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| Status |
Public on Jan 29, 2025 |
| Title |
CpG island methylator phenotype classification improves risk assessment in pediatric T-cell Acute Lymphoblastic Leukemia [methylation array] |
| Organism |
Homo sapiens |
| Experiment type |
Methylation profiling by genome tiling array
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| Summary |
Current intensive treatment of pediatric T-cell acute lymphoblastic leukemia (T-ALL) has substantial side-effects, highlighting a need for novel biomarkers to improve risk stratification. Canonical biomarkers such as genetics and immunophenotype are largely not used in pediatric T-ALL stratification. This study aimed to validate the prognostic relevance of DNA methylation CpG island methylator phenotype (CIMP) risk stratification in two pediatric T-ALL patient cohorts: the Nordic NOPHO ALL2008 T-ALL study cohort (n=192) and the Dutch DCOG ALL-10/ALL-11 validation cohorts (n=156). Both cohorts showed that combining CIMP classification at diagnosis with measurable residual disease (MRD) at treatment day 29 or 33 significantly improved outcome prediction. The poor prognosis subgroup, characterized by CIMP low/D29 or D33 MRD≥0.1%, showed a cumulative incidence of relapse (pCIR5yr) of 29.0% and 23%, and overall survival (pOS5yr) of 59.7% and 65.4%, in NOPHO and DCOG, respectively. Conversely, a good prognosis subgroup was also identified representing CIMP high/D29 or D33 MRD<0.1% with pCIR5yr of 0% and 3.4%, and pOS5yr of 98.2% and 94.8%, in NOPHO and DCOG, respectively. For NOPHO, MRD was also evaluated on D15, and the relapse prediction accuracy of CIMP/D29 MRD (0.79) and CIMP/D15 MRD (0.75) classification was comparable, indicating potential for earlier stratification. The evaluation of the biology behind the CIMP subgroups revealed associations with transcriptome profiles, genomic aberrations, and mitotic history, suggesting distinct routes for leukemia development. In conclusion, integrating MRD assessment with the novel CIMP biomarker has the potential to improve risk stratification in pediatric T-ALL and guide future therapeutic decisions.
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| Overall design |
DNA methylation profiling of primary pediatric (> 1-year-old and < 18-years-old) T-ALL samples taken at diagnosis (n = 128), and cell-sorted CD34+ and CD3+ cells and a fresh frozen lymph node as control samples (n = 3), analyzed on Illumina EPIC v1.0 DNA methylation arrays (Illumina, CA, USA). T-ALL samples analyzed by Illumina 450K DNA methylation arrays (Illumina, CA, USA) (n = 64) are available in GSE69954 (GSM1713872 T-ALL Sample 85 was excluded due to mislabeling). For the validation DCOG cohort, n = 156 samples (≥1 and <18 years-old) stored in the Princess Máxima biobank were analyzed using Illumina EPICv.2.0 arrays (Illumina, CA, USA).
***Submitters state that raw *.idat files will not be submitted to a repository because the patients providing the samples were not consented for raw data deposition****
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| Contributor(s) |
Hackenhaar FS, Refhagen N, Hagleitner M, van Leeuwen F, Marquart HV, Madsen HO, Landfors M, Osterman P, Schmiegelow K, Flaegstad T, Jónsson Ó, Kanerva J, Abrahamsson J, Heyman M, Nyström UN, Hultdin M, Degerman S |
| Citation(s) |
- Schäfer Hackenhaar F, Refhagen N, Hagleitner MM, van Leeuwen FN et al. CpG island methylator phenotype classification improves risk assessment in pediatric T-cell Acute Lymphoblastic Leukemia. Blood 2025 Jan 22. PMID: 39841000
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| Submission date |
Jul 11, 2024 |
| Last update date |
Feb 03, 2025 |
| Contact name |
Sofie Degerman |
| E-mail(s) |
sofie.degerman@umu.se
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| Organization name |
Umeå University
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| Department |
Medical Biosciensces
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| Lab |
Pathology
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| Street address |
NUS, Blg 6M, 2nd floor
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| City |
Umeå |
| State/province |
Sweden |
| ZIP/Postal code |
90185 |
| Country |
Sweden |
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| Platforms (1) |
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