Genome-wide association study identifies germline polymorphisms associated with relapse of childhood acute lymphoblastic leukemia

Abstract

With the use of risk-directed therapy for childhood acute lymphoblastic leukemia (ALL), outcome has improved dramatically in the past 40 years. However, a substantial portion of patients, many of whom have no known risk factors, experience relapse. Taking a genome-wide approach, in the present study, we evaluated the relationships between genotypes at 444 044 single nucleotide polymorphisms (SNPs) with the risk of relapse in 2535 children with newly diagnosed ALL after adjusting for genetic ancestry and treatment regimen. We identified 134 SNPs that were reproducibly associated with ALL relapse. Of 134 relapse SNPs, 133 remained prognostic after adjusting for all known relapse risk factors, including minimal residual disease, and 111 were significant even among patients who were negative for minimal residual disease after remission induction therapy. The C allele at rs7142143 in the PYGL gene was associated with 3.6-fold higher risk of relapse than the T allele (P = 6.7 × 10(-9)). Fourteen of the 134 relapse SNPs, including variants in PDE4B and ABCB1, were also associated with antileukemic drug pharmacokinetics and/or pharmacodynamics. In the present study, we systematically identified host genetic variations related to treatment outcome of childhood ALL, most of which were prognostic independent of known risk factors for relapse, and some of which also influenced outcome by affecting host dis-position of antileukemic drugs. All trials are registered at www.clinicaltrials.gov or www.cancer.gov (COG P9904: NCT00005585; COG P9905: NCT00005596; COG P9906: NCT00005603; St Jude Total XIIIB: NCI-T93-0101D; and St Jude Total XV: NCT00137111).

Figure 1

Iterative resampling approach to identify 134 SNPs reproducibly associated with ALL relapse. A total of 2535 children with newly diagnosed ALL were split into a discovery and a validation cohort at a 1:1 ratio with balanced representation of treatment and clinical features. GWAS was performed on the discovery cohort and then on filtered SNPs based on replication in the remaining patients (replication cohort). Resampling was performed for 100 iterations and 134 SNPs were selected as “relapse SNPs” because they were successfully replicated in multiple rounds of resampling. Ip indicates information profiling (see “GWAS for germline SNP genotypes related to risk of relapse”).

Figure 2

Association of genotypes at the PYGL SNP (rs7142143) with the risk of ALL relapse. The cumulative incidence of any relapse was compared for each genotype group at rs7142143 (CC/CT or TT) in all patients (A) and in those patients negative for MRD at the end of remission induction (B). The P value was estimated using the Fine and Gray hazard regression model.

Figure 3

An example of relapse-associated SNPs affecting pharmacokinetics and pharmacodynamics of antileukemic agents. Genotype at ABCB1 SNP rs10264856 is associated with both ALL relapse (A) and dexamethasone apparent oral plasma clearance (B). Note that the C allele is linked to lower dexamethasone clearance and also lower cumulative incidence of relapse. The association of SNP genotype with clearance and with relapse was estimated by linear regression and the Fine and Gray hazard regression model, respectively. Dexamethasone clearance was determined in St Jude Total XV protocol at week 7 of continuation therapy, which is shown for those in the standard-/high-risk arm.