Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia.

Abstract

Pediatric acute lymphoblastic leukemia (ALL) is the prototype for a drug-responsive malignancy. Although cure rates exceed 80%, considerable unexplained interindividual variability exists in treatment response. To assess the contribution of inherited genetic variation to therapy response and to identify germline single-nucleotide polymorphisms (SNPs) associated with risk of minimal residual disease (MRD) after remission induction chemotherapy. Genome-wide interrogation of 476,796 germline SNPs to identify genotypes that were associated with MRD in 2 independent cohorts of children with newly diagnosed ALL: 318 patients in St Jude Total Therapy protocols XIIIB and XV and 169 patients in Children's Oncology Group trial P9906. Patients were enrolled between 1994 and 2006 and last follow-up was in 2006. Minimal residual disease at the end of induction therapy, measured by flow cytometry. There were 102 SNPs associated with MRD in both cohorts (median odds ratio, 2.18; P < or = .0125), including 5 SNPs in the interleukin 15 (IL15) gene. Of these 102 SNPs, 21 were also associated with hematologic relapse (P < .05). Of 102 SNPs, 21 were also associated with antileukemic drug disposition, generally linking MRD eradication with greater drug exposure. In total, 63 of 102 SNPs were associated with early response, relapse, or drug disposition. Host genetic variations are associated with treatment response for childhood ALL, with polymorphisms related to leukemia cell biology and host drug disposition associated with lower risk of residual disease.