||5R01CA084087-05 Interpret this number
||University Of Washington
||Epidemiology of HPV and P53 Mutations in NM Skin Cancer
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
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.
Merkel cell polyomavirus is more frequently present in North American than Australian Merkel cell carcinoma tumors.
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