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

TY - JOUR

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 - 2015/2/7

Y1 - 2015/2/7

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

SN - 0887-6924

VL - 29

SP - 297

EP - 303

JO - Leukemia

JF - Leukemia

IS - 2

ER -