A Large-Scale Exome-Wide Association Study Identifies Novel Germline Mutations in Lung Cancer

Rationale: Genome-wide association studies have identified common variants of lung cancer. However, the contribution of rare exome-wide variants, especially protein-coding variants, to cancers remains largely unexplored. Objectives: To evaluate the role of human exomes in genetic predisposition to lung cancer. Methods: We performed exome-wide association studies to detect the association of exomes with lung cancer in 30,312 patients and 652,902 control subjects. A scalable and accurate implementation of a generalized mixed model was used to detect the association signals for loss-of-function, missense, and synonymous variants and gene-level sets. Furthermore, we performed association and Bayesian colocalization analyses to evaluate their relationships with intermediate exposures. Measurements and Main Results: We systematically analyzed 216,739 single-nucleotide variants in the human exome. The loss-of-function variants exhibited the most notable effects on lung cancer risk. We identified four novel variants, including two missense variants (rs202197044TET3 [Pmeta (P values of meta-analysis) = 3.6031028] and rs202187871POT1 [Pmeta= 2.2131028]) and two synonymous variants (rs7447927TMEM173 [Pmeta= 1.3231029] and rs140624366ATRN [Pmeta= 2.9731029]). rs202197044TET3 was significantly associated with emphysema (odds ratio, 3.55; Pfdr = 0.015), whereas rs7447927POT1 was strongly associated with telomere length (b = 1.08; Pfdr (FDR corrected P value) = 3.76310253). Functional evidence of expression of quantitative trait loci, splicing quantitative trait loci, and isoform expression was found for the four novel genes. Gene-level association tests identified several novel genes, including POT1 (protection of telomeres 1), RTEL1, BSG, and ZNF232. Conclusions: Our findings provide insights into the genetic architecture of human exomes and their role in lung cancer predisposition.

Automated summary

This study aimed to evaluate the contribution of rare exome-wide variants to lung cancer. Their findings demonstrated that loss-of-function variants in the exome had the most notable effects on lung cancer risk. They also identified four novel variants and found associations between these variants and intermediate exposures. These findings provide important insights into the role of exome genetics in lung cancer predisposition.