PMID- 24990611 OWN - NLM STAT- MEDLINE DCOM- 20150406 LR - 20211021 IS - 1476-5551 (Electronic) IS - 0887-6924 (Print) IS - 0887-6924 (Linking) VI - 29 IP - 2 DP - 2015 Feb TI - Genomic profiling of thousands of candidate polymorphisms predicts risk of relapse in 778 Danish and German childhood acute lymphoblastic leukemia patients. PG - 297-303 LID - 10.1038/leu.2014.205 [doi] AB - 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. FAU - Wesolowska-Andersen, A AU - Wesolowska-Andersen A AD - Center for Biological Sequence Analysis, Technical University of Denmark, Kgs. Lyngby, Denmark. FAU - Borst, L AU - Borst L AD - Pediatrics and Adolescent Medicine, The Juliane Marie Centre, The University Hospital Rigshospitalet, Copenhagen, Denmark. FAU - Dalgaard, M D AU - Dalgaard MD AD - Center for Biological Sequence Analysis, Technical University of Denmark, Kgs. Lyngby, Denmark. FAU - Yadav, R AU - Yadav R AD - Center for Biological Sequence Analysis, Technical University of Denmark, Kgs. Lyngby, Denmark. FAU - Rasmussen, K K AU - Rasmussen KK AD - Pediatrics and Adolescent Medicine, The Juliane Marie Centre, The University Hospital Rigshospitalet, Copenhagen, Denmark. FAU - Wehner, P S AU - Wehner PS AD - Department of Pediatric Hematology and Oncology, HC Andersen Children's Hospital, Odense University Hospital, Odense, Denmark. FAU - Rasmussen, M AU - Rasmussen M AD - Centre for GeoGenetics, Natural History Museum of Denmark, The University of Copenhagen, Copenhagen, Denmark. FAU - Orntoft, T F AU - Orntoft TF AD - Institute of Clinical Medicine, Arhus University Hospital, Arhus, Denmark. FAU - Nordentoft, I AU - Nordentoft I AD - Institute of Clinical Medicine, Arhus University Hospital, Arhus, Denmark. FAU - Koehler, R AU - Koehler R AD - Department of Human Genetics, University of Heidelberg, Heidelberg, Germany. FAU - Bartram, C R AU - Bartram CR AD - Department of Human Genetics, University of Heidelberg, Heidelberg, Germany. FAU - Schrappe, M AU - Schrappe M AD - Department of General Pediatrics, University Medical Center Schleswig-Holstein, Kiel, Germany. FAU - Sicheritz-Ponten, T AU - Sicheritz-Ponten T AD - Center for Biological Sequence Analysis, Technical University of Denmark, Kgs. Lyngby, Denmark. FAU - Gautier, L AU - Gautier L AD - Center for Biological Sequence Analysis, Technical University of Denmark, Kgs. Lyngby, Denmark. FAU - Marquart, H AU - Marquart H AD - Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany. FAU - Madsen, H O AU - Madsen HO AD - Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany. FAU - Brunak, S AU - Brunak S AD - Center for Biological Sequence Analysis, Technical University of Denmark, Kgs. Lyngby, Denmark. FAU - Stanulla, M AU - Stanulla M AD - Department of Clinical Immunology, Diagnostic Centre, The University Hospital Rigshospitalet, Copenhagen, Denmark. FAU - Gupta, R AU - Gupta R AD - Center for Biological Sequence Analysis, Technical University of Denmark, Kgs. Lyngby, Denmark. FAU - Schmiegelow, K AU - Schmiegelow K AD - 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. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140703 PL - England TA - Leukemia JT - Leukemia JID - 8704895 SB - IM MH - Adolescent MH - Child MH - Child, Preschool MH - Denmark MH - Female MH - Genome, Human MH - Genomics MH - Genotype MH - Germany MH - Humans MH - Infant MH - Male MH - Neoplasm Recurrence, Local/*diagnosis/*genetics MH - Neoplasm, Residual/genetics MH - *Polymorphism, Genetic MH - Polymorphism, Single Nucleotide MH - Precursor Cell Lymphoblastic Leukemia-Lymphoma/*diagnosis/*genetics MH - Risk Factors MH - Treatment Outcome PMC - PMC4320289 EDAT- 2014/07/06 06:00 MHDA- 2015/04/07 06:00 CRDT- 2014/07/04 06:00 PHST- 2014/04/16 00:00 [received] PHST- 2014/06/14 00:00 [revised] PHST- 2014/06/17 00:00 [accepted] PHST- 2014/07/04 06:00 [entrez] PHST- 2014/07/06 06:00 [pubmed] PHST- 2015/04/07 06:00 [medline] AID - leu2014205 [pii] AID - 10.1038/leu.2014.205 [doi] PST - ppublish SO - Leukemia. 2015 Feb;29(2):297-303. doi: 10.1038/leu.2014.205. Epub 2014 Jul 3.