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

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 ge...

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Hauptverfasser: Wesołowska, Agata (VerfasserIn) , Borst, L. (VerfasserIn) , Dalgaard, M. D. (VerfasserIn) , Yadav, R. (VerfasserIn) , Rasmussen, K. K. (VerfasserIn) , Wehner, P. S. (VerfasserIn) , Rasmussen, M. (VerfasserIn) , Ørntoft, T. F. (VerfasserIn) , Nordentoft, I. (VerfasserIn) , Köhler, Rolf (VerfasserIn) , Bartram, Claus R. (VerfasserIn) , Schrappe, M. (VerfasserIn) , Sicheritz-Ponten, T. (VerfasserIn) , Gautier, L. (VerfasserIn) , Marquart, H. (VerfasserIn) , Madsen, H. O. (VerfasserIn) , Brunak, S. (VerfasserIn) , Stanulla, M. (VerfasserIn) , Gupta, R. (VerfasserIn) , Schmiegelow, K. (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 2015
In: Leukemia
Year: 2014, Jahrgang: 29, Heft: 2, Pages: 297-303
ISSN:1476-5551
DOI:10.1038/leu.2014.205
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/leu.2014.205
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/leu2014205
Volltext
Verfasserangaben:A. Wesołowska-Andersen, L. Borst, M.D. Dalgaard, R. Yadav, K.K. Rasmussen, P.S. Wehner, M. Rasmussen, T.F. Ørntoft, I. Nordentoft, R. Koehler, C.R. Bartram, M. Schrappe, T. Sicheritz-Ponten, L. Gautier, H. Marquart, H.O. Madsen, S. Brunak, M. Stanulla, R. Gupta and K. Schmiegelow
Beschreibung
Zusammenfassung: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.
Beschreibung:advance online publication, 25 July 2014
Gesehen am 30.06.2020
Beschreibung:Online Resource
ISSN:1476-5551
DOI:10.1038/leu.2014.205

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