Commentary: Smoking and human papillomavirus infection: the pursuit of credibility for an epidemiologic association.

As the most important among the modifiable risk factors for many cancer types tobacco smoking is dutifully treated as a potent confounder when epidemiologists explore new candidate relations. The role for smoking changes from ‘confounder’ to ‘confounded’ variable in anogenital cancers. Among the latter, cervical cancer is a case in point. Smoking was first suspected as a risk factor for cervical cancer in the mid 60s but although most studies have replicated the finding the association was always seen with suspicion because of confounding by sexual activity. Number of sexual partners and age at first intercourse are unequivocal key determinants of risk, which has long suggested that an infectious sexually-transmitted agent plays an aetiological role. Controlling for these two measures of sexual behaviour tended to dampen the associations with smoking in cervical cancer studies but in many of them it remained statistically detectable. Concerns about residual confounding by unmeasured sexual behaviours or insufficient control of confounding due to misclassification of sexual activity information led the International Agency for Research on Cancer (IARC) to defer judgment about a carcinogenic role for smoking in cervical cancer in its first monograph focusing on tobacco products in 1986. This intractable situation was nicely captured in 1994 in an insightful article in the Journal which demonstrated that, as long as the putative sexuallytransmitted aetiologic agent remained unmeasured and uncontrolled for in an epidemiological study, the association with smoking would continue to be hopelessly confounded, despite best efforts at adjusting for sexual activity variables. It did not help when the first molecular epidemiologic studies in the late 80s heeded this advice by placing the human papillomavirus (HPV) at centre stage for the first time. Paradoxically, HPV infection measured in these earlier studies was not associated with sexual activity and was only feebly associated with cervical cancer. Epidemiologists learned that misclassification of HPV status could account for the incoherent results and were quick to adopt improved molecular techniques for detecting HPV, which led to the recognition of this virus as a necessary cause of cervical cancer and ushered in a new era in cervical cancer prevention via HPV vaccination and screening with HPV tests. Oncemeasurement error issues related to cervical HPV detection were largely resolved the smoking-cervical cancer association could be verified with reasonable confidence. The IARC revisited its previous conclusions and listed cervical cancer among those causally related to smoking in 2004. A pooled analysis of 23 modern molecular epidemiologic studies that included over 13 000 cases and 23 000 controls and carefully controlled for HPV status found an increased risk of squamous cell carcinomas with a dose–response relation with number of cigarettes. Although the controversy subsided, the role of epidemiology was not yet over; a mechanism for the carcinogenic action of tobacco smoking needed to be documented. The aetiological pathway that begins with sexual activity as distal variable, then includes HPV infection as intermediate endpoint, and ends with cervical cancer is consistent with both ‘upstream’ and ‘downstream’ smoking effects relative to HPV infection. Documenting both still requires careful attention to confounding by sexual activity, which is strongly correlated with smoking habits. In this issue of the Journal, Vaccarella et al. advanced our understanding of the upstream relation by focusing on smoking as a determinant of HPV infection in the large IARC multi-centre study of HPV prevalence, which included over 10 000 women throughout the world. Their state-of-the-art methods for detecting HPV DNA in cervical specimens were conducted in world-class laboratories. The authors were acutely aware of the confounding problem and made clever use of the standardized questionnaire information to control for age, number of sexual * Corresponding author. Department of Epidemiology & Biostalistics and Department of Oncology, McGill University, Montreal, Canada. E-mail: [email protected] Department of Epidemiology & Biostatistics and Department of Oncology, McGill University, Montreal, Canada. Published by Oxford University Press on behalf of the International Epidemiological Association