This application proposes a study to identify genes that are preferentially up-regulated in human papillomavirus(HPV)-associated cervical neoplasia for the purpose of creating reagents for the diagnosis of pre- invasive cervical neoplasia. This will entail the critical analysis of approximately 80 genes that have been identified in a prior comparison of expression arrays generated from two cervical carcinomas and three control tissues, including normal transformation zone, normal portio epithelium; and atrophic squamous cells. These genes, all of which demonstrated at least ten fold higher expression values over controls, will be studied further by the hybridization of secondary arrays containing these genes to radioactive probes generated from neoplasia- derived RNAs. Genes which alone or together are consistently up- regulated in neoplastic tissues will be studied by immunohistochemical analysis of tissue arrays containing a series of tissues which span the spectrum of cervical neoplasia and for which the HPV status and type have been determined. Finally, candidate genes will be assembled into smaller arrays and hybridized with radioactive cDNA probes from RNAs derived from exfoliated cervical samples in which the cytologic and viral (HPV) status have been determined. The last exercise is designed to determine the potential diagnostic value of selected genes in predicting the presence of HPV- positive cytologic abnormalities. These studies have broad implications for the future of testing women for preinvasive and invasive cervical neoplasia, and seek to identify methods of detecting cervical neoplasia that circumvent the potential limitations of cytologic screening (sensitivity) and HPV testing (specificity). Such methods, if successful, could conceivably revolutionize the approach to cervical cancer prevention by broadening the conditions under which screening could be conducted.
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