Gene‐Gene Interactions of Gemcitabine Metabolizing‐Enzyme Genes hCNT3 and WEE1 for Preventing Severe Gemcitabine‐Induced Hematological Toxicity

Abstract

Most patients experience severe hematological toxicity during treatment with gemcitabine; thus, preventing such toxicity would improve the treatment effects and patient quality of life. We analyzed 13 polymorphisms in the transporters, metabolizing enzymes, targets, and genes involved in DNA damage and the folate pathway among 132 patients treated with gemcitabine and studied their association with the severity of the hematological toxicities. Single‐locus analysis showed that the single‐nucleotide polymorphisms (SNPs) RRM1 rs12806698 and rs11031918 and DCTD rs7663494 were significantly associated with severe neutropenia, hENT1 rs760370 and hCNT3 rs7867504 and rs4877831 were associated with severe leukopenia, CDA rs2072671, DCTD rs7663494, and WEE1 rs3910384 were associated with severe anemia, and MTHFR rs1801133 was associated with severe thrombocytopenia after stringent Bonferroni correction (P < .0038). The gene‐gene interaction analysis identified the overall best models, including a 2‐way interaction model (hCNT3 rs7867504 and dCK rs12648166) for severe leukopenia (P = .0022) and a 3‐locus model (CDA rs207671, DCTD rs7663494, and WEE1 rs3910384) for severe anemia with a strong synergistic effect (P = .0001). The association with hematological toxicity was further strengthened by the results of a haplotype analysis, in which the homozygous genotype combination of rs3910384 CC, rs2072671 AA, rs12648166 GG, rs7867504 CC, and rs7663494 TT conferred high genetic susceptibility to severe thrombocytopenia. Our results suggest that the gene‐gene interaction of gemcitabine metabolic pathway genes and WEE1 contributes to susceptibility to gemcitabine‐induced hematological toxicity. Moreover, we propose a promising data‐mining analysis approach (generalized multifactor dimensionality reduction) to detect and characterize gene‐gene interactions.