Abstract 2351: Transcriptome-wide association study reveals candidate causal genes for lung cancer

Abstract

Abstract Genome-wide association studies have identified robust susceptibility loci associated with lung cancer. As part of the OncoArray-TRICL consortium, we have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of this study is to integrate the complete GWAS results with a large-scale expression quantitative trait loci (eQTL) mapping study in human lung tissues (n=1,038) to identify candidate causal genes for lung cancer. Transcriptome-wide association study (TWAS) was used to integrate GWAS and lung eQTL signals and identify genes whose levels of expression in lung tissue are causally related to lung cancer. TWAS was performed on six histologic and smoking subgroups, namely overall lung cancer, adenocarcinoma, squamous cell carcinoma, small cell carcinoma, never-smokers, and ever-smokers. As expected, the main TWAS signal for all histologic subtypes and ever-smokers was on chromosome 15q25. The genes most strongly associated with lung cancer at this locus were IREB2 (PTWAS=4.97E-104), and to a lower extent, CHRNA5 (PTWAS=5.26E20) and HYKK (PTWAS=2.04E-17). TWAS identified causal genes were different from those reported in GWAS, including JAML on 11q23.3 in overall lung cancer (PTWAS=1.39E-6) and adenocarcinoma (PTWAS=2.09E-8), NOTCH4 on 6p21.32 in squamous cell carcinoma (PTWAS=1.24E-12), ZNRD1 on 6p22.1 in overall lung cancer (PTWAS=3.41E-14) and ever-smokers (PTWAS=1.29E-9), HIST1H2BD on 6p22.2 for small cell carcinoma (PTWAS=1.54E-6), and NEXN on 1p31.1 in never-smokers (PTWAS=2.64E-5). In addition, a new small cell carcinoma susceptibility locus was identified on 4q32.2 and associated with the expression levels of TMA16 (PTWAS=4.2E-6). In conclusion, lung tissue TWAS on lung cancer, histologic subtypes and smoking subgroups revealed novel causal genes in GWAS-nominated loci. A new locus for small cell carcinoma (4q32.2-TMA16) was also identified and will require further validation. Citation Format: Alisson Clemenceau, Maxime Lamontagne, Robert Carreras Torres, Ma'en Obeidat, Wim Timens, Philippe Joubert, Christopher I. Amos, James D. McKay, Yohan Bossé. Transcriptome-wide association study reveals candidate causal genes for 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 2351.