Why males are more at risk for melanoma.

A team of researchers from the University Hospital of Tubingen, Germany, has shown that genetic variations in BRAF, a gene previously implicated in malignant melanoma, could account for a substantial proportion of the so-called sporadic form of the disease. Their results, published 14 November 2003 in the online Journal of Carcinogenesis, also point toward a possible genetic basis for the well-documented observation that men contract the disease at a much higher rate than women.

The sporadic form of malignant melanoma accounts for about 90% of melanoma cases and involves a complex interaction of genotype and environment. The American Cancer Society estimates more than 55,000 new cases of melanoma will be diagnosed in 2004 in the United States.

The scientists analyzed the genomes of 502 German male and female melanoma patients and 450 healthy control subjects, looking for single-nucleotide polymorphisms (SNPs) that might be significantly associated with elevated risk of sporadic melanoma. They found that certain SNPs in BRAF,, which encodes a protein that activates the growth and multiplication of cells, showed an association with the disease, mostly in males. They also found six noncoding SNPs and two haplotypes that conferred a significantly increased risk for developing melanoma in male patients. Although these predominantly male risk factors correlate with and may at least partially explain the higher incidence of melanoma in males versus females, the mechanism behind this sex-linked effect remains unclear, as does the role of BRAF aberrations in the etiology of melanoma.

"We are interested in addressing the question of whether carrying certain variants of the BRAF gene could predispose people to having or developing more moles, and thus to an increased risk of developing melanoma," says principal investigator Claus Garbe. Based on genotype frequencies, they estimate that BRAF could put as much as 4% of the German population (both male and female) at risk for the condition, more than four times that attributed to another major melanoma susceptibility gene, CDKN2A.

Lead author Peter Meyer says the group also found other genetic variations that might be associated with elevated melanoma risk. He hopes that replication studies and functional approaches will elucidate the significance of these additional findings. "We hope that others will test BRAF in their study populations to replicate our results," he says. "Later, functional assays should lead us to understand what are the genetic variations that really influence melanoma risk."

James Evans, director of clinical cancer genetics at the University of North Carolina at Chapel Hill, sees the work as "a potentially important study, as the identification of genetic predisposition toward this common malignancy would be helpful on both the clinical and research fronts." Evans agrees, however, that replication studies will be critical, in the German cohort as well as in other populations. "The human genome is a big place," he says, "and coincidental 'associations' are common."

Ultimately, says Meyer, BRAF could be useful as a biomarker for screening purposes to help identify both males and females at heightened risk for melanoma. Those individuals could then be clinically monitored more frequently and counseled to take preventive lifestyle measures such as avoiding the sun. The clinical decision as to whether to prophylactically remove atypical or dysplastic moles, which are potential melanoma precursors, would also be easier in patients identified to carry risk haplotypes.