Genetic analysis of lung cancer reveals novel susceptibility loci and germline impact on somatic mutation burden

Abstract

Large international efforts are describing how germline variants influence susceptibility to lung cancer. We have undertaken a genome-wide association by proxy (GWAx) study of lung cancer in 48,843 proxy “cases” with a parent/sibling with lung cancer to 195,387 proxy controls without a family history of any cancer from the UK Biobank and meta-analysed the results with previously described GWA study results. 21 loci achieved genome-wide statistical significance, including 8 novel loci including expression quantitative trait loci (eQTLs) in DNA repair genes (CHEK1, MDM4) and metabolic genes (CYP1A1). This study also discovered loci associated with propensity to smoke, such as both subunits of a key element in nicotine response, the neuronal α4β2 nicotinic acetylcholine receptor. Polygenic risk scores (PRS) analysis of variants below genome-wide significant threshold in an independent lung cancer population demonstrated that variants related to eQTLs and/or smoking propensity are enriched for susceptibility variants. PRS of lung cancer variants related to propensity to smoke were associated with somatic mutation burden in matched tumours from the same patients, with individuals with higher polygenic genetic risk having increased mutation burden in two case cohorts. This study has expanded the number of susceptibility loci linked with lung cancer and provided insights into how the molecular mechanisms by which these susceptibility variants contribute to the development of lung cancer.TagsLung Cancer, GWAx, GWAS, Smoking, Cancer, CHRNA4, CHRNB2, Mutational Burden, CHEK1, MDM4, CYP1A1, α4β2 nicotinic acetylcholine receptor, Mutational Signatures, RP11-10O17.1

UGT1A1 Gene Polymorphism Contributes as a Risk Factor for Lung Cancer: A Pilot Study with Patients from the Amazon

“…Pulmonary carcinogenesis is a complex process, with interactions that modulate the potential risks for the disease [ 7 , 31 ]. Many studies have described how germline variants influence susceptibility to lung cancer, including those linked to smoking [ 32 , 33 , 34 ].…”

The Blood Proteome of Imminent Lung Cancer Diagnosis

“…With the advent of early detection by LDCT screening, a strong focus has been placed on lung cancer. A wide array of circulating biomarkers have been proposed, including germline gene variants, 27,28 microRNA, 29,30 epigenetic markers, 31 autoantibodies, 32 protein markers, 33,34 and circulating tumor DNA. 35 However, few have been independently validated, and none are widely used in screening.…”

Common genetic variations in telomere length genes and lung cancer

“…Analyses of molecular phenotypes were performed using 343 lung adenocarcinoma samples of European ancestry from The Cancer Genome Atlas (TGCA) cohort with both germline and RNA-sequencing data available. Genotyping and imputation of germline variants have been described elsewhere [21]. The total somatic mutation burden of TCGA samples were obtained from Ellrott et al, 2018 [22] and DNA mutational signatures were extracted and attributed, as previously described [21].…”

“…Genotyping and imputation of germline variants have been described elsewhere [21]. The total somatic mutation burden of TCGA samples were obtained from Ellrott et al, 2018 [22] and DNA mutational signatures were extracted and attributed, as previously described [21]. RNA-sequencing data were obtained from TCGA data portal using TCGAbiolinks package in R (version 2.22.3) [23].…”

“…Associations were estimated per standard deviation increase in the PRS, which was normalized to have a mean of zero across lung adenocarcinoma samples of European ancestry within the TCGA cohort. The associations between the eigenvalues of the gene expression principal components (outcome) and demographic, clinical, and genomic features related to genome stability (predictors derived from TCGA published papers and TCGA data portal, except for the DNA mutational signatures [21]), were calculated using a multivariate linear regression model.…”