PTCH (patched) and XPA genes in radiation-induced basal cell carcinomas

Abstract

A study of X-irradiated tinea capitis patients has identified a small subgroup (about 1.5%) of people at high risk for developing multiple basal cell carcinomas (BCCs). Among 1680 Caucasians who received about 3 Gy of low voltage X-ray, the incidence of BCCs, 35 years after exposure, was 0.10 tumors per person. A random distribution indicates that no one should have developed three or more BCCs and yet 25 with three or more were observed. Among three selected from the latter group, one presented with five previously unreported BCCs; one presented with four; and one presented with one. Varied patterns of loss of heterozygosity (LOH) were found in the BCCs from all three patients in the region of the PTCH and xeroderma pigmentosum A ( XPA) genes in chromosome region 9q22.3–31. The subject with five BCCs reported that 25 BCCs had previously been removed. Amplification primers for XPA were picked from intronic sequences and positive SSCP results were followed-up by sequencing the identified regions to establish the exact nature of the mutation. A large number of negative SSCP results were sequenced, but no mutations undetected by SSCP were found. Normal blood DNA of the subject with five BCCs showed a 14 base deletion in exon 6 of the XPA gene, strongly suggesting XPA heterozygosity. Biopsy samples of the BCCs showed the same 14 base deletion in all five BCCs. Allelic identification verified that the normal XPA allele was missing in two of two BCCs selected for testing. These data imply that a mutational inactivation of one XPA allele increased the susceptibility to BCC induction by ionizing radiation, possibly because the normal XPA allele was lost in the same deletional event that produced LOH in the PTCH region. These findings support the idea that the lost event associated with LOH at 9q22.3 frequently (5/5) includes both the PTCH and XPA loci. Frequently, an XPA allele located within about 3 megabases distal to PTCH is lost along with the PTCH gene. Overall, these results suggest how inactivation of the XPA gene may play an important role in susceptibility to BCC induction by increasing the UV-induced mutational rate of PTCH or other cancer-relevant genes (work supported by NIEHS, NCI, and EPA).