Associations of polymorphisms in DNA repair genes and MDR1 gene with chemotherapy response and survival of non-small cell lung cancer

PLoS One. 2014 Jun 16;9(6):e99843. doi: 10.1371/journal.pone.0099843. eCollection 2014.

Abstract

Objectives: We aimed to determine the associations of genetic polymorphisms of excision repair cross-complementation group 1 (ERCC1) rs11615, xeroderma pigmentosum group D (XPD/ERCC2) rs13181, X-ray repair cross complementing group 1 (XRCC1) rs25487, XRCC3 rs1799794, and breast cancer susceptibility gene 1 (BRCA1) rs1799966 from the DNA repair pathway and multiple drug resistance 1 (MDR1/ABCB1) rs1045642 with response to chemotherapy and survival of non-small cell lung cancer (NSCLC) in a Chinese population.

Materials and methods: A total of 352 NSCLC patients were enrolled to evaluate the associations of the six SNPs with response to chemotherapy and overall survival. Logistic regressions were applied to test the associations of genetic polymorphisms with response to chemotherapy in 161 advanced NSCLC patients. Overall survival was analyzed in 161 advanced and 156 early stage NSCLC patients using the Kaplan-Meier method with log-rank test, respectively. Multivariate Cox proportional hazards model was performed to determine the factors independently associated with NSCLC prognosis.

Results: BRCA1 rs1799966 minor allele C (TC+CC vs. TT, OR = 0.402, 95% CI = 0.204-0.794, p = 0.008) and MDR1/ABCB1 rs1045642 minor allele A (GA +AA vs. GG, OR = 0.478, 95% CI = 0.244-0.934, p = 0.030) were associated with a better response to chemotherapy in advanced NSCLC patients. Survival analyses indicated that BRCA1 rs1799966 TC+CC genotypes were associated with a decreased risk of death (HR = 0.617, 95% CI = 0.402-0.948, p = 0.028) in advanced NSCLC patients, and the association was still significant after the adjustment for covariates. Multivariate Cox regression analysis showed that ERCC1 rs11615 AA genotype (P = 0.020) and smoking (p = 0.037) were associated with increased risks of death in early stage NSCLC patients after surgery.

Conclusions: Polymorphisms of genes in DNA repair pathway and MDR1 could contribute to chemotherapy response and survival of patients with NSCLC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • Adult
  • Aged
  • Aged, 80 and over
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / surgery
  • DNA Repair / genetics*
  • DNA-Binding Proteins / genetics
  • Demography
  • Endonucleases / genetics
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / surgery
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Polymorphism, Single Nucleotide / genetics*
  • Survival Analysis

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • DNA-Binding Proteins
  • ERCC1 protein, human
  • Endonucleases

Grant support

This study was supported by Key Project of Shanghai Science and Technology Committee grant (06DZ19503 to G. Cao) and National Natural Science Foundation of China (81025015 to G. Cao). The funding agencies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.