VIROLOGIC/GENETIC FACTORS OF HPV NEOPLASMS

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The overall aim of this project is the identification of genetic and epigenetic changes in human cells expressing human papillomaviruses (HPV) genes, with particular reference to cells expressing the E6/E7 oncogenes of HPV 16 and 18. The underlying hypothesis driving these studies is that while HPV oncogene expression initiates and maintains abnormal cell replication, by interacting with the p53 and retinoblastoma (Rb) gene products, subsequent changes in host cell gene expression, as a consequence of genetic instability, result in progression to invasive carcinoma. In conjunction with the population studies in Project #1, we will test this hypothesis in the context of virologic and genetic factors associated with primary and secondary anogenital tumors. A study of the viral integration sites in multiple tumors from the same individual, aimed at identification of the cellular sequences flanking integrated HPV DNA, will provide significant evidence for the independent origin of relatedness of multiple tumors. We will extend our current CGF studies of chromosomal changes in cervical to other anogenital tumors and to tissues from individual with multiple anogenital cancers. This analysis will identify any regions common to an initial tumor and subsequent tumors at the same or different anogenital sites. The results will be examined for relationship to other risk factors, e.g. smoking, family history, sexually transmitted disease, etc., identified in other projects in the program. We will use array methods to identify genes contributing to tumor progression, for example as potential tumor suppressor genes. Initially we will restrict these experiments to regions of chromosomes #3, #5 and #20, because these have been identified by use and others as frequently showing loss or gain in cervical carcinoma. The finding that the E6 oncogene of the high-risk viruses can induce telomerase suggest that this property could contribute to the progress of HPV-infected cervical and other epithelial cells to malignancy. The response of primary human epithelial cells to E6, in terms of the level of telomerase induction, has been shown to be variable. We will use a model system to investigate whether the extent of these variable response can be utilized as a marker of potential progression.