BACKGROUND: Although smoking and HPV infection are recognized as important risk factors for oropharyngeal cancer, how their joint exposure impacts on oropharyngeal cancer risk is unclear. Specifically, whether smoking confers any additional risk to HPV-positive oropharyngeal cancer is not understood. METHODS: Using HPV serology as a marker of HPV-related cancer, we examined the interaction between smoking and HPV16 in 459 oropharyngeal (and 1445 oral cavity and laryngeal) cancer patients and 3024 control participants from two large European multi-centre studies. Odds ratios and credible intervals [CrI], adjusted for potential confounders, were estimated using Bayesian logistic regression. RESULTS: Both smoking [odds ratio (OR [CrI]: 6.82 [4.52, 10.29]) and HPV seropositivity (OR [CrI]: 235.69 [99.95, 555.74]) were independently associated with oropharyngeal cancer. The joint association of smoking and HPV seropositivity was consistent with that expected on the additive scale (synergy index [CrI]: 1.32 [0.51, 3.45]), suggesting they act as independent risk factors for oropharyngeal cancer. CONCLUSIONS: Smoking was consistently associated with increase in oropharyngeal cancer risk in models stratified by HPV16 seropositivity. In addition, we report that the prevalence of oropharyngeal cancer increases with smoking for both HPV16-positive and HPV16-negative persons. The impact of smoking on HPV16-positive oropharyngeal cancer highlights the continued need for smoking cessation programmes for primary prevention of head and neck cancer.

Cancer Epidemiology Unit Nuffield Department of Population Health University of Oxford Oxford UK

Cancer Registry and Histopathology Unit Civic M P Arezzo Hospital ASP Ragusa Ragusa Italy

Cancer Registry of Norway Oslo Norway

Centre for Oral Health Research Newcastle University Newcastle upon Tyne UK

CIBER of Epidemiology and Public Health Madrid Spain Department of Epidemiology Murcia Regional Health Council IMIB Arrixaca Murcia Spain Department of Health and Social Sciences Universidad de Murcia Murcia Spain

CIBER of Epidemiology and Public Health Madrid Spain Instituto de Investigación Biosanitaria Universidad de Granada Granada Spain

CIBER of Epidemiology and Public Health Madrid Spain Navarre Public Health Institute Pamplona Spain

Croatian National Cancer Registry Croatian National Institute of Public Health Zagreb Croatia Section of Cancer Surveillance International Agency for Research on Cancer Lyon France

Danish Cancer Society Institute of Cancer Epidemiology Copenhagen Denmark

Dental School College of Medicine Veterinary and Life Sciences University of Glasgow Glasgow UK

Department for Determinants of Chronic Diseases Bilthoven The Netherlands Department of Gastroenterology and Hepatology University Medical Centre Utrecht The Netherlands Department of Epidemiology and Biostatistics Imperial College London School of Public Health London UK Department of Social and Preventive Medicine Faculty of Medicine University of Malaya Kuala Lumpur Malaysia

Department of Biobank Research Umeå University Umeå Sweden

Department of Clinical Sciences Lund University Lund Sweden

Department of Community Medicine Faculty of Health Science University of Tromsø Arctic University of Norway Tromsø Norway

Department of Community Medicine Faculty of Health Science University of Tromsø Arctic University of Norway Tromsø Norway Cancer Registry of Norway Oslo Norway Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden Department of Genetic Epidemiology Folkhälsan Research Centre Helsinki Finland

Department of Epidemiology Julius Centre for Health Sciences and Primary Care University Medical Centre Utrecht The Netherlands MRC PHE Imperial College London School of Public Health London UK

Department of Hygiene Epidemiology and Medical Statistics University of Athens Medical School Athens Greece

Department of Otorhinolaryngology of Malmö and Lund

Department of Surgical Sciences Uppsala University Uppsala Sweden

Dipartimento di Medicina Clinica e Chirurgia Federico 2 University Naples Italy

Division of Cancer Epidemiology German Cancer Research Centre Heidelberg Germany

Epidemiology and Prevention Unit Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy

Genetic Epidemiology Group International Agency for Research on Cancer Lyon France

German Cancer Research Centre Heidelberg Germany and

German Institute of Human Nutrition Potsdam Rehbruecke Nuthetal Germany

Hellenic Health Foundation Athens Greece Bureau of Epidemiologic Research Academy of Athens Athens Greece

Hellenic Health Foundation Athens Greece Bureau of Epidemiologic Research Academy of Athens Athens Greece Department of Epidemiology Harvard School of Public Health Boston MA USA

Hellenic Health Foundation Athens Greece Department of Hygiene Epidemiology and Medical Statistics University of Athens Medical School Athens Greece

Human Genetics Foundation Torino Italy Cancer Epidemiology Centre Cancer Council Victoria Melbourne VIC Australia Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health University of Melbourne VIC Australia

INSERM Centre for research in Epidemiology and Population Health Villejuif France Université Paris Sud Villejuif France Institut Gustave Roussy Villejuif France

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

Institute of Public Health Aarhus Denmark

Laboratory of Public Health and Population Studies Department of Molecular Medicine University of Padova Padova Italy

Leibniz Institute for Prevention Research and Epidemiology BIPS Bremen Germany Faculty of Mathematics and Computer Science University of Bremen Bremen Germany

Molecular and Nutritional Epidemiology Unit Cancer Research and Prevention Institute ISPO Florence Italy

National Cancer Institute NIH Bethesda MD USA

Public Health Directorate Asturias Oviedo Spain

Public Health Division of Gipuzkoa BIODonostia Research Institute Basque Health Department San Sebastián Spain CIBER of Epidemiology and Public Health Madrid Spain

School of Dental Science Trinity College Dublin Dublin Ireland

School of Medicine and Dentistry University of Aberdeen Aberdeen UK

School of Public Health Imperial College London London UK

Unit of Cancer Epidemiology Citta' della Salute e della Scienza Hospital University of Turin and Centre for Cancer Prevention Turin Italy

Unit of Cancer Epidemiology Department of Medical Sciences University of Turin Turin Italy

Unit of Epidemiology and Biostatistics CRO Aviano National Cancer Institute Aviano Italy

Unit of Infections and Cancer Institut Català d'Oncologia IDIBELL CIBERESP L'Hospitalet de Llobregat Barcelona Spain

Unit of Nutrition and Cancer Institut Català d'Oncologia L'Hospitalet de Llobregat Barcelona Spain

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Smoking and alcohol by HPV status in head and neck cancer: a Mendelian randomization study

A risk prediction model for head and neck cancers incorporating lifestyle factors, HPV serology and genetic markers