A Decade of GWAS Results in Lung Cancer

Abstract

Genome-wide association studies (GWAS) were successful to identify genetic factors robustly associated with lung cancer. This review aims to synthesize the literature in this field and accelerate the translation of GWAS discoveries into results that are closer to clinical applications. A chronologic presentation of published GWAS on lung cancer susceptibility, survival, and response to treatment is presented. The most important results are tabulated to provide a concise overview in one read. GWAS have reported 45 lung cancer susceptibility loci with varying strength of evidence and highlighted suspected causal genes at each locus. Some genetic risk loci have been refined to more homogeneous subgroups of lung cancer patients in terms of histologic subtypes, smoking status, gender, and ethnicity. Overall, these discoveries are an important step for future development of new therapeutic targets and biomarkers to personalize and improve the quality of care for patients. GWAS results are on the edge of offering new tools for targeted screening in high-risk individuals, but more research is needed if GWAS are to pay off the investment. Complementary genomic datasets and functional studies are needed to refine the underlying molecular mechanisms of lung cancer preliminarily revealed by GWAS and reach results that are medically actionable.

Genetic modifiers of radon-induced lung cancer risk: a genome-wide interaction study in former uranium miners

“…Interestingly, no modification of risk was found across smoking categories or histological subtypes of LC (Bosse and Amos 2018; Sakoda et al 2011). Also, evidence exists that nAChRs can be directly associated with lung carcinogenesis owing to the complexity of nAChR function in the brain (Papke 2014).…”

“…We detected a genome-wide significant gene-radon interaction for marker rs12440014 ( p mt = 0.03856) located within the gene CHRNB4 on chromosome 15q25.1 , a well-known LC susceptibility region (Bosse and Amos 2018; Sakoda et al 2011). Previously this intronic marker was described as associated with LC (p=2.8×10 −52 ; OR=0.80; 95% CI: 0.78–0.83) in Caucasians (McKay et al 2017).…”

“…The most significant gene-radon interaction outside suspected LC susceptibility regions (Bosse and Amos 2018) was observed for UBE2U (1p21.3), a gene of the family of ubiquitin-conjugating enzymes UBE2, also known as E2 enzymes. The coded enzyme performs a central step in the ubiquitination reaction that targets a protein for degradation, a major factor for life and death of proteins (van Wijk and Timmers 2010).…”

“…5p15.33, 6p21–22 and 15q25 and further 42 LC susceptibility loci influence LC risk in European populations (Bosse and Amos 2018). In total 92 genes are postulated to be suspected causal genes for LC.…”

“…Although the strongest genetic association with an odds ratio (OR) of 7.2 was reported for 15q25 in a familial form of LC, for sporadic LC an OR of only ~1.3 was observed, albeit highly significant (p = 3.08 × 10 −103 ). However, “cumulative effects of loci have shown promising results to improve the discriminatory performance of risk prediction models”(Bosse and Amos 2018) Nevertheless, genes can be associated to several traits and contribute to the functional efficacy of multiple interlocked biological processes. One may assume that for example nicotine dependency or DNA repair play a role in an individual’s susceptibility to developing LC (Brennan et al 2011; Romero-Laorden and Castro 2017).…”