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Grant Details

Grant Number: 5R01CA084087-05 Interpret this number
Primary Investigator: Kiviat, Nancy
Organization: University Of Washington
Project Title: Epidemiology of HPV and P53 Mutations in NM Skin Cancer
Fiscal Year: 2005
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Abstract

DESCRIPTION (provided by applicant): Although little mortality is associated with squamous cell skin cancer (SCSC), these cancers constitute a major public health problem due to the high costs associated with treatment. The relationship between ultraviolet radiation (UVR) exposure and development of SCSC is well established, however, the molecular biology underlying this association is unclear. We hypothesize that many of these tumors result from acquisition of UVR-induced mutations in genes that normally maintain genetic stability, and in particular mutations in the p53 gene, along with infection with certain cutaneous human papillomaviruses (HPVs). Confirming this hypothesis has significant public health implications, since, if true, HPV type-specific vaccines (similar to those now being tested for prevention of cervical cancer) could be developed and specific p53 mutations (or associated proteins) could serve as a target for the design of additional preventive therapeutics. Animal and cell culture models support a role for specific p53 mutations acquired with the formation of UVR-induced dipyrimidine dimers, however, systematic, DNA sequence and cloning based examination of tissue from incident SCSC and nonlesional control tissues has yet to be undertaken in humans. The limited available data suggest that p53 mutations might be present in over 90 percent of SCSC tissue and in up to 50 percent of sun exposed non-cancerous skin cells. Similarly, small case series in immunocompetent patients have shown that cutaneous HPV DNAs are present in over 90 percent of SCSC lesions and in up to 50 percent of control tissues. Interestingly, our recent studies show that the upstream regulatory region (URR) of specific cutaneous HP Vs is activated by UVR exposure via p53 proteins binding to a p53 consensus sequence in the URR of some cutaneous HPVs. Further, different p53 proteins appear to differ in their ability to activate HPV. These findings, along with the fact that cutaneous HPV E6/E7 proteins are known to induce proliferation and clonal expansion of infected cells, lead us to propose the following. We hypothesize that UVR exposure of epithelial cells results in acquisition of pyrimidine dimers with selection of mutations in the p53 gene, as well as selection of mutations in those genes that normally maintain genetic stability. Such cells, which have acquired a "mutator phenotype," have the potential both to accumulate the many mutations characteristic of, and necessary for, progression to cancer and the ability to abrogate apoptosis. However, the ability of these abnormal cells to progress to malignancy most likely requires increased proliferation and clonal expansion. We hypothesize that if such abnormal cells are infected with a cutaneous HPV type that is activated upon UVR exposure, that such exposure leads to HPV dependent proliferation and clonal expansion. Subsequent exposure of this population of cells to UVR, with successive rounds of mutation, selection and HPV-dependent clonal expansion, could lead to accumulation of those mutations associated with development of a malignant phenotype. We propose to examine this hypothesis by undertaking a case-control study and a laboratory based study designed to provide confirmation of the biologic relevance of our clinical findings.

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Publications

Merkel cell polyomavirus is more frequently present in North American than Australian Merkel cell carcinoma tumors.
Authors: Garneski KM, Warcola AH, Feng Q, Kiviat NB, Leonard JH, Nghiem P
Source: J Invest Dermatol, 2009 Jan;129(1), p. 246-8.
EPub date: 2008 Jul 24.
PMID: 18650846
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Environmental and chemical carcinogenesis.
Authors: Wogan GN, Hecht SS, Felton JS, Conney AH, Loeb LA
Source: Semin Cancer Biol, 2004 Dec;14(6), p. 473-86.
PMID: 15489140
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