DENVER — Identification of individuals possessing certain melanocortin-1 receptor gene variants may aid in detection of those at increased risk of melanoma.
New evidence indicates the melanoma risk associated with melanocortin-1 receptor (MC1R) high-risk variants is strongest in individuals who would be classified as lower risk by the classic phenotypic criteria such as darker hair, skin, and eye color and absence of freckles, Peter A. Kanetsky, Ph.D., reported at the annual meeting of the American Association for Cancer Research.
“What these data are showing us is that, for certain people, genotype does mean something. If you have red hair we know you're at increased risk for melanoma, and knowledge of MC1R really isn't going to tell us a lot; however, for somebody who has dark hair, knowing MC1R might give us a clue as to who is going to be at increased risk,” explained Dr. Kanetsky, an epidemiologist at the University of Pennsylvania, Philadelphia.
In the past decade MC1R has emerged as a potent marker of melanoma risk. What is now clear, however, is that the increased risk associated with inheritance of high-risk MC1R variants is fortuitously stronger in, and perhaps confined to, individuals with protective phenotypes such as darker complexion and absence of freckles, he continued.
Dr. Kanetsky presented a case-control study involving 779 melanoma patients and 325 controls, all with complete MC1R genotyping.
Possession of a high-risk MC1R variant was associated with an overall 1.9-fold increased risk of melanoma. Upon closer inspection, though, the risk was essentially confined to individuals who wouldn't usually be thought to be at increased risk because they possessed protective phenotypes.
Among individuals with moderate or heavy freckling, a high-risk MC1R variant didn't confer any additional increase in melanoma risk beyond that associated with a low-risk MC1R genotype, but in subjects with mild freckling, a high-risk MC1R variant was associated with a 2.5-fold increase in risk compared with a low-risk genotype. In those with no freckling, a high-risk MC1R variant brought an eightfold increase in risk.
Similarly, a high-risk MC1R variant didn't increase melanoma risk in individuals with red or blond hair, but in those with dark hair it boosted the risk 2.4-fold. And again, subjects with 11 or more sunburns prior to age 18 years had no further increase in melanoma risk if they possessed a high-risk MC1R variant, while a high-risk variant conferred a 2.6-fold increase in risk among individuals with one to three sunburns prior to age 18 and a 3.7-fold increased risk in those with no sunburns before age 18.
In contrast, the risk of melanoma associated with high-risk MC1R variants was greatest in those with a total nevus count of 54 or more or with 4 or more dysplastic nevi, both known to be strong markers of increased melanoma risk.
To confirm their findings, he and his coinvestigators turned to the published literature. They found seven studies on melanoma risk stratified by MC1R associations, which they compiled in a metaanalysis. As in their own study, the metaanalysis showed that the risk associated with inheritance of a high-risk MC1R variant was largely confined to individuals with darker hair, eyes, and skin color or with a high nevus count.
Based upon his study findings, Dr. Kanetsky estimated that 8%-33% of all melanomas could be detected at an early stage and potentially cured by screening for high-risk MC1R variants in patients with protective phenotypes.
'What these data are showing us is that, for certain people, genotype does mean something.'
Source DR. KANETSKY