Abstract 1275: Genetic variations in cancer-related significantly mutated genes and lung cancer susceptibility

Abstract

Abstract Cancer initiation and development are driven by key mutations in driver genes. Applying high-throughput sequencing technologies and bioinformatics analyses, The Cancer Genome Atlas (TCGA) project has recently identified panels of genetic mutations that contributed to or associated with the etiology of various cancers. However, there are few studies investigating the germline genetic variations in these highly mutated genes and lung cancer susceptibility. In this multi-phase study, we aimed to comprehensively evaluate the 1655 tagSNPs located in the 127 significantly mutated genes (SMGs) identified by TCGA, and test their association with risk of lung cancer in a total of 7355 patients and 7301 healthy controls. We found that 11 SNPs in 8 genes showed consistent association (P<0.1) and 8 SNPs significantly associated with lung cancer risk (P<0.05) in both discovery and validation phases. The most significant SNP A was associated with a decreased risk of lung cancer (OR=0.91, 95%CI: 0.87-0.96, P=2.3×10-4). Cumulative analysis of the 11 SNPs showed consistently elevated risk with increasing number of unfavorable genotypes (P for trend=1.2×10-10). In stratified analyses, the association of SNP A and lung cancer risk appeared stronger among population of younger age at diagnosis and never smokers. The eQTL-analysis indicated that genotypes of four SNPs significantly correlated with the expression of their genes respectively. From TCGA data, expression of the identified genes were significantly different in lung tumors compared with normal tissues, and the genes’ highest mutation frequency was found in lung cancers. Integrative pathway analysis (IPA) indicated the identified genes were mainly involved in major cell cycle regulatory pathway suggesting the underlying biological processes. In summary, this study revealed novel genetic variants in SMGs associated with lung cancer risk, which might contribute to elucidating the biological network involved in lung cancer development. Citation Format: Liren Zhang, Yanwei Zhang, Rong Li, David W. Chang, Yuanqing Ye, John D. Minna, Jack A. Roth, Baohui Han, Xifeng Wu. Genetic variations in cancer-related significantly mutated genes and lung cancer susceptibility [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1275. doi:10.1158/1538-7445.AM2017-1275