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Dissecting BCC Risk

Some genetic components of the risk for basal cell carcinoma have nothing to do with pigmentation.

We don't understand the molecular basis for susceptibility to basal cell carcinoma nearly as well as we understand the basis for susceptibility to cutaneous melanoma. Because sun exposure is the main risk factor for BCC, alleles associated with light pigmentation likely contribute to BCC risk. However, variants that do not directly influence pigment may ultimately provide the greatest insight into the pathogenesis of BCCs and other nonmelanoma skin cancers.

The authors of the deCODE study, who previously identified several BCC risk loci (see JW Dermatol Nov 7 2008), extended their analysis to 30 likely single nucleotide polymorphisms (SNPs) from a genome-wide association study. Genotyping an additional 903 Icelandic BCC cases and a case-control sample from eastern Europe, the researchers found three additional SNPs significantly associated with risk for BCC but not for squamous cell carcinomas or melanoma. The SNP at rs11170164 in the keratin 5 gene (KRT5) was particularly interesting because it implicates a structural protein rather than a pigmentation gene in BCC risk (odds ratio in non-Icelandic samples, 1.49; P=4.6x10⁶). This SNP had only a weak association with SCC risk and none with melanoma, and because it had no relation to hair or eye color, pointed to an element of BCC risk unrelated to pigmentation. On further examination, this locus contained another polymorphism independently related to BCC risk.

The researchers also identified a BCC-risk locus on 9p21, the site of the cyclin-dependent kinase inhibitor genes CDKN2A and CDKN2B, the ARF tumor suppressor encoded by CDKN2A, and the noncoding RNA ANRIL. The involvement of CDKN2A in hereditary melanoma is well known, but the SNP here was not associated with cutaneous melanoma, SCCs, or pigmentation. Interestingly, a BCC-associated SNP near the telomerase gene (TERT) appeared to be protective against melanoma.

Comment: These highly complex findings may prove pivotal to our understanding of BCC formation. The association between structural protein keratin 5 and blistering disorders is well known, but common KRT5 variants now appear to also influence BCC and SCC risk. This represents a paradigm shift in BCC etiology, because the KRT5 association is independent of pigmentation. In addition, chromosome 9p21 appears to be a disease hotbed, and refined assessment of this region is needed before a coherent disease model can be formulated. Finally, some SNPs associated with increased BCC risk are clearly distinct from those that confer melanoma risk — in fact, some variants confer BCC risk but protect against melanoma. These competing genetic events underscore the complexity of skin cancer biology, belying the theory that most skin cancers arise from "too much sun."

— Hensin Tsao, MD, PhD

Published in Journal Watch Dermatology August 21, 2009

Citation(s):

Stacey SN et al. New common variants affecting susceptibility to basal cell carcinoma. Nat Genet 2009 Aug; 41:909.

• Medline abstract (Free)

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