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Leukemia. 2015 Feb;29(2):297-303. doi: 10.1038/leu.2014.205. Epub 2014 Jul 3.

Genomic profiling of thousands of candidate polymorphisms predicts risk of relapse in 778 Danish and German childhood acute lymphoblastic leukemia patients.

Author information

1
Center for Biological Sequence Analysis, Technical University of Denmark, Kgs. Lyngby, Denmark.
2
Pediatrics and Adolescent Medicine, The Juliane Marie Centre, The University Hospital Rigshospitalet, Copenhagen, Denmark.
3
Department of Pediatric Hematology and Oncology, HC Andersen Children's Hospital, Odense University Hospital, Odense, Denmark.
4
Centre for GeoGenetics, Natural History Museum of Denmark, The University of Copenhagen, Copenhagen, Denmark.
5
Institute of Clinical Medicine, Århus University Hospital, Århus, Denmark.
6
Department of Human Genetics, University of Heidelberg, Heidelberg, Germany.
7
Department of General Pediatrics, University Medical Center Schleswig-Holstein, Kiel, Germany.
8
Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
9
Department of Clinical Immunology, Diagnostic Centre, The University Hospital Rigshospitalet, Copenhagen, Denmark.
10
1] Pediatrics and Adolescent Medicine, The Juliane Marie Centre, The University Hospital Rigshospitalet, Copenhagen, Denmark [2] Institute of Clinical Medicine, Faculty of Health and Medical Sciences, The University of Copenhagen, Copenhagen, Denmark.

Abstract

Childhood acute lymphoblastic leukemia survival approaches 90%. New strategies are needed to identify the 10-15% who evade cure. We applied targeted, sequencing-based genotyping of 25 000 to 34 000 preselected potentially clinically relevant single-nucleotide polymorphisms (SNPs) to identify host genome profiles associated with relapse risk in 352 patients from the Nordic ALL92/2000 protocols and 426 patients from the German Berlin-Frankfurt-Munster (BFM) ALL2000 protocol. Patients were enrolled between 1992 and 2008 (median follow-up: 7.6 years). Eleven cross-validated SNPs were significantly associated with risk of relapse across protocols. SNP and biologic pathway level analyses associated relapse risk with leukemia aggressiveness, glucocorticosteroid pharmacology/response and drug transport/metabolism pathways. Classification and regression tree analysis identified three distinct risk groups defined by end of induction residual leukemia, white blood cell count and variants in myeloperoxidase (MPO), estrogen receptor 1 (ESR1), lamin B1 (LMNB1) and matrix metalloproteinase-7 (MMP7) genes, ATP-binding cassette transporters and glucocorticosteroid transcription regulation pathways. Relapse rates ranged from 4% (95% confidence interval (CI): 1.6-6.3%) for the best group (72% of patients) to 76% (95% CI: 41-90%) for the worst group (5% of patients, P<0.001). Validation of these findings and similar approaches to identify SNPs associated with toxicities may allow future individualized relapse and toxicity risk-based treatments adaptation.

PMID:
24990611
PMCID:
PMC4320289
DOI:
10.1038/leu.2014.205
[Indexed for MEDLINE]
Free PMC Article

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