Journal article
Genomic profiling of thousands of candidate polymorphisms predicts risk of relapse in 778 Danish and German childhood acute lymphoblastic leukemia patients
Department of Systems Biology, Technical University of Denmark1
Integrative Systems Biology, Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark2
Functional Human Variation, Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark3
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark4
Copenhagen University Hospital Herlev and Gentofte5
DTU Multi Assay Core, Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark6
Odense University Hospital7
University of Copenhagen8
Aarhus University Hospital9
Heidelberg University 10
Metagenomics, Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark11
...and 1 moreChildhood 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 singlenucleotide 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 riskbased treatments adaptation.
Language: | English |
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Publisher: | Nature Publishing Group |
Year: | 2015 |
Pages: | 297-303 |
ISSN: | 14765551 and 08876924 |
Types: | Journal article |
DOI: | 10.1038/leu.2014.205 |
ORCIDs: | Gupta, Ramneek |