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DNA methylation-based subtype prediction for pediatric acute lymphoblastic leukemia
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2015 (English)In: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 7, 11Article in journal (Refereed) Published
Abstract [en]

Background: We present a method that utilizes DNA methylation profiling for prediction of the cytogenetic subtypes of acute lymphoblastic leukemia (ALL) cells from pediatric ALL patients. The primary aim of our study was to improve risk stratification of ALL patients into treatment groups using DNA methylation as a complement to current diagnostic methods. A secondary aim was to gain insight into the functional role of DNA methylation in ALL. Results: We used the methylation status of similar to 450,000 CpG sites in 546 well-characterized patients with T-ALL or seven recurrent B-cell precursor ALL subtypes to design and validate sensitive and accurate DNA methylation classifiers. After repeated cross-validation, a final classifier was derived that consisted of only 246 CpG sites. The mean sensitivity and specificity of the classifier across the known subtypes was 0.90 and 0.99, respectively. We then used DNA methylation classification to screen for subtype membership of 210 patients with undefined karyotype (normal or no result) or non-recurrent cytogenetic aberrations('other' subtype). Nearly half (n = 106) of the patients lacking cytogenetic subgrouping displayed highly similar methylation profiles as the patients in the known recurrent groups. We verified the subtype of 20% of the newly classified patients by examination of diagnostic karyotypes, array-based copy number analysis, and detection of fusion genes by quantitative polymerase chain reaction (PCR) and RNA-sequencing (RNA-seq). Using RNA-seq data from ALL patients where cytogenetic subtype and DNA methylation classification did not agree, we discovered several novel fusion genes involving ETV6, RUNX1, and PAX5. Conclusions: Our findings indicate that DNA methylation profiling contributes to the clarification of the heterogeneity in cytogenetically undefined ALL patient groups and could be implemented as a complementary method for diagnosis of ALL. The results of our study provide clues to the origin and development of leukemic transformation. The methylation status of the CpG sites constituting the classifiers also highlight relevant biological characteristics in otherwise unclassified ALL patients.

Place, publisher, year, edition, pages
2015. Vol. 7, 11
Keyword [en]
DNA methylation, Pediatric acute lymphoblastic leukemia, CpG site, Subtyping, Cytogenetics, RNA- q, 450 k array, epigenetics
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:umu:diva-101397DOI: 10.1186/s13148-014-0039-zISI: 000350260800001PubMedID: 25729447OAI: oai:DiVA.org:umu-101397DiVA: diva2:839547
Available from: 2015-07-03 Created: 2015-03-30 Last updated: 2017-12-04Bibliographically approved

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Forestier, Erik

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