By Greg Feero, M.D.
The American Cancer Society and the National Cancer Institute estimate that 62,480 people in the United States will be diagnosed with melanoma this year, and that 8,420 people will die from it.
Although melanoma rates have risen steadily in recent decades, data from the Centers for Disease Control show that those rates are particularly high among young women, probably because of the increase in suntanning and use of tanning booths in that population.
Many public health campaigns have focused on exposure to ultraviolet light as a risk factor for melanoma. However, many melanomas occur in areas of the skin that are not exposed to high levels of sun, and many arise outside of previously existing nevi.
In general, the risk factors for melanoma include a history of severe sunburn, numbers of nevi, pale skin, red or blonde hair, light-colored eyes, freckles, history of dysplastic nevi or melanoma, exposure to sunny climates, age, gender, and of course, genetics.
For example, if you are a fair-skinned male living in Australia, your lifetime risk for developing melanoma may be as high as 4%. In the United States, one's lifetime risk of melanoma is about 1%, and this risk almost doubles with a family history of the disorder. If one has a family history of melanoma and a personal history of dysplastic nevi, one's risk for melanoma soars, so that someone with two relatives with melanoma and who has dysplastic nevi has an estimated 500-fold risk of developing a melanoma.
Dysplastic nevus syndrome is a distinct disorder that is inherited in an autosomal dominant manner. Dysplastic nevi are a precursor to malignant melanoma, though only about 5% of all melanomas arise from such high-risk settings.
Genetic testing in these high-risk cases is available but is not routinely recommended. Four loci—CDKN2A, CDK, ARF, and chromosome 1p22—have been associated with dysplastic nevus syndrome. The risk incurred by mutations in CDKN2A, which accounts for about 10%-40% of the families with dysplastic nevus syndrome, confers a roughly 76% lifetime risk of developing melanoma.
Findings from a recent study suggested some value in conducting genetic testing in these families by showing that individuals with a positive test result increased their self-screening beyond recommended levels. Of course, this could lead to more false-positive biopsies, but that may be a reasonable trade-off in this population. There is no indication to use this type of genetic testing in a screening setting, but taking a family history in routine care might identify those needing specialized—and potentially lifesaving—surveillance.
Over the last year or so, genome-wide association studies have begun to shed some light on the underpinnings of sporadic cases of melanoma. Some of the associations are not that surprising because genes that seem to be related to traits such as fair skin or eye color (ASIP, TYR, and TYRP1) turn up as melanoma risk factors.
More recently, an area on chromosome 20q11.22 that contains a number of potentially important genes has been identified.
As with most results from genome-wide association studies, the effect sizes are very small (odds ratio less than 2) but are highly significant. In addition, we are finding that seemingly unrelated disorders can share common genetic defects. A most striking example of this is the shared association found for melanoma, diabetes, and heart disease with the CDKN2A/2B genes.
What mechanistic relationship do these disorders share? Could it be a link though immune function?
It is increasingly likely that in a few years we will have more answers and perhaps be able to develop more effective treatments. In the meantime, advise your patients to cover up—especially when visiting Australia—and watch out for those who have a family history of this serious disorder.
Dr. Greg Feero is a family physician with a doctorate in human genetics from the University of Pittsburgh. He is a senior adviser for genomic medicine in the Office of the Director at the National Human Genome Research Institute.