The ongoing epidemiological study of about 2000 x-radiated tinea capitis
patients and 1400 controls is providing evidence that x-irradiation in
childhood causes a significant increase (relative risk = 3.7 for single
tumors and = 8.0 for multiple tumors) in the incidence of basal cell
carcinomas (BCCs). Other evidence suggests Uv light also plays a role,
possibly as a promoter of x-ray initiated tumors, although Uv may also
act as an tumor initiator by producing DNA damage in the form of CC to
TT or C to T base changes. Some patients in the tinea study exhibit
evidence of substantially higher than normal risk of a skin cancers. The
heightened risk is apparent in patients who have already developed a
cancer; the risk of a second cancer is roughly 40% per 5 years versus
only about 2% per 5 years for those without a prior cancer. A preliminary
study of skin tumors from the x-irradiated patients showed evidence of
possible x-ray damage to the p53 gene; 5 of 6 BCCs or epitheliomas
exhibited deletion or translocation damage to exons 7, 8 or 9, and 1 of
6 patients showed a total p53 deletion in DNA from blood leukocytes. The
research proposed here is designed to answer the following questions
raised by the initial findings in this unique patient population: 1. How
closely are the genetic changes in the p53 gene of the induced cancers
linked to the probable etiologic agent (UV or x-ray), 2. are p53 gene
alterations as measured in blood leukocytes of high cancer risk patients
a possible genetic basis for their increased susceptibility, and 3. are
multiple skin cancers on the same patient derived from distinct and
independent genetic lesions. Skin cancers presenting in the clinic will
be removed and examined histologically. Tumor DNA will be extracted and
analyzed by polymerase chain reaction (PCR) as a way to quantity major
internal deletions and other rearrangements, while SSCP followed by DNA
sequencing will be used to identify base pair alterations. DNA
fingerprinting techniques will be used to establish whether multiple
cancers on the same patient are genetically distinct. Specific exon
probes will be utilized to on Southern blots to distinguish small
deletions from translocations. The proposed work will establish the types
and incidence of p53 gene alterations in radiation-induced skin BCCs and
whether the type of p53 alteration is predictive of the response to
secondary prevention by topical 5-fluorouracil.
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