This project is based on the hypothesis that the """"""""high-risk"""""""" human papillomavirus types 16 and 18 initiate a multi-step process that can lead to anogenital carcinoma but are not sufficient for the induction of malignancy. Continued expression of the viral E6/E7 oncogenes is required for continued cell proliferation but other changes resulting from genetic instability are also required for completion of the pathway to malignancy. We will use comparative genomic hybridization (CGH) and chromosome microdissection to focus on chromosomal regions subject to non-random deletion or amplification in an effort to identify tumor suppressor genes of significance. DNA from archival specimens of cervical carcinoma and other anogenital carcinomas acquired in the epidemiologic studies (Project 3) will be used in allelotype analyses with probes for loci mapping in chromosome regions identified by CGH or with probes for known or putative tumor suppressor genes. The prevalence of microsatellite instability in anogenital tumors will be investigated, since instability of these sequences has been observed in many tumor types as an indicator of a mutator phenotype leading to genetic errors. As well as examining the effects of genetic instability on tumor progression, we will examine the effects of inhibitors of apoptosis, since such inhibition may also affect tumor progression by the continued proliferation of cells that would otherwise be eliminated through apoptosis.
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