Common genetic variations in telomere length genes and lung cancer

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=9.9×10−15), lung cancer in never smokers (OR=2.02, 95%CI=1.45-2.83, p=3.78×10−05), and lung adenocarcinoma (OR=2.43, 95%CI=2.02-2.92, p=3.8×10−21). 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=1.0×10−3). 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=3.6×10−30) and genomic features related to genome stability, including copy number changes (p=1.6×10−5) and telomerase activity (p=1.3×10−5) 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the Institut National du Cancer (INCa) (GeniLuc 2017-1-TABAC-03-CIRC-1 - [TABAC 17‐022], NIH/NCI, INTEGRAL NIH 5U19CA203654-03, Cancer Research UK [grant number C18281/A29019], the France Genomique National infrastructure (contract ANR-10-INBS-09). Christopher Amos is a Research Scholar of the Cancer Prevention Institute of Texas and supported by RR170048. The work of Ricardo Cortez Cardoso Penha reported in this paper was undertaken during the tenure of an IARC Postdoctoral Fellowship at the International Agency for Research on Cancer. Linda Kachuri is supported by funding from the National Institutes of Health (K99CA246076). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Not applicable I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Lung cancer summary statistics obtained from ILCCO can be accessed by the database of Genotypes and Phenotypes (dbGAP) under accession phs000876.v1.p1. The GWAS summary statistics for tobacco-smoking behaviors (GSCAN: ), LTL (), and GTEx version 8 (downloaded via GTEx google cloud resource) are publicly available. TCGA data was accessed by dbGAP through Project #2731. RNA-sequencing data and TCGA-related data are publicly available as described in the data section. The data generated in this study are available within the article and its supplementary data files. * FEV1 : Forced expiratory volume in 1 second FVC : Forced vital capacity GWAS : Genome-wide association studies LTL : Leukocyte telomere length LDSC : Linkage disequilibrium score regression MR : Mendelian randomization PCA : Principal component analysis PP : Posterior probability PRS : Polygenic risk score UKBB : UK Biobank TCGA : The Cancer Genome Atlas