Abstract
Abstract Background: Emerging evidence has shown that genetic factors can interact with host factors to influence patient's clinical outcomes. Inflammatory biomarkers have been identified as prognostic factors independent of tumor stage. To test the hypothesis that genetic variants in inflammation-related genes may modulate clinical outcome in non-small cell lung cancer (NSCLC) patients, we conducted a three-stage study, including an initial discovery phase and two validation phases. Methods: In the discovery phase, we analyzed the association between 19,458 SNPs in inflammation-related genes and SNPs from GWAS risk analysis, and clinical outcomes in 1,408 NSCLC patients. In the validation phases, the significant SNPs (p<0.05) were first validated in an additional 1,104 NSCLC patients from MD Anderson and then validated in 978 NSCLC patients from Harvard University. Meta-analysis was used to summarize the combined effect of each SNP in all three stages. Results: A total of 16 SNPs were identified as top candidate predictors of respective outcomes after showing consistent associations in all three stages. Among them, 5 SNPs were associated with overall survival in the entire populations. The most significant SNP is located on chromosome 6 (discovery: HR=1.49, 95%CI=1.10-2.01, P=0.010; combined validation: HR=1.45, 95%CI=1.17-1.78, P=0.001; all combined: HR=1.46, 95% CI=1.23-1.73, P=1.59×10-5). Five SNPs were associated with overall survival in late stage unresectable patients receiving chemotherapy. The most significant SNP, located on chromosome 13, consistently showed increased risk of death in all three phases (discovery: HR=1.40, 95%CI=1.09-1.81, P=0.010; combined validation: HR=1.36, 95%CI=1.14-1.63, P=0.001; all combined: HR=1.37, 95% CI=1.19-1.59, P=2.26×10-5). Six SNPs were consistently associated with progression in early stage patient receiving surgery only. The top SNP was on chromosome 1 with protective effect against developing progression in all three phases (discovery: HR=0.52, 95%CI=0.32-0.86, P=0.033; combined validation: HR=0.63, 95%CI=0.49-0.82, P=0.001; all combined: HR=0.62, 95% CI=0.5-0.79, P=5.47×10-5). To our knowledge, this is the first study to systematically evaluate the association of genetic variations in major inflammation genes and NSCLC patients’ clinical outcomes with a multi-stage design using two of the largest lung studies in the US. Our study provides evidence that genetic variations in inflammation genes may affect clinical outcomes in NSCLC patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4662. doi:10.1158/1538-7445.AM2011-4662
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