The association of genetic variations in DNA repair pathways with severe toxicities in NSCLC patients undergoing platinum-based chemotherapy

Abstract

Genetic variations in genes involved in repairing platinum-induced DNA lesions may contribute to the toxicity of platinum-based chemotherapy. The role of single nucleotide polymorphisms (SNPs) within DNA repair pathways in the occurrence of severe toxicity is not yet understood. Current studies prefer to do original works rather than analyze previously published data. Our study aimed to replicate associations between previously investigated SNPs and toxicities as well as to identify new genetic makers. We systematically examined the relevance of 97 SNPs in 54 candidate genes responsible for repairing DNA inter-strand and intra-strand crosslinks to severe toxicity in a discovery cohort of 437 NSCLC patients receiving platinum-based chemotherapy. Statistically significant SNPs were then assessed for replication in an independent validation cohort of 781 NSCLC patients. We found that 7 SNPs were significant at P<0.01 (RRM1 rs12806698, XPC rs2228000, XPF rs1799801, hMLH1 rs1800734, PMS2 rs1062372, REV3L rs462779, and FANCC rs4647554) in the discovery cohort. Among them, two SNPs (RRM1 rs12806698 and hMLH1 rs1800734) remained significant after Bonferroni correction. XPC rs2228000 showed a significant relationship with gastrointestinal toxicity in the validation cohort. When the two cohorts were combined, XPC rs2228000 presented better tolerance of severe hematologic toxicity, gastrointestinal toxicity and leukopenia (OR=0.677, 95% CI: 0.510-0.899, P=0.007; OR=0.565, 95% CI: 0.368-0.869, P=0.009; and OR=0.628, 95% CI: 0.439-0.899, P=0.011, respectively). Our findings can offer comprehensive pharmacogenetic information for platinum-induced toxicities. This article is protected by copyright. All rights reserved.

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