BACKGROUND: Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses. METHODS: We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16 396 cases, 13 013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects. RESULTS: The multi-allelic 5p15.33 instrument explained 1.49-2.00% of TL variation in our data (p = 2.6 × 10-9). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung cancer [odds ratio (OR) = 1.41, 95% confidence interval (CI): 1.20-1.65] and lung adenocarcinoma (OR = 1.92, 95% CI: 1.51-2.22), but not squamous lung carcinoma (OR = 1.04, 95% CI: 0.83-1.29) or head and neck cancers (OR = 0.90, 95% CI: 0.70-1.05). Mediation analysis of the 5p15.33 instrument indicated an absence of direct effects on lung cancer risk (OR = 1.00, 95% CI: 0.95-1.04). Analysis of distinct 5p15.33 susceptibility variants estimated that TL mediates up to 40% of the observed associations with lung cancer risk. CONCLUSIONS: Our findings support a causal role for long telomeres in lung cancer aetiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci.

BC Cancer Agency Vancouver BC Canada

Clalit National Cancer Control Center at Carmel Medical Center and Technion Faculty of Medicine Haifa Israel

College of Pharmacy Washington State University Spokane WA USA

Departamento de Medicina Preventiva Faculdade de Medicina da Universidade de São Paulo São Paulo Brazil

Department of Cancer Epidemiology and Prevention Cancer Center Maria Sklodowska Curie Institute of Oncology Warsaw Poland

Department of Cancer Epidemiology H Lee Moffitt Cancer Center and Research Institute Tampa FL USA

Department of Clinical Biochemistry Herlev and Gentofte Hospital Copenhagen University Hospital Herlev Ringvej 75 Herlev Denmark

Department of Environmental Epidemiology Nofer Institute of Occupational Medicine Lodz Poland

Department of Epidemiology and Prevention Russian N N Blokhin Cancer Research Centre Moscow Russian Federation

Department of Epidemiology Division of Cancer Prevention and Population Sciences The University of Texas MD Anderson Cancer Center Houston TX USA

Department of Epidemiology Geisel School of Medicine Dartmouth College Hanover NH USA

Department of Epidemiology Gillings School of Global Public Health University of North Carolina at Chapel Hill Chapel Hill NC USA

Department of Gastroenterology Radboud University Nijmegen Medical Center Nijmegen The Netherlands

Department of Genetic Epidemiology University Medical Center Georg August University Göttingen Germany

Department of Human Genetics Graduate School of Public Health University of Pittsburgh Pittsburgh PA USA

Department of Hygiene Epidemiology and Medical Statistics School of Medicine National and Kapodistrian University of Athens Athens Greece

Department of Medicine Massachusetts General Hospital and Harvard Medical School Boston MA USA

Department of Molecular Biology School of Medicine of São José do Rio Preto São José do Rio Preto Brazil

Department of Oral Pathology School of Dentistry University of São Paulo São Paulo Brazil

Department of Otolaryngology Head and Neck Surgery University of North Carolina at Chapel Hill Chapel Hill NC USA

Department of Otorhinolaryngology Head and Neck Surgery Maastricht University Medical Center Maastricht The Netherlands

Department of Population Health Sciences Huntsman Cancer Institute Salt Lake City UT USA

Department of Public Health Section for Epidemiology Aarhus University Aarhus Denmark

Department of Thoracic Surgery and Division of Epidemiology Vanderbilt University Medical Center Nashville TN USA

Department of Thoracopulmonary Pathology Service of Pathology Clinical Center of Serbia Belgrade Serbia

Departments of Epidemiology and Environmental Health Harvard TH Chan School of Public Health Boston MA USA

Dipartimento di Medicina Clinica e Chirurgia Federico 2 University Naples Italy

Division of Biostatistics Dalla Lana School of Public Health University of Toronto Toronto Ontario Canada

Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Bethesda MD USA

Division of Epidemiology Dalla Lana School of Public Health University of Toronto Toronto Ontario Canada

Division of Epigenomics and Cancer Risk Factors German Cancer Research Center Heidelberg Germany

Epidemiology Program University of Hawaii Cancer Center Honolulu HI USA

Faculdade de Saúde Pública Universidade de São Paulo Brazil

Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

Faculty of Health Sciences Palacky University Olomouc Czech Republic

Faculty of Medicine University of Oviedo and CIBERESP Campus del Cristo Oviedo Spain

Fondazione Policlinico Universitario A Gemelli IRCCS Rome Italia

Fred Hutchinson Cancer Research Center Seattle WA USA

Hellenic Health Foundation and WHO Collaborating Center for Nutrition and Health Unit of Nutritional Epidemiology and Nutrition in Public Health Athens Greece

Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo Disciplina de Cirurgia de Cabeça e Pescoço São Paulo Brasil

Icahn School of Medicine at Mount Sinai New York NY USA

Institute for Clinical and Translational Research Baylor College of Medicine Houston TX USA

Institute of Epidemiology 2 Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany

Institute of Medical Informatics Biometry and Epidemiology Ludwig Maximilians University Munich Germany

Institute of Medical Statistics and Epidemiology Technical University Munich Germany

Institute of Public Health and Preventive Medicine 2nd Faculty of Medicine Charles University Prague Czech Republic

International Agency for Research on Cancer Lyon France

Lunenfeld Tanenbaum Research Institute Sinai Health System Toronto Ontario Canada

Markey Cancer Center University of Kentucky Lexington KY USA

MRC PHE Centre for Environment and Health Department of Epidemiology and Biostatistics School of Public Health Imperial College London London UK

National Institute of Public Health Bucharest Romania

Ontario Cancer Institute Princess Margaret Cancer Center Toronto Ontario Canada

Population Health Science Bristol Medical School MRC Integrative Epidemiology Unit University of Bristol Bristol UK

Radboud Institute for Health Sciences Radboud University Medical Centre Nijmegen The Netherlands

Roy Castle Lung Cancer Research Programme University of Liverpool Cancer Research Centre Institute of Translational Medicine University of Liverpool Liverpool UK

School of Health and Related Research University of Sheffield Sheffield UK

School of Oral and Dental Sciences University of Bristol Bristol UK

Section of Hygiene Institute of Public Health Università Cattolica del Sacro Cuore Rome Italy

Skåne University Hospital Lund University Lund Sweden

The Institute of Applied Health Sciences School of Medicine University of Aberdeen Aberdeen UK

The National Institute of Occupational Health Oslo Norway

Unit of Nutrition and Cancer Catalan Institute of Oncology Barcelona Spain

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VOYAGER: an international consortium investigating the role of human papilloma virus and genetics in oral and oropharyngeal cancer risk and survival

Diagnostic accuracy of HPV16 early antigen serology for HPV-driven oropharyngeal cancer is independent of age and sex