Common genetic variations in telomere length genes and lung cancer

Abstract

Background: Genome-wide association studies (GWAS) have identified genetic susceptibility variants for both leukocyte telomere length (LTL) and lung cancer susceptibility. Recently, 108 novel genetic loci within genes involved in telomere biology and DNA repair have been linked to LTL in UK Biobank. In the current work, we investigated the relationship between genetically predicted LTL and lung cancer. Methods: To explore the shared genetic basis between LTL and lung cancer, we performed genetic correlation, Mendelian Randomization (MR), and colocalisation analyses using the largest available GWASs of LTL (N=464,716) and lung cancer (29,239 cases; 56,450 controls). To further characterize the molecular mechanisms underlying this relationship, principal component analysis (PCA) was used to summarize gene expression profiles in lung adenocarcinoma tumours from The Cancer Genome Atlas. Results: Although there was no genome-wide genetic correlation between LTL and lung cancer risk (rg=-0.01, p=0.88), MR analyses using 144 instruments identified a putatively causal association. Longer LTL conferred an increased risk of lung cancer (OR=1.62, 95%CI=1.44-1.83, p=9.9x10-15), lung cancer in never smokers (OR=2.02, 95%CI=1.45-2.83, p=3.78x10-05), and lung adenocarcinoma (OR=2.43, 95%CI=2.02-2.92, p=3.8x10-21). Of these 144 LTL genetic instruments, 12 showed evidence of colocalisation with lung adenocarcinoma risk and revealed novel susceptibility loci, including MPHOSPH6 (rs2303262), PRPF6 (rs80150989), and POLI (rs2276182). A polygenic risk score for LTL was associated with the second principal component (PC2) of gene expression (Beta=0.17, p=1.0x10-3). The aspect of PC2 associated with longer LTL was also associated with being female (p=0.005), never smokers (p=0.04), and earlier tumour stage (p=0.002). PC2 was strongly associated with cell proliferation score (p=3.6x10-30) and genomic features related to genome stability, including copy number changes (p=1.6x10-5) and telomerase activity (p=1.3x10-5) in the multivariate regression analyses. Conclusions: This study identified an association between longer genetically predicted LTL and lung cancer and sheds light on the potential molecular mechanisms related to LTL in lung adenocarcinomas.