Abstract 238: Interaction analysis between germline susceptibility loci and somatic alterations in lung cancer

Abstract

Abstract Emerging evidence indicates that germline variations may interact with somatic events in carcinogenesis. However, the germline-somatic interaction in lung cancer remains largely unknown. In the present study, we investigated whether lung cancer driver genes (CDGs) were more likely to locate within cancer susceptibility regions. Additional pathway enrichment analysis was performed to identify common pathways underlying CDGs and cancer susceptibility genes (CSGs). Next, we analyzed the associations between lung cancer risk SNPs and somatic alterations, including mutations and copy number alterations, in the level of genes, pathways, and overall burden of alterations. Enrichment analysis showed that lung CDGs are more likely to locate within cancer susceptibility regions (P = 8.40×10-3). Both of lung CSGs and CDGs showed significant enrichment in pathways such as cell cycle and p53 signaling pathway. Gene-based analysis showed that rs36600 (22q12.2) was associated with somatic mutations within ARID1A (OR = 2.45, 95%CI: 1.47-4.08, P = 5.78×10-4). Pathway-based analysis identified rs2395185 and rs3817963 at 6p22.1 were associated with somatic truncation mutations in cell cycle pathway (OR = 1.56, P = 3.61×10-4 for rs2395185; OR = 1.58, P = 4.15×10-4 for rs3817963), and rs3817963 was also associated with somatic truncation mutations in MAPK signaling pathway (OR = 1.54, P = 8.58×10-4). Further analysis associated rs2395185 at 6p22.1 (HLA class II genes) with increased APOBEC3A expression (P = 9.50×10-3) and elevated APOBEC mutagenesis (P = 3.58×10-3). These results provide evidence for the germline-somatic interactions on lung tumorigenesis. This can help to uncover the molecular mechanisms by which risk SNPs influence lung cancer risk. Citation Format: Yuzhuo Wang, Cheng Wang, Meng Zhu, Guangfu Jin, Hongbing Shen. Interaction analysis between germline susceptibility loci and somatic alterations in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 238.