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Int J Cancer. 2017 Dec 1;141(11):2336-2347. doi: 10.1002/ijc.30921. Epub 2017 Aug 22.

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

Zheng Y1,2,3, Deng Z4, Yin J1,2, Wang S5, Lu D5, Wen X3, Li X6, Xiao D6, Hu C4, Chen X7, Zhang W1,2, Zhou H1,2, Liu Z1,2.

Author information

1
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, People's Republic of China.
2
Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, 410078, People's Republic of China.
3
Key Laboratory of Hunan Province for Traditional Chinese Medicine in Obstetrics and Gynecology Research, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, 410008, People's Republic of China.
4
Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China.
5
State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, 20000, People's Republic of China.
6
Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, 410008, People's Republic of China.
7
Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China.

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 and to identify new genetic makers. We systematically examined the relevance of 97 SNPs in 54 candidate genes responsible for repairing DNA interstrand and intrastrand cross-links 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 severe 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; OR = 0.628, 95% CI: 0.439-0.899, p = 0.011, respectively). Our findings can offer comprehensive pharmacogenetic information for platinum-induced toxicities.

KEYWORDS:

DNA repair pathway; lung cancer; platinum; single nucleotide polymorphism; toxicity

PMID:
28791697
DOI:
10.1002/ijc.30921
[Indexed for MEDLINE]

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