The applicants' objective is to advance the understanding of the role played by genital human papillomavirus (HPV) in the etiology of carcinoma in situ (CIS) -- and inferentially invasive cancer -- of the cervix. While a causal role of HPV is likely, no large population-based, prospective study has examined its role in the natural history from normal epithelium to CIS, nor the role of cell-mediated immunity (as determined by HLA haplotype), microheterogeneity (or mutations) in the HPV genome, or of other factors that may determine transience/persistence of HPV infection. Nor has the purported orderly progression or monoclonal origin of cervix neoplasia been established. They propose a broad, interdisciplinary case-control study, nested in a population-based cohort. This study uses unique Swedish opportunities for a stringent study base definition, long-term follow-up and retrieval of smears and histopathologic specimens; it has an extensive morphologic and molecular component. The main specific questions relate to 1) determinants of progression: long-term pattern of infection (transience, persistence, reinfection) by HPV type, concordance between HPV in smears and CIS lesions, microheterogeneity or acquired mutations in the HPV genome, effect modification by HLA haplotype and/or smoking; 2) progression and clonality: correlation between HPV and the morphology as well as mono- or polyclonality of concomitant lesions as indicated by x-chromosome inactivation. They will follow up through 1993 a population-based cohort of women whose first PAP smear after 1969 was normal. At least 400 incident cases of CIS and 400 matched controls will be included and subjected to a telephone interview. On average five sequential smears from each subject (a total of about 4,000 smears) will undergo DNA extraction and PCR-based analyses including typing of 19 HPV-types, and of HLA class II haplotypes (HLA-DQB1 and HLA-DRB1) in one smear per individual. Also, in a selected set (about 100 cases) sequencing of a proportion of the HPV genome will be performed to study microheterogeneity. Detailed studies of progression and clonality will be carried out; the specimens from about 50 cases of CIS with multiple discrete lesions will be microdissected, followed by DNA extraction and analysis of HPV as well as X-chromosome inactivation. These data will be used on a number of different analyses including conditional logistic regression.
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