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.
Using a genome-wide approach, 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.
Design, Setting, and Patients
We performed a genome-wide interrogation of 476,796 germline SNPs to identify genotypes that predicted MRD in two independent cohorts of children with newly diagnosed ALL: 318 patients on St. Jude trials Total XIIIB and XV and 169 patients on a Children’s Oncology Group (COG) trial P9906.
Main Outcome Measures
MRD at the end of induction therapy, measured by flow cytometry.
There were 102 SNPs associated with MRD in both cohorts (P≤0.0125), including 5 SNPs in the interleukin 15 (IL15) gene. A high proportion, 21 of these 102 SNPs, also predicted hematologic relapse (P<0.05). 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 also associated with early response, relapse, or with drug disposition.
Host genetic variability affected treatment response for childhood ALL, and germline variants may exert their effects on MRD by effects on leukemic cell biology and on host disposition of antileukemic drugs.