Prognostic implications of genetic variants in advanced non-small cell lung cancer: a genome-wide association study.

The prognostic significance of inherited genetic variants in advanced-stage non-small cell lung cancer (NSCLC) patients remains unknown. In this study, we genotyped 271 817 single-nucleotide polymorphisms in 348 advanced NSCLC patients who received chemotherapy and analyzed their association with prognosis by using Cox proportional hazard regression model adjusted for known prognostic factors. Top candidate single-nucleotide polymorphisms (SNPs) were selected using the bootstrap re-sampling procedure. Median age of patient population was 56 years. Proportions of female, never smokers and adenocarcinoma were 64.9, 67.5 and 80.4%, respectively. We identified 17 top candidate SNPs related to prognosis using cut-off minimum P value of <5.0 × 10(-5) in at least 70% of 1000 bootstrap samples. These SNPs were located in the genomic regions of the FAM154A, ANKS1A, DLST, THSD7B, NCOA2, CDH8, SLC35D2, NALCN and EGF genes. The most significant SNP, rs1571228 (9p22.1:FAM154A), was significantly associated with overall survival in dominant model [AG+GG to AA, hazard ratio (HR) of death (95% CI) = 0.53 (0.42-0.67); P = 2.025 × 10(-7)]. The SNP at 4q25:EGF, rs11098063, for which some genetic variations was previously reported to be associated with prognosis, also showed significant association with overall survival in additive model [CC versus CT versus TT, HR (95% CI) = 1.00 versus 0.61 (0.47-0.78) versus 0.39 (0.19-0.79); P = 9.582 × 10(-6)]. Survival differences according to the genotype of these SNPs were independent of sex, smoking, histology and chemotherapy regimens. These results suggested the variants at multiple genetic loci might contribute to the risk of death in advanced NSCLC patients receiving chemotherapy.