RELATIONSHIP BETWEEN SUNLIGHT EXPOSURE AND A KEY GENETIC ALTERATION IN BASAL-CELL CARCINOMA

Background: Basal cell carcinoma (BCC) of the skin is the most common cancer in humans. Epidemiologic studies implicate sunlight exposure as one risk factor, but the limited association between BCCs and UVB rad iation (i.e., UV radiation of a wavelength of 280-320 nm) suggests tha t additional factors must be involved. At the molecular level, not muc h is known about the role of specific environmental agents in the path ogenesis of BCCs. Point mutations of the types produced by UVB radiati on are seen in the p53 gene (also known as TP53; chromosome 17p) of 40 %-56% of BCCs, Loss of heterozygosity (LOH) on chromosome 9q22, howeve r, is the most frequent genetic alteration in these tumors, and its ca usative agent is unknown. Purpose: We investigated whether the genetic alteration in chromosome 9 is common to all clinical subtypes of BCCs and whether inactivation of this putative tumor suppressor is related to sunlight exposure. The presence of UVB radiation-related point mut ations in the p53 gene was used as an internal control for sunlight ex posure to the precursor cells. Methods: Tumor and blood samples were o btained from skin cancer patients by a surgeon who used Mohs' microgra phic surgical technique, Clinical information on each tumor included l ocation, size, histologic subtype, and whether it was primary or recur rent and sporadic or hereditary. Sixty BCCs from 58 patients were eval uated for LOH with 12 polymorphic markers that span chromosome 9. A su bset of 18 tumors was evaluated for point mutations in exons 2-11 of t he p53 gene, and a subset of 26 tumors was evaluated for LOH by use of a polpmorphism in exon 4 of the p53 gene. Associations between tumor characteristics and molecular alterations were tested by a two-tailed chi-squared analysis or a two-tailed Fisher's exact test, depending on sample size. Results: In a clinically diverse series of 47 informativ e tumors, 32 (68%) showed LOH for chromosome 9q markers, irrespective of histologic characteristics or clinical behavior. Forty-four (94%) o f the 47 tumors were from sun-exposed areas of the body, defined as th e head and neck in both sexes, shoulders or chest in males, and legs i n females. No association was found between chromosome 9q LOH and sunl ight exposure, as assessed by either the location of tumors on the bod y or the presence of UVB radiation-related p53 mutations. Of note, the re was a striking difference between the frequency of LOH on chromosom e 17p (two [12.5%] of 16 informative turners) and on chromosome 9q (32 [68%] of 47 informative tumors; P<.001). Conclusions: Inactivation of a gene on chromosome 9q22 may be a necessary event for basal cell car cinogenesis. The pathogenesis of mutations in this gene may involve fa ctors other than sunlight in a large proportion of tumors. Implication s: The limited association between sunlight exposure and BCC incidence may reflect an etiologic contribution of additional environmental age nts.