Abstract
Cervical cancer is caused by persistent infection with one of approximately a dozen carcinogenic human papillomavirus (HPV) infections. HPV16 is the most carcinogenic HPV type, causing one half of cases worldwide.
Cervical cancer arises via three well-defined steps: acute HPV infection; viral persistence linked to development of a high-grade intraepithelial lesion, and invasion. Infections peak in late adolescence and early adulthood, high-grade lesions grow superficially in the years following infection, and invasion of high-grade lesions typically takes decades to occur.
Host susceptibility given exposure to HPV is best considered by stage of the carcinogenic process. Infection is nearly ubiquitous among sexually active women, who appear (at our present state of knowledge) to be universally susceptible if previously unexposed. Common exposure leads to at least partial type-specific immunity as women age. Virtually all infections “clear” within 1-2 years and failure to clear, i.e., persistence, is highly associated with development of a high-grade lesion. Susceptibility to viral persistence is poorly understood, but is apparently the major determinant of carcinogenic risk from infection. If undiagnosed and untreated, high-grade lesions invade in a substantial minority of cases and we have determined no definitively established determinants of susceptibility to invasion.
Accordingly, this talk will focus on what is known about risk factors for HPV persistence/high-grade lesions given HPV infection. The risk factors can be divided conceptually into three groups: 1) viral factors, 2) host behavioral factors, and 3) intrinsic host factors.
Definite viral factors include HPV genetic factors (type and variant lineage) and HPV epigenetic factors (viral methylation). Established host behavioral factors include smoking, long-term oral contraceptive use, and multiparity; the associations are firm but mechanisms are not known. The few known intrinsic host factors include immune status (e.g., HIV immunosuppression), possibly specific HLA associations, and possibly some common genetic variants and methylation patterns. The leading candidates will be mentioned.
Understanding of the viral-host interaction has led to promising biomarkers used to distinguish between acute HPV infection and high-grade lesions, most notably p16 staining, a marker of disruption of the Rb pathway.
Citation Format: Mark Schiffman. Susceptibility to neoplasia following HPV infection. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr IA16.
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