Common genetic variations in telomere length genes and lung cancer: a Mendelian randomisation study and its novel application in lung tumour transcriptome
MRC Integrative Epidemiology Unit, Bristol Population Health Science Institute, Bristol Medical School (PHS), Bristol, United Kingdom
Siddhartha Kar
MRC Integrative Epidemiology Unit, Bristol Population Health Science Institute, Bristol Medical School (PHS), Bristol, United Kingdom
Veryan Codd
Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom
Nilesh J Samani
Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom
Christopher Nelson
Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom
Maja Milojevic
Genomic Epidemiology branch, International Agency for Research on Cancer/World Health Organization (IARC/WHO), Lyon, France
Aurélie AG Gabriel
Ludwig Lausanne Branch, Faculty of Biology and Medicine, Lausanne, Switzerland
Christopher Amos
Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, United States
Paul Brennan
Genomic Epidemiology branch, International Agency for Research on Cancer/World Health Organization (IARC/WHO), Lyon, France
Rayjean J Hung
Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, Canada
Linda Kachuri
Departament of Epidemiology and Population Health, Stanford University, Stanford, United States
Background: Genome-wide association studies (GWASs) have identified genetic susceptibility variants for both leukocyte telomere length (LTL) and lung cancer susceptibility. Our study aims to explore the shared genetic basis between these traits and investigate their impact on somatic environment of lung tumours. Methods: We performed genetic correlation, Mendelian randomisation (MR), and colocalisation analyses using the largest available GWASs summary statistics of LTL (N=464,716) and lung cancer (N=29,239 cases and 56,450 controls). Principal components analysis based on RNA-sequencing data was used to summarise gene expression profile in lung adenocarcinoma cases from TCGA (N=343). Results: Although there was no genome-wide genetic correlation between LTL and lung cancer risk, longer LTL conferred an increased risk of lung cancer regardless of smoking status in the MR analyses, particularly for lung adenocarcinoma. Of the 144 LTL genetic instruments, 12 colocalised with lung adenocarcinoma risk and revealed novel susceptibility loci, including MPHOSPH6, PRPF6, and POLI. The polygenic risk score for LTL was associated with a specific gene expression profile (PC2) in lung adenocarcinoma tumours. The aspect of PC2 associated with longer LTL was also associated with being female, never smokers, and earlier tumour stages. PC2 was strongly associated with cell proliferation score and genomic features related to genome stability, including copy number changes and telomerase activity. 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. Funding: Institut National du Cancer (GeniLuc2017-1-TABAC-03-CIRC-1-TABAC17‐022), INTEGRAL/NIH (5U19CA203654-03), CRUK (C18281/A29019), and Agence Nationale pour la Recherche (ANR-10-INBS-09).
