HPV-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) are recognized as distinct entities. There remains uncertainty surrounding the causal effects of smoking and alcohol on the development of these two cancer types. Here we perform multivariable Mendelian randomization (MR) to evaluate the causal effects of smoking and alcohol on the risk of HPV-positive and HPV-negative HNSCC in 3431 cases and 3469 controls. Lifetime smoking exposure, as measured by the Comprehensive Smoking Index (CSI), is associated with increased risk of both HPV-negative HNSCC (OR = 3.03, 95%CI:1.75-5.24, P = 7.00E-05) and HPV-positive HNSCC (OR = 2.73, 95%CI:1.39-5.36, P = 0.003). Drinks Per Week is also linked with increased risk of both HPV-negative HNSCC (OR = 7.72, 95%CI:3.63-16.4, P = 1.00E-07) and HPV-positive HNSCC (OR = 2.66, 95%CI:1.06-6.68, P = 0.038). Smoking and alcohol independently increase the risk of both HPV-positive and HPV-negative HNSCC. These findings have important implications for understanding the modifying risk factors between HNSCC subtypes.

Cancer Epidemiology Research Programme Catalan Institute of Oncology L'Hospitalet de Llobregat Barcelona Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública Madrid Spain

Cancer Surveillance Branch International Agency for Research on Cancer World Health Organization Lyon France

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

Department of Biostatistics Princess Margaret Cancer Centre University Health Network University of Toronto Toronto Ontario Canada

Department of Epidemiological Methods and Etiological Research Leibniz Institute for Prevention Research and Epidemiology BIPS Bremen Germany; Department of Mathematics and Computer Science University of Bremen Bremen Germany

Department of Epidemiology and Biostatistics University of Western Ontario London Ontario Canada

Department of Epidemiology University of North Carolina Chapel Hill North Carolina USA

Department of Human Genetics School of Public Health University of Pittsburgh and UPMC Hillman Cancer Center Pittsburgh PA 15260 USA

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

Department of Medical Sciences University of Turin and CPO Piemonte Turin Italy

Department of Oral and Maxillofacial Surgery Oral Medicine and Oral Pathology Dublin Dental University Hospital Trinity College Dublin Dublin Ireland

Department of Otolaryngology Head and Neck Surgery Sinai Health System Toronto Ontario Canada

Department of Otolaryngology Head and Neck Surgery University of Toronto Toronto Ontario Canada

Department of Psychiatry Washington University School of Medicine St Louis MO USA

Department of Public and Community Health School of Public Health University of West Attica Athens Greece

Department of Radiation Oncology University of Toronto Toronto Ontario Canada

Department of Research Cancer Registry of Norway Norwegian Institute of Public Health Oslo Norway

Division of Medical Oncology and Center for Cancer Research University of Tennessee Health Science Center Memphis TN USA

Division of Medical Oncology and Hematology Department of Medicine University of Toronto Toronto Ontario Canada

Epidemiology Group School of Medicine Medical Sciences and Nutrition University of Aberdeen Aberdeen UK

Genomic Epidemiology Branch International Agency for Research on Cancer World Health Organization Lyon France

Infections and Cancer Epidemiology German Cancer Research Center Heidelberg Germany

Institute of Hygiene and Epidemiology 1st Faculty of Medicine Charles University Prague Czech Republic

MRC Integrative Epidemiology Unit Population Health Sciences Bristol Medical School University of Bristol Bristol BS8 1TL UK

Princess Margaret Cancer Centre University Health Network Toronto Ontario Canada

Prosserman Centre for Population Health Research Lunenfeld Tanenbaum Research Institute Sinai Health Toronto Canada

School of Medicine Dentistry and Nursing University of Glasgow Glasgow UK

Unit of Cancer Epidemiology Centro di Riferimento Oncologico di Aviano IRCCS Aviano Italy

University Hospitals Bristol and Weston NHS Foundation Trust National Institute for Health Research Bristol Biomedical Research Centre University of Bristol Bristol BS1 3NU UK

University of Bristol Dental School 1 Trinity Walk Avon Street Bristol BS2 0PT UK

University of Padua Padova Italy

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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