Finding the Missing Heritability of Lung Cancer

Abstract

Globally, lung cancer has been the most common type of cancer diagnosed and the leading cause of death from cancer for several decades. There were an estimated 2.1 million new cases of lung cancer diagnosed (11.6% of all new cancer cases) and 1.8 million lung cancer deaths (18.4% of all cancer deaths) in 2018. The heritability of lung cancer has been estimated at 18%. Over the past decade, genome-wide association studies (GWAS) have successfully identified multiple loci that are associated with the disease and improved our understanding of genetic mechanisms to the disease. However, these variants only account for a small fraction of hereditability of lung cancer while a larger proportion of heritability remains unexplained. Therefore, to solve the problem of missing heritability in lung cancer, we propose the following research strategies: In Chapter 1, we conducted gene-set analyses (GSA) to test the joint effects of rare and common variants in 7,801 biological pathways using the OncoArray data of the TRICL-ILCCO consortium with 34,432 individuals. We identified 16 significant pathways using three GSA methods, including pathways related to nicotinic acetylcholine receptor activities and pathways involved interferon gamma signaling. We also observed striking heterogeneity in the genetic architecture of lung cancer by histological subtypes as well as by smoking status. These results shed light upon the underlying mechanism for disease etiology and provide novel insights for marker-guided cancer intervention and prevention strategies. In Chapter 2, we performed causal interaction and mediation analysis for cholinergic receptors nicotinic subunit (CHRN) genes, smoking, and lung cancer risk. We revealed that the CHRN genes increase lung cancer risk primarily through pathways unrelated to nicotine dependence and increasing smoking behaviors; however, tobacco control efforts targeting population with genetic susceptibility could effectively mitigate the total genetic effects due to substantial gene-smoking interaction. In Chapter 3, we analyzed the epigenome-wide 5-hydroxymethylcytosine (5hmC) profiles of paired tumor and adjacent normal tissues from patients with primary lung squamous cell carcinoma (LUSC), using the TET-Assisted Bisulfite (TAB) array - Infinium MethylationEPIC BeadChip (EPIC) approach. We observed global hypomethylation of 5hmC in lung cancers, and hypermethylated 5hmC enriched in CpG islands and gene upstream. We found that the genome-wide 5hmC levels do not correlate with the total methylation, and the gene set analysis suggested different biological functions of 5hmC compared to total methylation. Our results indicated the potential of 5hmC as a novel biomarker for lung cancer and demanded further work to validate differentially methylated loci for lung cancer diagnosis and prognosis as well as to explore the functional role of 5hmC in lung cancer etiology. Added together, the thesis tackles the problem of missing heritability in lung cancer from different angles and contribute to the understanding of the genetic mechanisms for lung cancer development.