"Patched" Gene Mosacism as a Basis for Differences in Skin Cancer SusceptibilityEPA Grant Number: R827018
Title: "Patched" Gene Mosacism as a Basis for Differences in Skin Cancer Susceptibility
Investigators: Burns, Fredric J.
Current Investigators: Burns, Fredric J. , Roy, Nirmal , Shore, Roy E. , Sun, Tung-Tien
Institution: New York University
Current Institution: New York University
EPA Project Officer: Louie, Nica
Project Period: October 1, 1998 through September 30, 2001 (Extended to September 30, 2002)
Project Amount: $570,271
RFA: Interindividual Variation in Human Susceptibility to Environmentally-caused Disease (1998) RFA Text | Recipients Lists
Research Category: Human Health , Health Effects , Health
Objectives/Hypotheses: This proposal will examine the role of the PTCH (patched) gene as a basis for differences in skin cancer susceptibility of people exposed to ionizing radiation. About 200 out of about 2200 people who were exposed to x-irradiation for tinea capitis at 8 years of age developed non-melanoma skin cancer in the irradiated region by 35 years after exposure. Most interestingly, about 30 subjects developed 3 or more skin cancers in comparison to only 2 such subjects expected if the tumor distribution were random. One hypothesis to explain the higher than expected occurrence of multiple basal cell carcinomas in the x-irradiated population is that 1 of the 2 required PTCH gene mutations occurred during embryonic development while the second occurred during x-irradiation.
Our approach here will be to compare the PTCH gene configuration in the cancers to its configuration in the immediately underlying or surrounding normal skin. A preliminary analysis of tumor DNA from donors with greater than 8 cancers revealed a high (90%) incidence of loss of heterozygosity (LOH) of the PTCH gene, i.e. one allele has been deleted. PTCH is the gene for the autosomal dominant condition known as, nevoid basal cell carcinoma syndrome (Gorlin's syndrome). As none of the donors were diagnosed with Gorlin's syndrome, the inactivation of both PTCH alleles in the cancers must have occurred somatically. Almost certainly 1 inactivation occurred during x-irradiation, but the other may have occurred at any time. If it occurred during embryonic development, a mosaic of high cancer susceptibility cells would be expected in the adult.
The expectation is that the skin of PTCH-damaged individual might be a mosaic were cancers occur most frequently in regions where 1 PTCH allele has been inactivated during embryogenesis producing adult cells with high sensitivity to exogenous carcinogens, such as, x-radiation. If so, normal skin cells in the vicinity of PTCH-altered tumors should exhibit a mutation identical to one of the mutations found in the tumor itself. The potential risk assessment value is that a small sample of normal skin cells, eg. a shave biopsy, could be used to determine the cancer risk status of tissue prior to its exposure to a potential carcinogen.