Genomic profiling of thousands of candidate polymorphisms predicts risk of relapse in 778 Danish and German childhood acute lymphoblastic leukemia patients
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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. / Wesołowska-Andersen, A; Borst, L; Dalgaard, M D; Yadav, R; Rasmussen, K K; Wehner, P S; Rasmussen, Morten; Ørntoft, T F; Nordentoft, I; Koehler, R; Bartram, C R; Schrappe, M; Sicheritz-Ponten, T; Gautier, L; Marquart, H; Madsen, H O; Brunak, S; Stanulla, M; Gupta, R; Schmiegelow, K.
I: Leukemia, Bind 29, Nr. 2, 2015, s. 297-303.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Genomic profiling of thousands of candidate polymorphisms predicts risk of relapse in 778 Danish and German childhood acute lymphoblastic leukemia patients
AU - Wesołowska-Andersen, A
AU - Borst, L
AU - Dalgaard, M D
AU - Yadav, R
AU - Rasmussen, K K
AU - Wehner, P S
AU - Rasmussen, Morten
AU - Ørntoft, T F
AU - Nordentoft, I
AU - Koehler, R
AU - Bartram, C R
AU - Schrappe, M
AU - Sicheritz-Ponten, T
AU - Gautier, L
AU - Marquart, H
AU - Madsen, H O
AU - Brunak, S
AU - Stanulla, M
AU - Gupta, R
AU - Schmiegelow, K.
PY - 2015
Y1 - 2015
N2 - 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.
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.
KW - Adolescent
KW - Child
KW - Child, Preschool
KW - Denmark
KW - Female
KW - Genome, Human
KW - Genomics
KW - Genotype
KW - Germany
KW - Humans
KW - Infant
KW - Male
KW - Neoplasm Recurrence, Local
KW - Neoplasm, Residual
KW - Polymorphism, Genetic
KW - Polymorphism, Single Nucleotide
KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma
KW - Risk Factors
KW - Treatment Outcome
U2 - 10.1038/leu.2014.205
DO - 10.1038/leu.2014.205
M3 - Journal article
C2 - 24990611
VL - 29
SP - 297
EP - 303
JO - Leukemia
JF - Leukemia
SN - 0887-6924
IS - 2
ER -
ID: 152246116