DNA methylation-based subtype prediction for pediatric acute lymphoblastic leukemia

Clinical Epigenetics

Ann-Christine Syvänen⁹  Erik Forestier^1,11  Gudmar Lönnerholm⁶  Mats G Gustafsson⁴  Kjeld Schmiegelow⁷  Josefine Palle⁶  Rolf Larsson⁴  Jukka Kanerva^1,12  Ólafur G Jónsson⁵  Mats M Heyman²  Trond Flaegstad⁸  Jonas Abrahamsson³  Elin Övernäs⁹  Ann Nordgren^1,10  Gisela Barbany^1,10  Ingegerd Öfverholm^1,10  Johan Dahlberg⁹  Lucia Cavelier¹  Vasilios Zachariadis^1,10  Christofer L Bäcklin⁴  Jessica Nordlund⁹ 

[1] Department of Immunology, Genetics and Pathology, Uppsala University, Rudbecklaboratoriet, Uppsala, SE-751 85, Sweden;Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden;Department of Pediatrics, Queen Silvia Children’s Hospital, Gothenburg, SE-416 85, Sweden;Department of Medical Sciences, Cancer Pharmacology and Computational Medicine, Uppsala University, Uppsala University Hospital, Uppsala, SE-751 85, Sweden;Pediatric Hematology-Oncology, Children’s Hospital, Barnaspitali Hringsins, Landspitali University Hospital, Reykjavik, Iceland;Department of Women’s and Children’s Health, Pediatric Oncology, Uppsala University, Uppsala University Hospital, Uppsala, SE-751 85, Sweden;Pediatrics and Adolescent Medicine, Rigshospitalet, and the Medical Faculty, Institute of Clinical Medicine, University of Copenhagen, Copenhagen, DK-2100, Denmark;Department of Pediatrics, Tromsø University and University Hospital, Tromsø, N-9038, Norway;Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, SE-751 44, Sweden;Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, SE-171 76, Sweden;Department of Medical Biosciences, University of Umeå, Umeå, SE-901 85, Sweden;Division of Hematology-Oncology and Stem Cell Transplantation, Children’s Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, FIN-00029, Finland

关键词: epigenetics;    k array;    450 ;    RNA-seq;    Cytogenetics;    Subtyping;    CpG site;    Pediatric acute lymphoblastic leukemia;    DNA methylation;   

Others  :  1147927
DOI  :  10.1186/s13148-014-0039-z

 received in 2014-09-26, accepted in 2014-12-18,  发布年份 2015

【 摘 要 】

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 ~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.

【 授权许可】

   
2015 Nordlund et al.; licensee Biomed Central.

【 图 表 】

Figure 1.

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