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 radiation (i.e., UV radiation of a wavelength of 280-320 nm) suggests that additional factors must be involved. At the molecular level, not much is known about the role of specific environmental agents in the pathogenesis of BCCs. Point mutations of the types produced by UVB radiation are seen in the p53 gene (also known as TP53; chromosome 17p) of 40%-56% of BCCs. Loss of heterozygosity (LOH) on chromosome 9q22, however, is the most frequent genetic alteration in these tumors, and its causative agent is unknown.


OBJECTIVE
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 mutations in the p53 gene was used as an internal control for sunlight exposure to the precursor cells.


METHODS
Tumor and blood samples were obtained from skin cancer patients by a surgeon who used Mohs' micrographic surgical technique. Clinical information on each tumor included location, size, histologic, subtype and whether it was primary or recurrent and sporadic or hereditary. Sixty BCCs from 58 patients were evaluated for LOH with 12 polymorphic markers that span chromosome 9. A subset of 18 tumors was evaluated for point mutations in exons 2-11 of the p53 gene, and a subset of 26 tumors was evaluated for LOH by use of a polymorphism 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 informative tumors, 32 (68%) showed LOH for chromosome 9q markers, irrespective of histologic characteristics or clinical behavior. Forty-four (94%) of the 47 tumors were from sun-exposed areas of the body, defined as the head and neck in both sexes, shoulders or chest in males, and legs in females. No association was found between chromosome 9q LOH and sunlight exposure, as assessed by either the location of tumors on the body or the presence of UVB radiation-related p53 mutations. Of note, there was a striking difference between the frequency of LOH on chromosome 17p (two [12.5%] of 16 informative tumors) 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 carcinogenesis. The pathogenesis of mutations in this gene may involve factors other than sunlight in a large proportion of tumors.


CONCLUSIONS
The limited association between sunlight exposure and BCC incidence may reflect an etiologic contribution of additional environmental agents.
Gailani
M R
MR
Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520-8005, USA.
Leffell
D J
DJ
Ziegler
A
A
Gross
E G
EG
Brash
D E
DE
Bale
A E
AE
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D002280:Basal Cell Carcinoma / Q000209:etiology / Q000235:genetics*; D002648:Child; D002899:Chromosomes, Human, Pair 9 / Q000528:radiation effects; D005260:Female; D017353:Gene Deletion; D016158:Genes, p53; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009381:Neoplasms, Radiation-Induced / Q000209:etiology / Q000235:genetics*; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics*; D013472:Sunlight / Q000009:adverse effects*; D014466:Ultraviolet Rays / Q000009:adverse effects