BACKGROUND: The increasing incidence of oropharyngeal cancer in many developed countries has been attributed to human papillomavirus type 16 (HPV16) infections. Recently, HPV16 E6 serology has been identified as a promising early marker for oropharyngeal cancer. Therefore, characterization of HPV16 E6 seropositivity among individuals without cancer is warranted. METHODS: A total of 4,666 controls were pooled from several studies of cancer and HPV seropositivity, all tested within the same laboratory. HPV16 E6 seropositive controls were classified as having (i) moderate [mean fluorescent intensity (MFI) ≥ 484 and <1,000] or (ii) high seroreactivity (MFI ≥ 1,000). Associations of moderate and high HPV16 E6 seroreactivity with (i) demographic risk factors; and seropositivity for (ii) other HPV16 proteins (E1, E2, E4, E7, and L1), and (iii) E6 proteins from non-HPV16 types (HPV6, 11, 18, 31, 33, 45, and 52) were evaluated. RESULTS: Thirty-two (0.7%) HPV16 E6 seropositive controls were identified; 17 (0.4%) with moderate and 15 (0.3%) with high seroreactivity. High HPV16 E6 seroreactivity was associated with former smoking [odds ratio (OR), 5.5; 95% confidence interval (CI), 1.2-51.8], and seropositivity against HPV16 L1 (OR, 4.8; 95% CI, 1.3-15.4); E2 (OR, 7.7; 95% CI, 1.4-29.1); multiple HPV16 proteins (OR, 25.3; 95% CI, 2.6-119.6 for three HPV16 proteins beside E6) and HPV33 E6 (OR, 17.7; 95% CI, 1.9-81.8). No associations were observed with moderate HPV16 E6 seroreactivity. CONCLUSIONS: High HPV16 E6 seroreactivity is rare among individuals without diagnosed cancer and was not explained by demographic factors. IMPACT: Some HPV16 E6 seropositive individuals without diagnosed HPV-driven cancer, especially those with seropositivity against other HPV16 proteins, may harbor a biologically relevant HPV16 infection.

Cancer Epidemiology Unit Nuffield Department of Population Health University of Oxford Oxford United Kingdom

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

Charles University Prague 1st Faculty of Medicine Prague Czech Republic

CRO Aviano National Cancer Institute Aviano Italy

Croatian National Institute of Public Health Zagreb Croatia

Danish Cancer Society Research Center Copenhagen Denmark

Department of Clinical Sciences Lund University Lund Sweden

Department of Medical Sciences University of Turin Turin Italy

Department of Research Cancer Registry of Norway Oslo Norway

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

Escuela Andaluza de Salud Pública Instituto de Investigación Biosanitaria ibs GRANADA Hospitales Universitarios de Granada Universidad de Granada Granada Spain CIBER de Epidemiología y Salud Pública Madrid Spain

Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy

German Cancer Research Center Heidelberg Germany

Hellenic Health Foundation Athens Greece Academy of Athens Athens Greece University of Athens Medical School Athens Greece

Imperial College London London United Kingdom

International Agency for Research on Cancer Lyon France

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

Leibniz Institute for Prevention Research and Epidemiology Bremen Germany

National Cancer Institute NIH Bethesda Maryland

National Cancer Institute NIH Bethesda Maryland Ontario Institute for Cancer Research Toronto Ontario Canada

National Institute for Public Health and the Environment Bilthoven the Netherlands University Medical Centre Utrecht the Netherlands The School of Public Health Imperial College London London United Kingdom University of Malaya Kuala Lumpur Malaysia

Trinity College School of Dental Science Dublin Ireland

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

University of Aberdeen Aberdeen United Kingdom

University of Athens Medical School Athens Greece

University of Glasgow Glasgow United Kingdom University of Aberdeen Aberdeen United Kingdom

University of Newcastle on Tyne Newcastle United Kingdom

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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

Combined effects of smoking and HPV16 in oropharyngeal cancer