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International Consensus Definition of DNA Methylation Subgroups in Juvenile Myelomonocytic Leukemia
- Source :
- Clin Cancer Res
- Publication Year :
- 2021
- Publisher :
- American Association for Cancer Research (AACR), 2021.
-
Abstract
- Purpose: Known clinical and genetic markers have limitations in predicting disease course and outcome in juvenile myelomonocytic leukemia (JMML). DNA methylation patterns in JMML have correlated with outcome across multiple studies, suggesting it as a biomarker to improve patient stratification. However, standardized approaches to classify JMML on the basis of DNA methylation patterns are lacking. We, therefore, sought to define an international consensus for DNA methylation subgroups in JMML and develop classification methods for clinical implementation. Experimental Design: Published DNA methylation data from 255 patients with JMML were used to develop and internally validate a classifier model. Accuracy across platforms (EPIC-arrays and MethylSeq) was tested using a technical validation cohort (32 patients). The suitability of both methods for single-patient classification was demonstrated using an independent cohort (47 patients). Results: Analysis of pooled, published data established three DNA methylation subgroups as a de facto standard. Unfavorable prognostic parameters (PTPN11 mutation, elevated fetal hemoglobin, and older age) were significantly enriched in the high methylation (HM) subgroup. A classifier was then developed that predicted subgroups with 98% accuracy across different technological platforms. Applying the classifier to an independent validation cohort confirmed an association of HM with secondary mutations, high relapse incidence, and inferior overall survival (OS), while the low methylation subgroup was associated with a favorable disease course. Multivariable analysis established DNA methylation subgroups as the only significant factor predicting OS. Conclusions: This study provides an international consensus definition for DNA methylation subgroups in JMML. We developed and validated methods which will facilitate the design of risk-stratified clinical trials in JMML.
- Subjects :
- Male
0301 basic medicine
Oncology
Cancer Research
medicine.medical_specialty
Consensus
Adolescent
Datasets as Topic
Kaplan-Meier Estimate
Risk Assessment
Article
Epigenesis, Genetic
03 medical and health sciences
0302 clinical medicine
Internal medicine
medicine
Humans
Child
Juvenile myelomonocytic leukemia
Gene Expression Regulation, Leukemic
business.industry
Infant, Newborn
Infant
Methylation
DNA Methylation
Prognosis
medicine.disease
PTPN11
Clinical trial
030104 developmental biology
Leukemia, Myelomonocytic, Juvenile
Genetic marker
Child, Preschool
030220 oncology & carcinogenesis
Cohort
DNA methylation
Classification methods
CpG Islands
Female
business
Subjects
Details
- ISSN :
- 15573265 and 10780432
- Volume :
- 27
- Database :
- OpenAIRE
- Journal :
- Clinical Cancer Research
- Accession number :
- edsair.doi.dedup.....bb0af31486df495d8f93fb0b0d7cc4c6