Comprehensive genetic analysis of cytarabine sensitivity in a cell-based model identifies polymorphisms associated with outcome in AML patients

Awhole-genome approach was used to investigate the genetic determinants of cytarabineinduced cytotoxicity. We performed a meta-analysis of genome-wide association studies involving 523 lymphoblastoid cell lines (LCLs) from individuals of European, African, Asian, and African American ancestry. Several of the highest-ranked single-nucleotide polymorphisms (SNPs) were within the mutated in colorectal cancers (MCC) gene. MCC expression was induced by cytarabine treatment from1.7- to 26.6-fold in LCLs.A total of 33 SNPs ranked at the top of the meta-analysis (P < 10^-5) were successfully tested in a clinical trial of patients randomized to receive low-dose or high-dose cytarabine plus daunorubicin and etoposide; of these, 18 showed association (P < .05) with either cytarabine 50% inhibitory concentration in leukemia cells or clinical response parameters (minimal residual disease, overall survival (OS), and treatment-relatedmortality). This count (n518) was significantly greater than expected by chance (P5 .016). For rs1203633, LCLs with AA genotype weremore sensitive to cytarabine-induced cytotoxicity (P 5 1.31310⁶) andAA (vs GA or GG) genotype was associated with poorer OS (P 5 .015), likely as a result of greater treatment-related mortality (P 5 .0037) in patients with acute myeloid leukemia (AML). This multicenter AML02 study trial was registered at www.clinicaltrials.gov as #NCT00136084.