticancer drugs and individualized anticancer therapy. We established 23 PDXs from 88 surgical specimens of lung cancer patients and determined gene mutations in these PDXs and their paired primary tumors by ultradeep exome sequencing on 202 cancer-related genes. The numbers of primary tumors with deleterious mutations in TP53, KRAS, PI3KCA, ALK, STK11, and EGFR were 43.5%, 21.7%, 17.4%, 17.4%, 13.0%, and 8.7%, respectively. Other genes with deleterious mutations in ≥3 (13.0%) primary tumors were MLL3, SETD2, ATM, ARID1A, CRIPAK, HGF, BAI3, EP300, KDR, PDGRRA and RUNX1. Of 315 mutations detected in the primary tumors, 293 (93%) were also detected in their corresponding PDXs, indicating that PDXs have the capacity to recapitulate the mutations in primary tumors. Nevertheless, a substantial number of mutations had higher allele frequencies in the PDXs than in the primary tumors, or were not detectable in the primary tumor, suggesting the possibility of tumor cell enrichment in PDXs or heterogeneity in the primary tumors. The molecularly annotated PDXs generated from this study could be useful for future translational studies. |
2015 |
04 |
21 |
Cancer Lett |
Hao |
Chuncheng |
| 75 |
25779943 |
10.1158/1078-0432.CCR-14-2759 |
Genetics and Prognostication in Splenic Marginal Zone Lymphoma: Revelations from Deep Sequencing. |
Mounting evidence supports the clinical significance of gene mutations and immunogenetic features in common mature B-cell malignancies. We undertook a detailed characterization of the genetic background of splenic marginal zone lymphoma (SMZL), using targeted resequencing and explored potential clinical implications in a multinational cohort of 175 patients with SMZL. We identified recurrent mutations in TP53 (16%), KLF2 (12%), NOTCH2 (10%), TNFAIP3 (7%), MLL2 (11%), MYD88 (7%), and ARID1A (6%), all genes known to be targeted by somatic mutation in SMZL. KLF2 mutations were early, clonal events, enriched in patients with del(7q) and IGHV1-2*04 B-cell receptor immunoglobulins, and were associated with a short median time to first treatment (0.12 vs. 1.11 years; P = 0.01). In multivariate analysis, mutations in NOTCH2 [HR, 2.12; 95% confidence interval (CI), 1.02-4.4; P = 0.044] and 100% germline IGHV gene identity (HR, 2.19; 95% CI, 1.05-4.55; P = 0.036) were independent markers of short time to first treatment, whereas TP53 mutations were an independent marker of short overall survival (HR, 2.36; 95 % CI, 1.08-5.2; P = 0.03). We identify key associations between gene mutations and clinical outcome, demonstrating for the first time that NOTCH2 and TP53 gene mutations are independent markers of reduced treatment-free and overall survival, respectively. |
2016 |
08 |
02 |
Clin Cancer Res |
Parry |
Marina |
| 76 |
25918285 |
10.1200/JCO.2014.59.2444 |
Genomic Characterization of Non-Small-Cell Lung Cancer in African Americans by Targeted Massively Parallel Sequencing. |
Technologic advances have enabled the comprehensive analysis of genetic perturbations in non-small-cell lung cancer (NSCLC); however, African Americans have often been underrepresented in these studies. This ethnic group has higher lung cancer incidence and mortality rates, and some studies have suggested a lower incidence of epidermal growth factor receptor mutations. Herein, we report the most in-depth molecular profile of NSCLC in African Americans to date. A custom panel was designed to cover the coding regions of 81 NSCLC-related genes and 40 ancestry-informative markers. Clinical samples were sequenced on a massively parallel sequencing instrument, and anaplastic lymphoma kinase translocation was evaluated by fluorescent in situ hybridization. The study cohort included 99 patients (61% males, 94% smokers) comprising 31 squamous and 68 nonsquamous cell carcinomas. We detected 227 nonsilent variants in the coding sequence, including 24 samples with nonoverlapping, classic driver alterations. The frequency of driver mutations was not significantly different from that of whites, and no association was found between genetic ancestry and the presence of somatic mutations. Copy number alteration analysis disclosed distinguishable amplifications in the 3q chromosome arm in squamous cell carcinomas and pointed toward a handful of targetable alterations. We also found frequent SMARCA4 mutations and protein loss, mostly in driver-negative tumors. Our data suggest that African American ancestry may not be significantly different from European/white background for the presence of somatic driver mutations in NSCLC. Furthermore, we demonstrated that using a comprehensive genotyping approach could identify numerous targetable alterations, with potential impact on therapeutic decisions. |
2015 |
08 |
21 |
J Clin Oncol |
Araujo |
Luiz H |
| 77 |
26192917 |
10.1038/ng.3358 |
Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma. |
Natural killer/T-cell lymphoma (NKTCL) is a malignant proliferation of CD56(+) and cytoCD3(+) lymphocytes with aggressive clinical course, which is prevalent in Asian and South American populations. The molecular pathogenesis of NKTCL has largely remained elusive. We identified somatic gene mutations in 25 people with NKTCL by whole-exome sequencing and confirmed them in an extended validation group of 80 people by targeted sequencing. Recurrent mutations were most frequently located in the RNA helicase gene DDX3X (21/105 subjects, 20.0%), tumor suppressors (TP53 and MGA), JAK-STAT-pathway molecules (STAT3 and STAT5B) and epigenetic modifiers (MLL2, ARID1A, EP300 and ASXL3). As compared to wild-type protein, DDX3X mutants exhibited decreased RNA-unwinding activity, loss of suppressive effects on cell-cycle progression in NK cells and transcriptional activation of NF-κB and MAPK pathways. Clinically, patients with DDX3X mutations presented a poor prognosis. Our work thus contributes to the understanding of the disease mechanism of NKTCL. |
2016 |
01 |
13 |
Nat Genet |
Jiang |
Lu |
| 78 |
26256760 |
10.1016/S1470-2045(15)00169-2 |
Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: a retrospective analysis of a prospective clinical trial and validation in a population-based registry. |
Follicular lymphoma is a clinically and genetically heterogeneous disease, but the prognostic value of somatic mutations has not been systematically assessed. We aimed to improve risk stratification of patients receiving first-line immunochemotherapy by integrating gene mutations into a prognostic model. We did DNA deep sequencing to retrospectively analyse the mutation status of 74 genes in 151 follicular lymphoma biopsy specimens that were obtained from patients within 1 year before beginning immunochemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). These patients were recruited between May 4, 2000, and Oct 20, 2010, as part of a phase 3 trial (GLSG2000). Eligible patients had symptomatic, advanced stage follicular lymphoma and were previously untreated. The primary endpoints were failure-free survival (defined as less than a partial remission at the end of induction, relapse, progression, or death) and overall survival calculated from date of treatment initiation. Median follow-up was 7·7 years (IQR 5·5-9·3). Mutations and clinical factors were incorporated into a risk model for failure-free survival using multivariable L1-penalised Cox regression. We validated the risk model in an independent population-based cohort of 107 patients with symptomatic follicular lymphoma considered ineligible for curative irradiation. Pretreatment biopsies were taken between Feb 24, 2004, and Nov 24, 2009, within 1 year before beginning first-line immunochemotherapy consisting of rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). Median follow-up was 6·7 years (IQR 5·7-7·6). We established a clinicogenetic risk model (termed m7-FLIPI) that included the mutation status of seven genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11), the Follicular Lymphoma International Prognostic Index (FLIPI), and Eastern Cooperative Oncology Group (ECOG) performance status. In the training cohort, m7-FLIPI defined a high-risk group (28%, 43/151) with 5-year failure-free survival of 38·29% (95% CI 25·31-57·95) versus 77·21% (95% CI 69·21-86·14) for the low-risk group (hazard ratio [HR] 4·14, 95% CI 2·47-6·93; p<0·0001; bootstrap-corrected HR 2·02), and outperformed a prognostic model of only gene mutations (HR 3·76, 95% CI 2·10-6·74; p<0·0001; bootstrap-corrected HR 1·57). The positive predictive value and negative predictive value for 5-year failure-free survival were 64% and 78%, respectively, with a C-index of 0·80 (95% CI 0·71-0·89). In the validation cohort, m7-FLIPI again defined a high-risk group (22%, 24/107) with 5-year failure-free survival of 25·00% (95% CI 12·50-49·99) versus 68·24% (58·84-79·15) in the low-risk group (HR 3·58, 95% CI 2·00-6·42; p<0.0001). The positive predictive value for 5-year failure-free survival was 72% and 68% for negative predictive value, with a C-index of 0·79 (95% CI 0·69-0·89). In the validation cohort, risk stratification by m7-FLIPI outperformed FLIPI alone (HR 2·18, 95% CI 1·21-3·92), and FLIPI combined with ECOG performance status (HR 2·03, 95% CI 1·12-3·67). Integration of the mutational status of seven genes with clinical risk factors improves prognostication for patients with follicular lymphoma receiving first-line immunochemotherapy and is a promising approach to identify the subset at highest risk of treatment failure. Deutsche Krebshilfe, Terry Fox Research Institute. |
2015 |
12 |
14 |
Lancet Oncol |
Pastore |
Alessandro |
| 79 |
26415585 |
10.1038/ncomms9470 |
Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sézary syndrome. |
Sézary syndrome (SS) is an aggressive leukaemia of mature T cells with poor prognosis and limited options for targeted therapies. The comprehensive genetic alterations underlying the pathogenesis of SS are unknown. Here we integrate whole-genome sequencing (n=6), whole-exome sequencing (n=66) and array comparative genomic hybridization-based copy-number analysis (n=80) of primary SS samples. We identify previously unknown recurrent loss-of-function aberrations targeting members of the chromatin remodelling/histone modification and trithorax families, including ARID1A in which functional loss from nonsense and frameshift mutations and/or targeted deletions is observed in 40.3% of SS genomes. We also identify recurrent gain-of-function mutations targeting PLCG1 (9%) and JAK1, JAK3, STAT3 and STAT5B (JAK/STAT total ∼11%). Functional studies reveal sensitivity of JAK1-mutated primary SS cells to JAK inhibitor treatment. These results highlight the complex genomic landscape of SS and a role for inhibition of JAK/STAT pathways for the treatment of SS. |
2016 |
05 |
24 |
Nat Commun |
Kiel |
Mark J |
| 80 |
26446488 |
10.1038/ncomms9325 |
LRF maintains genome integrity by regulating the non-homologous end joining pathway of DNA repair. |
Leukemia/lymphoma-related factor (LRF) is a POZ/BTB and Krüppel (POK) transcriptional repressor characterized by context-dependent key roles in cell fate decision and tumorigenesis. Here we demonstrate an unexpected transcription-independent function for LRF in the classical non-homologous end joining (cNHEJ) pathway of double-strand break (DSB) repair. We find that LRF loss in cell lines and mouse tissues results in defective cNHEJ, genomic instability and hypersensitivity to ionizing radiation. Mechanistically, we show that LRF binds and stabilizes DNA-PKcs on DSBs, in turn favouring DNA-PK activity. Importantly, LRF loss restores ionizing radiation sensitivity to p53 null cells, making LRF an attractive biomarker to direct p53-null LRF-deficient tumours towards therapeutic treatments based on genotoxic agents or PARP inhibitors following a synthetic lethal strategy. |
2016 |
05 |
06 |
Nat Commun |
Liu |
Xue-Song |
| 81 |
26468873 |
10.1371/journal.ppat.1005158 |
Distinct Viral and Mutational Spectrum of Endemic Burkitt Lymphoma. |
Endemic Burkitt lymphoma (eBL) is primarily found in children in equatorial regions and represents the first historical example of a virus-associated human malignancy. Although Epstein-Barr virus (EBV) infection and MYC translocations are hallmarks of the disease, it is unclear whether other factors may contribute to its development. We performed RNA-Seq on 20 eBL cases from Uganda and showed that the mutational and viral landscape of eBL is more complex than previously reported. First, we found the presence of other herpesviridae family members in 8 cases (40%), in particular human herpesvirus 5 and human herpesvirus 8 and confirmed their presence by immunohistochemistry in the adjacent non-neoplastic tissue. Second, we identified a distinct latency program in EBV involving lytic genes in association with TCF3 activity. Third, by comparing the eBL mutational landscape with published data on sporadic Burkitt lymphoma (sBL), we detected lower frequencies of mutations in MYC, ID3, TCF3 and TP53, and a higher frequency of mutation in ARID1A in eBL samples. Recurrent mutations in two genes not previously associated with eBL were identified in 20% of tumors: RHOA and cyclin F (CCNF). We also observed that polyviral samples showed lower numbers of somatic mutations in common altered genes in comparison to sBL specimens, suggesting dual mechanisms of transformation, mutation versus virus driven in sBL and eBL respectively. |
2016 |
04 |
04 |
PLoS Pathog |
Abate |
Francesco |
| 82 |
26473533 |
10.1038/bcj.2015.89 |
Mutation of chromatin modifiers; an emerging hallmark of germinal center B-cell lymphomas. |
Subtypes of non-Hodgkin's lymphomas align with different stages of B-cell development. Germinal center B-cell (GCB)-like diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and Burkitt's lymphoma (BL) each share molecular similarities with normal GCB cells. Recent next-generation sequencing studies have gained insight into the genetic etiology of these malignancies and revealed a high frequency of mutations within genes encoding proteins that modifying chromatin. These include activating and inactivating mutations of genes that perform post-translational modification of histones and organize chromatin structure. Here, we discuss the function of histone acetyltransferases (CREBBP, EP300), histone methyltransferases (KDM2C/D, EZH2) and regulators of higher order chromatin structure (HIST1H1C/D/E, ARID1A and SMARCA4) that have been reported to be mutated in ⩾5% of DLBCL, FL or BL. Mutations of these genes are an emerging hallmark of lymphomas with GCB-cell origins, and likely represent the next generation of therapeutic targets for these malignancies. |
2016 |
01 |
25 |
Blood Cancer J |
Lunning |
M A |
| 83 |
26551670 |
10.1038/ng.3444 |
Genomic profiling of Sézary syndrome identifies alterations of key T cell signaling and differentiation genes. |
Sézary syndrome is a rare leukemic form of cutaneous T cell lymphoma characterized by generalized redness, scaling, itching and increased numbers of circulating atypical T lymphocytes. It is rarely curable, with poor prognosis. Here we present a multiplatform genomic analysis of 37 patients with Sézary syndrome that implicates dysregulation of cell cycle checkpoint and T cell signaling. Frequent somatic alterations were identified in TP53, CARD11, CCR4, PLCG1, CDKN2A, ARID1A, RPS6KA1 and ZEB1. Activating CCR4 and CARD11 mutations were detected in nearly one-third of patients. ZEB1, encoding a transcription repressor essential for T cell differentiation, was deleted in over one-half of patients. IL32 and IL2RG were overexpressed in nearly all cases. Our results demonstrate profound disruption of key signaling pathways in Sézary syndrome and suggest potential targets for new therapies. |
2016 |
06 |
21 |
Nat Genet |
Wang |
Linghua |
| 84 |
24366360 |
10.1182/blood-2013-09-525808 |
The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis. |
The genetic basis for Waldenström macroglobulinemia (WM) remains to be clarified. Although 6q losses are commonly present, recurring gene losses in this region remain to be defined. We therefore performed whole genome sequencing (WGS) in 30 WM patients, which included germline/tumor sequencing for 10 patients. Validated somatic mutations occurring in >10% of patients included MYD88, CXCR4, and ARID1A that were present in 90%, 27%, and 17% of patients, respectively, and included the activating mutation L265P in MYD88 and warts, hypogammaglobulinemia, infection, and myelokathexis-syndrome-like mutations in CXCR4 that previously have only been described in the germline. WGS also delineated copy number alterations (CNAs) and structural variants in the 10 paired patients. The CXCR4 and CNA findings were validated in independent expansion cohorts of 147 and 30 WM patients, respectively. Validated gene losses due to CNAs involved PRDM2 (93%), BTG1 (87%), HIVEP2 (77%), MKLN1 (77%), PLEKHG1 (70%), LYN (60%), ARID1B (50%), and FOXP1 (37%). Losses in PLEKHG1, HIVEP2, ARID1B, and BCLAF1 constituted the most common deletions within chromosome 6. Although no recurrent translocations were observed, in 2 patients deletions in 6q corresponded with translocation events. These studies evidence highly recurring somatic events, and provide a genomic basis for understanding the pathogenesis of WM. |
2014 |
06 |
16 |
Blood |
Hunter |
Zachary R |
| 85 |
24435047 |
10.1182/blood-2013-05-500264 |
Mutations in linker histone genes HIST1H1 B, C, D, and E; OCT2 (POU2F2); IRF8; and ARID1A underlying the pathogenesis of follicular lymphoma. |
Follicular lymphoma (FL) constitutes the second most common non-Hodgkin lymphoma in the western world. FL carries characteristic recurrent structural genomic aberrations. However, information regarding the coding genome in FL is still evolving. Here, we describe the results of massively parallel exome sequencing and single nucleotide polymorphism 6.0 array genomic profiling of 11 highly purified FL cases, and 1 transformed FL case and the validation of selected mutations in 102 FL cases. We report the identification of 15 novel recurrently mutated genes in FL. These include frequent mutations in the linker histone genes HIST1H1 B-E (27%) and mutations in OCT2 (also known as POU2F2; 8%), IRF8 (6%), and ARID1A (11%). A subset of the mutations in HIST1H1 B-E affected binding to DNMT3B, and mutations in HIST1H1 B-E and in EZH2 or ARID1A were largely mutually exclusive, implicating HIST1H1 B-E in epigenetic deregulation in FL. Mutations in OCT2 (POU2F2) affected its transcriptional and functional properties as measured through luciferase assays, the biological analysis of stably transduced cell lines, and global expression profiling. Finally, multiple novel mutated genes located within regions of acquired uniparental disomy in FL are identified. In aggregate, these data substantially broaden our understanding of the genomic pathogenesis of FL. |
2014 |
05 |
09 |
Blood |
Li |
Hongxiu |
| 86 |
23292937 |
10.1073/pnas.1205299110 |
Genetic heterogeneity of diffuse large B-cell lymphoma. |
Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma in adults. The disease exhibits a striking heterogeneity in gene expression profiles and clinical outcomes, but its genetic causes remain to be fully defined. Through whole genome and exome sequencing, we characterized the genetic diversity of DLBCL. In all, we sequenced 73 DLBCL primary tumors (34 with matched normal DNA). Separately, we sequenced the exomes of 21 DLBCL cell lines. We identified 322 DLBCL cancer genes that were recurrently mutated in primary DLBCLs. We identified recurrent mutations implicating a number of known and not previously identified genes and pathways in DLBCL including those related to chromatin modification (ARID1A and MEF2B), NF-κB (CARD11 and TNFAIP3), PI3 kinase (PIK3CD, PIK3R1, and MTOR), B-cell lineage (IRF8, POU2F2, and GNA13), and WNT signaling (WIF1). We also experimentally validated a mutation in PIK3CD, a gene not previously implicated in lymphomas. The patterns of mutation demonstrated a classic long tail distribution with substantial variation of mutated genes from patient to patient and also between published studies. Thus, our study reveals the tremendous genetic heterogeneity that underlies lymphomas and highlights the need for personalized medicine approaches to treating these patients. |
2013 |
03 |
21 |
Proc Natl Acad Sci U S A |
Zhang |
Jenny |
| 87 |
22585168 |
10.1158/2159-8290.CD-11-0208 |
Molecular ontogeny of donor-derived follicular lymphomas occurring after hematopoietic cell transplantation. |
The relative timing of genetic alterations that contribute to follicular lymphoma remains unknown. We analyzed a donor-recipient pair who both developed grade 2/3A follicular lymphoma 7 years after allogeneic transplantation and donor lymphocyte infusions. Both patients harbored identical BCL2/IGH rearrangements also present in 1 in 2,000 cells in the donor lymphocyte infusion, and the same V(D)J rearrangement, which underwent somatic hypermutation both before and after clonal divergence. Exome sequencing of both follicular lymphomas identified 15 shared mutations, of which 14 (including alterations in EP300 and KLHL6) were recovered from the donor lymphocyte infusion by ultra-deep sequencing (average read coverage, 361,723), indicating acquisition at least 7 years before clinical presentation. Six additional mutations were present in only one follicular lymphoma and not the donor lymphocyte infusion, including an ARID1A premature stop, indicating later acquisition during clonal divergence. Thus, ultrasensitive sequencing can map clonal evolution within rare subpopulations during human lymphomagenesis in vivo. For the first time, we define the molecular ontogeny of follicular lymphoma during clonal evolution in vivo. By using ultrasensitive mutation detection, we mapped the time-course of somatic alterations after passage of a malignant ancestor by hematopoietic cell transplantation. |
2013 |
01 |
15 |
Cancer Discov |
Weigert |
Oliver |
| 88 |
22915242 |
10.1007/s00428-012-1303-2 |
ARID1A expression loss in gastric cancer: pathway-dependent roles with and without Epstein-Barr virus infection and microsatellite instability. |
The AT-rich interactive domain 1A gene (ARID1A), which encodes one of the subunits in the Switch/Sucrose Nonfermentable chromatin remodeling complex, carries mutations and is responsible for loss of protein expression in gastric carcinoma, particularly with Epstein-Barr virus (EBV) infection and a microsatellite instability-high phenotype. We used immunohistochemistry to investigate the significance of ARID1A loss in 857 gastric carcinoma cases, including 67 EBV(+) and 136 MLH1-lost gastric carcinomas (corresponding to a microsatellite instability-high phenotype). Loss of ARID1A expression was significantly more frequent in EBV(+) (23/67; 34 %) and MLH1-lost (40/136; 29 %) gastric carcinomas than in EBV(-)MLH1-preserved (32/657; 5 %) gastric carcinomas (P < 0.01). Loss of ARID1A correlated with larger tumor size, advanced invasion depth, lymph node metastasis, and poor prognosis in EBV(-)MLH1-preserved gastric carcinoma. A correlation was found only with tumor size and diffuse-type histology in MLH1-lost gastric carcinoma, but no correlation was observed in EBV(+) gastric carcinoma. Loss of ARID1A expression in EBV(+) gastric carcinoma was highly frequent in the early stage of gastric carcinoma, although EBV infection did not cause downregulation of ARID1A: EBV-positive nasopharyngeal carcinomas (n = 8) and lymphomas (n = 15) failed to show loss of ARID1A, and EBV infection did not cause loss of ARID1A in gastric carcinoma cell lines. Taken together, loss of ARID1A may be an early change in carcinogenesis and may precede EBV infection in gastric epithelial cells, while loss of ARID1A promotes cancer progression in gastric cancer cells without EBV infection or loss of MLH1 expression. Loss of ARID1A has different and pathway-dependent roles in gastric carcinoma. |
2012 |
12 |
31 |
Virchows Arch |
Abe |
Hiroyuki |
| 89 |
22931316 |
10.1056/NEJMoa1200710 |
MYD88 L265P somatic mutation in Waldenström's macroglobulinemia. |
Waldenström's macroglobulinemia is an incurable, IgM-secreting lymphoplasmacytic lymphoma (LPL). The underlying mutation in this disorder has not been delineated. We performed whole-genome sequencing of bone marrow LPL cells in 30 patients with Waldenström's macroglobulinemia, with paired normal-tissue and tumor-tissue sequencing in 10 patients. Sanger sequencing was used to validate the findings in samples from an expanded cohort of patients with LPL, those with other B-cell disorders that have some of the same features as LPL, and healthy donors. Among the patients with Waldenström's macroglobulinemia, a somatic variant (T→C) in LPL cells was identified at position 38182641 at 3p22.2 in the samples from all 10 patients with paired tissue samples and in 17 of 20 samples from patients with unpaired samples. This variant predicted an amino acid change (L265P) in MYD88, a mutation that triggers IRAK-mediated NF-κB signaling. Sanger sequencing identified MYD88 L265P in tumor samples from 49 of 54 patients with Waldenström's macroglobulinemia and in 3 of 3 patients with non-IgM-secreting LPL (91% of all patients with LPL). MYD88 L265P was absent in paired normal tissue samples from patients with Waldenström's macroglobulinemia or non-IgM LPL and in B cells from healthy donors and was absent or rarely expressed in samples from patients with multiple myeloma, marginal-zone lymphoma, or IgM monoclonal gammopathy of unknown significance. Inhibition of MYD88 signaling reduced IκBα and NF-κB p65 phosphorylation, as well as NF-κB nuclear staining, in Waldenström's macroglobulinemia cells expressing MYD88 L265P. Somatic variants in ARID1A in 5 of 30 patients (17%), leading to a premature stop or frameshift, were also identified and were associated with an increased disease burden. In addition, 2 of 3 patients with Waldenström's macroglobulinemia who had wild-type MYD88 had somatic variants in MLL2. MYD88 L265P is a commonly recurring mutation in patients with Waldenström's macroglobulinemia that can be useful in differentiating Waldenström's macroglobulinemia and non-IgM LPL from B-cell disorders that have some of the same features. (Funded by the Peter and Helen Bing Foundation and others.). |
2012 |
09 |
07 |
N Engl J Med |
Treon |
Steven P |
| 90 |
23091298 |
10.1182/blood-2012-06-437624 |
Targeted genomic sequencing of pediatric Burkitt lymphoma identifies recurrent alterations in antiapoptotic and chromatin-remodeling genes. |
To ascertain the genetic basis of pediatric Burkitt lymphoma (pBL), we performed clinical-grade next-generation sequencing of 182 cancer-related genes on 29 formalin-fixed, paraffin embedded primary pBL samples. Ninety percent of cases had at least one mutation or genetic alteration, most commonly involving MYC and TP53. EBV(-) cases were more likely than EBV(+) cases to have multiple mutations (P < .0001). Alterations in tumor-related genes not previously described in BL were identified. Truncating mutations in ARID1A, a member of the SWI/SNF nucleosome remodeling complex, were seen in 17% of cases. MCL1 pathway alterations were found in 22% of cases and confirmed in an expanded panel. Other clinically relevant genomic alterations were found in 20% of cases. Our data suggest the roles of MCL1 and ARID1A in BL pathogenesis and demonstrate that comprehensive genomic profiling may identify additional treatment options in refractory disease. |
2013 |
02 |
15 |
Blood |
Giulino-Roth |
Lisa |
| 91 |
23143597 |
10.1038/ng.2468 |
The genetic landscape of mutations in Burkitt lymphoma. |
Burkitt lymphoma is characterized by deregulation of MYC, but the contribution of other genetic mutations to the disease is largely unknown. Here, we describe the first completely sequenced genome from a Burkitt lymphoma tumor and germline DNA from the same affected individual. We further sequenced the exomes of 59 Burkitt lymphoma tumors and compared them to sequenced exomes from 94 diffuse large B-cell lymphoma (DLBCL) tumors. We identified 70 genes that were recurrently mutated in Burkitt lymphomas, including ID3, GNA13, RET, PIK3R1 and the SWI/SNF genes ARID1A and SMARCA4. Our data implicate a number of genes in cancer for the first time, including CCT6B, SALL3, FTCD and PC. ID3 mutations occurred in 34% of Burkitt lymphomas and not in DLBCLs. We show experimentally that ID3 mutations promote cell cycle progression and proliferation. Our work thus elucidates commonly occurring gene-coding mutations in Burkitt lymphoma and implicates ID3 as a new tumor suppressor gene. |
2013 |
02 |
13 |
Nat Genet |
Love |
Cassandra |
| 92 |
21590771 |
10.1002/path.2911 |
Loss of BAF250a (ARID1A) is frequent in high-grade endometrial carcinomas. |
Mutation of the ARID1A gene and loss of the corresponding protein BAF250a has recently been described as a frequent event in clear cell and endometrioid carcinomas of the ovary. To determine whether BAF250a loss is common in other malignancies, immunohistochemistry (IHC) for BAF250a was performed on tissue microarrays (TMAs) in more than 3000 cancers, including carcinomas of breast, lung, thyroid, endometrium, kidney, stomach, oral cavity, cervix, pancreas, colon and rectum, as well as endometrial stromal sarcomas, gastrointestinal stromal tumours, sex cord-stromal tumours and four major types of lymphoma (diffuse large B cell lymphoma, primary mediastinal B cell lymphoma, mantle cell lymphoma and follicular lymphoma). We found that BAF250a loss is frequent in endometrial carcinomas but infrequent in other types of malignancies, with loss observed in 29% (29/101) of grade 1 or 2 and 39% (44/113) of grade 3 endometrioid carcinomas of the endometrium, 18% (17/95) of uterine serous carcinomas and 26% (6/23) of uterine clear cell carcinomas. Since endometrial cancers showed BAF250a loss, we stained whole tissue sections for BAF250a expression in nine cases of atypical hyperplasia and 10 cases of atypical endometriosis. Of the nine cases of complex atypical endometrial hyperplasia, all showed BAF250a expression; however, of 10 cases of atypical endometriosis (the putative precursor lesion for ovarian clear cell and endometrioid carcinoma), one case showed loss of staining for BAF250a in the atypical areas, with retention of staining in areas of non-atypical endometriosis. This was the sole case that recurred as an endometrioid carcinoma, indicating that BAF250a loss may be an early event in carcinogenesis. Since BAF250a loss is seen in endometrial carcinomas at a rate similar to that seen in ovarian carcinomas of clear cell and endometrioid type, and is uncommon in other malignancies, we conclude that loss of BAF250a is a particular feature of carcinomas arising from endometrial glandular epithelium. |
2011 |
08 |
24 |
J Pathol |
Wiegand |
Kimberly C |
| 93 |
19066270 |
10.1093/jnci/djn416 |
The SWI/SNF chromatin-remodeling complex and glucocorticoid resistance in acute lymphoblastic leukemia. |
Glucocorticoids are used in the curative treatment of acute lymphoblastic leukemia (ALL). Resistance to glucocorticoids is an important adverse prognostic factor in newly diagnosed ALL patients but its mechanism is unknown. Because SWI/SNF complex-mediated chromatin remodeling is required for glucocorticoid transcriptional activity in vitro, we investigated whether expression of subunits of the SWI/SNF complex was related to glucocorticoid resistance in ALL. Gene expression and in vitro sensitivity to prednisolone and dexamethasone were assessed in a training set of primary ALL cells from 177 children with newly diagnosed ALL and a validation set of cells from an independent cohort of 95 ALL patients. The global test method was used to select pathways whose genes were associated with drug sensitivity. Genes involved in chromatin remodeling were identified by use of the Gene Ontology database. Short hairpin RNA (shRNA) was used to knock down mRNA expression of SMARCA4 in glucocorticoid-sensitive Jurkat human ALL cells. Spearman rank correlation, multiple linear regression, and logistic regression were used to investigate associations between gene expression and glucocorticoid sensitivity. All statistical tests were two-sided. Statistically significant associations between decreased expression in ALL cells of genes for core subunits of the SWI/SNF complex-SMARCA4, ARID1A, and SMARCB1-and resistance to prednisolone and dexamethasone were identified in the training cohort. In the validation cohort, expression of SMARCA4 (P < .001 and r = -0.43), ARID1A (P = .016 and r = -0.29), and SMARCB1 (P = .019 and r = -0.29) in ALL cells was statistically significantly associated with dexamethasone sensitivity, and SMARCA4 expression (P = .018 and r = -0.28) was statistically significantly associated with prednisolone sensitivity. Prednisolone resistance was higher in SMARCA4 shRNA-transfected Jurkat cells (drug concentration lethal to 50% of the leukemia cells [LC(50)] = 277 microM) than in control shRNA-transfected cells (LC(50) = 174 microM, difference = 103 microM, 95% confidence interval of the difference = 100 to 106 microM; P < .001, t test). Decreased expression of as many as three subunits of the SWI/SNF complex appears to be associated with glucocorticoid resistance in primary ALL cells. |
2009 |
01 |
06 |
J Natl Cancer Inst |
Pottier |
Nicolas |
| 94 |
33788417 |
10.1002/pbc.29036 |
Novel risk factors for glucarpidase use in pediatric acute lymphoblastic leukemia: Hispanic ethnicity, age, and the ABCC4 gene. |
Carboxypeptidase G<sub>2</sub> (CPDG<sub>2</sub> ; glucarpidase) is a rescue drug for patients at risk for kidney injury from high-dose methotrexate (MTX). As there are no strategies for predicting patients who will require CDPG<sub>2</sub> , we evaluated the role of demographic, clinical, and genetic factors for CPDG<sub>2</sub> use. Cases who received CPDG<sub>2</sub> and controls who did not were identified by chart review of acute lymphoblastic leukemia (ALL) patients who received MTX doses between 1000 and 5000 mg/m<sup>2</sup> between 2010 and 2017. We used multivariable Bayesian logistic regression to evaluate the association of CPDG<sub>2</sub> use with demographic and clinical variables and, on a subset of patients, with genetic ancestry and 49 single nucleotide variants previously associated with MTX toxicity. We identified 423 patients who received 1592 doses of MTX. Of the 18 patients who received CPDG<sub>2</sub> , 17 (94%) were Hispanic. No patients who received 1000 or 2000 mg/m<sup>2</sup> of MTX received CPDG<sub>2</sub> . Hispanic ethnicity (odds ratio: 4.68; 95% compatibility interval: 1.63-15.06) and older age (1.87 [1.17-3.17]) were associated with receiving CPDG<sub>2</sub> . Of the 177 patients in the genomic cohort, 11 received CPDG<sub>2</sub> . Each additional G allele of rs7317112 in ABCC4 increased the odds of requiring CPDG<sub>2</sub> (3.10 [1.12-6.75]). Six other loci (NTRK1/rs10908521, TSG1/rs9345389, STT3B/rs1353327, SCLO1B1/rs4149056, GATA3/rs3824662, ARID5B/rs10821936) demonstrated probabilities of association between 88% and 97%. We demonstrated that demographic characteristics, including Hispanic ethnicity and age, are associated with CPDG<sub>2</sub> use. Additionally, we provide evidence that inherited genetic variation is associated with risk of requiring CPDG<sub>2</sub> . If validated in independent populations, this information could be leveraged to develop targeted toxicity prevention strategies for children with ALL. |
2022 |
03 |
11 |
Pediatr Blood Cancer |
Zobeck |
Mark C |
| 95 |
33891562 |
10.18632/aging.202903 |
Age-related differences of genetic susceptibility to patients with acute lymphoblastic leukemia. |
Inherited predispositions to acute lymphoblastic leukemia have been well investigated in pediatric patients, but studies on adults, particularly Chinese patients, are limited. In this study, we conducted a genome-wide association study in 466 all-age Chinese patients with Acute lymphoblastic leukemia (ALL) and 1,466 non-ALL controls to estimate the impact of age on ALL susceptibility in the Chinese population. Among the 17 reported loci, 8 have been validated in pediatric and 1 in adult patients. The strongest association signal was identified at <i>ARID5B</i> locus and gradually decreased with age, while the signal at <i>GATA3</i> exhibited the opposite trend and significantly impact on adult patients. With genome-wide approaches, germline variants at 2q14.3 rank as the top inherited predisposition to adult patients (e.g., rs73956024, <i>P</i> = 4.3 × 10<sup>-5</sup>) and separate the genetic risk of pediatric vs. adult patients (<i>P</i> = 3.6 × 10<sup>-6</sup>), whereas variants at 15q25.3 (e.g., rs11638062) have a similar impact on patients in different age groups (overall <i>P</i> = 2.9 × 10<sup>-7</sup>). Our analysis highlights the impact of age on genetic susceptibility to ALL in Chinese patients. |
2021 |
07 |
26 |
Aging (Albany NY) |
Hao |
Qing |
| 96 |
31573954 |
10.1158/1078-0432.CCR-19-0190 |
<i>ARID5B</i> Influences Antimetabolite Drug Sensitivity and Prognosis of Acute Lymphoblastic Leukemia. |
Treatment outcomes for childhood acute lymphoblastic leukemia (ALL) have improved steadily, but a significant proportion of patients still experience relapse due to drug resistance, which is partly explained by inherited and/or somatic genetic alternations. Recently, we and others have identified genetic variants in the <i>ARID5B</i> gene associated with susceptibility to ALL and also with relapse. In this study, we sought to characterize the molecular pathway by which ARID5B affects antileukemic drug response in patients with ALL. We analyzed association of ARID5B expression in primary human ALL blasts with molecular subtypes and treatment outcome. Subsequent mechanistic studies were performed in ALL cell lines by manipulating <i>ARID5B</i> expression isogenically, in which we evaluated drug sensitivity, metabolism, and molecular signaling events. <i>ARID5B</i> expression varied substantially by ALL subtype, with the highest level being observed in hyperdiploid ALL. Lower <i>ARID5B</i> expression at diagnosis was associated with the risk of ALL relapse, and further reduction was noted at ALL relapse. In isogenic ALL cell models <i>in vitro</i>, <i>ARID5B</i> knockdown led to resistance specific to antimetabolite drugs (i.e., 6-mercaptopurine and methotrexate), without significantly affecting sensitivity to other antileukemic agents. <i>ARID5B</i> downregulation significantly inhibited ALL cell proliferation and caused partial cell-cycle arrest. At the molecular level, the cell-cycle checkpoint regulator p21 (encoded by <i>CDKN1A</i>) was most consistently modulated by ARID5B, plausibly as its direct transcription regulation target. Our data indicate that ARID5B is an important molecular determinant of antimetabolite drug sensitivity in ALL, in part, through p21-mediated effects on cell-cycle progression. |
2020 |
10 |
01 |
Clin Cancer Res |
Xu |
Heng |
| 97 |
31704777 |
10.1136/jmedgenet-2019-106339 |
Novel phenotypes observed in patients with <i>ETV6</i>-linked leukaemia/familial thrombocytopenia syndrome and a biallelic <i>ARID5B</i> risk allele as leukaemogenic cofactor. |
<i>Background.</i> The phenotypes of patients with the recently discovered, dominant, <i>ETV6</i>-linked leukaemia predisposition and familial thrombocytopenia syndrome are variable, and the exact mechanism of leukaemogenesis remains unclear. <i>Patients and Methods.</i> Here, we present novel clinical and laboratory phenotypes of seven individuals from three families with <i>ETV6</i> germline mutations and a refined genetic analysis of one child with additional high-hyperdiploid acute lymphoblastic leukaemia (HD-ALL), aiming to elucidate second oncogenic hits. <i>Results.</i> Four individuals from two pedigrees harboured one novel or one previously described variant in the central domain of <i>ETV6</i> (c.592C>T, p.Gln198* or c.641C>T, p.Pro241Leu, respectively). Neutropenia was an accompanying feature in one of these families that also harboured a variant in <i>RUNX1</i> (c.1098_1103dup, p.Ile366_Gly367dup), while in the other, an autism-spectrum disorder was observed. In the third family, the index patient suffered from HD-ALL and life-threatening pulmonary mucor mycosis, and had a positive family history of 'immune' thrombocytopenia. Genetic analyses revealed a novel heterozygous mutation in the ETS domain of <i>ETV6</i> (c.1136T>C, p.Leu379Pro) along with absence of heterozygosity of chromosome (10)(q21.2q21.3), yielding a biallelic leukaemia risk allele in <i>ARID5B</i> (rs7090445-C). The neutrophil function was normal in all individuals tested, and the platelet immune histochemistry of all three pedigrees showed delta-storage-pool defect-like features and cytoskeletal defects. <i>Conclusions.</i> Our clinical observations and results of high-resolution genetic analyses extend the spectrum of possible phenotypes cosegregating with <i>ETV6</i> germline mutations. Further, we propose <i>ARID5B</i> as potential leukaemogenic cofactor in patients with <i>ETV6</i>-linked leukaemia predisposition and familial thrombocytopenia syndrome. |
2021 |
06 |
08 |
J Med Genet |
Karastaneva |
Anna |
| 98 |
31870219 |
10.1080/08880018.2019.1705949 |
Association of <i>ABCC2</i> with levels and toxicity of methotrexate in Malaysian Childhood Acute Lymphoblastic Leukemia (ALL). |
Studies had shown that genetic polymorphism plays a significant role in the pharmacokinetics and pharmacodynamics variation of high dose methotrexate (MTX), 5000 mg/m<sup>2</sup> regimen. The objective of this study was to investigate the genetic variations associated with the serum level and toxicity of MTX in Malaysian children with acute lymphoblastic leukemia (ALL). Thirty-eight patients were genotyped for rs717620 (<i>ABCC2</i>), rs4948496 (<i>ARID5B</i>), rs1801133 (<i>MTHFR</i>) and rs4149056 (<i>SLCO1B1</i>). Serum levels of MTX at 48 h post 24 h of intravenous infusion were analyzed by high<i>-</i>performance liquid chromatography<i>-</i>mass spectrometry. The <i>ABCC2</i> genotype was significantly associated with the serum levels of MTX at 48 h after treatment (<i>p</i> = 0.017). Patients with CT and TT of rs717620 (<i>ABCC2</i>) and TC and CC of rs4948496 (<i>ARID5B</i>) were significantly associated with leukopenia grade I-IV (Fisher Exact Test; <i>p</i> = 0.03 and 0.02, respectively). The three most common MTX related toxicities were leukopenia (60.5%), increased alanine aminotransferase enzyme (47.4%), and thrombocytopenia (47.4%). Our results demonstrate that by prescreening of patients for <i>ABCC2</i> and <i>ARID5B</i> associated with the serum levels and adverse effects of MTX would identify patients at risk and therefore help a pediatric oncologist to personalize chemotherapy drugs for precision health. |
2020 |
11 |
13 |
Pediatr Hematol Oncol |
Razali |
Rizal Husaini |
| 99 |
32488880 |
10.1002/jcla.23414 |
Association of TLX1 gene polymorphisms with the risk of acute lymphoblastic leukemia and B lineage acute lymphoblastic leukemia in Han Chinese children. |
Studies on gene polymorphism association are centered on childhood acute lymphoblastic leukemia (ALL), a common hematological malignancy in children younger than 16 years. Single-nucleotide polymorphisms (SNPs) in some genes, such as ARID5B and CDKN2B, are associated with the risk of childhood ALL. T-cell leukemia homeobox 1 (TLX1), a member of the HOX gene family, was identified based on its abnormal expression in T-lineage leukemia. This study aimed to determine whether TLX1 is associated with B-ALL and which SNP plays a significant role in ALL. A total of 217 cases of ALL and 241 controls were included in this study. Six tag SNPs (rs75329544, rs946328, rs12415670, rs2075879, rs17113735, and rs1051723) were selected, and genotyping was carried out on Sequenom MassARRAY platform. Rs17113735 was possibly the risk locus associated with increased risk for ALL, whereas rs946328 was possibly associated with decreased risk for ALL. Moreover, rs17113735 was likely to be the risk locus for B-cell ALL (B-ALL), and rs2075879 was associated with decreased risk for B-ALL (P < .05). All SNPs in the two sample types (ALL and B-ALL samples) demonstrated linkage disequilibrium except between rs75329544 and rs2075879. Haplotype analysis showed no significant difference between the cases and controls in the two sample types. TLX1 gene polymorphisms are associated with ALL (rs17113735 and rs946328) and possibly play a significant role in B-ALL (rs17113735 and rs2075879). This work provides a reference for the diagnosis and therapy of this disease. |
2021 |
07 |
05 |
J Clin Lab Anal |
Mei |
Endian |
| 100 |
30770347 |
10.1158/1055-9965.EPI-18-0801 |
Is There Etiologic Heterogeneity between Subtypes of Childhood Acute Lymphoblastic Leukemia? A Review of Variation in Risk by Subtype. |
Although substantial advances in the identification of cytogenomic subtypes of childhood acute lymphoblastic leukemia (ALL) have been made in recent decades, epidemiologic research characterizing the etiologic heterogeneity of ALL by subtype has not kept pace. The purpose of this review is to summarize the current literature concerning subtype-specific epidemiologic risk factor associations with ALL subtype defined by immunophenotype (e.g., B-cell vs. T-cell) and cytogenomics (including gross chromosomal events characterized by recurring numerical and structural abnormalities, along with cryptic balanced rearrangements, and focal gene deletions). In case-control analyses investigating nongenetic risk factors, home paint exposure is associated with hyperdiploid, <i>MLL</i>-rearranged, and <i>ETV6</i>-<i>RUNX1</i> subtypes, yet there are few differences in risk factor associations between T- and B-ALL. Although the association between maternal smoking and ALL overall has been null, maternal smoking is associated with an increasing number of gene deletions among cases. GWAS-identified variants in <i>ARID5B</i> have been the most extensively studied and are strongly associated with hyperdiploid B-ALL. <i>GATA3</i> single nucleotide variant rs3824662 shows a strong association with Ph-like ALL (OR = 3.14). However, there have been relatively few population-based studies of adequate sample size to uncover risk factors that may define etiologic heterogeneity between and within the currently defined cytogenomic ALL subtypes. |
2020 |
07 |
16 |
Cancer Epidemiol Biomarkers Prev |
Williams |
Lindsay A |
Datasets
Models
