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.
