DENVER — Identification of individuals possessing certain melanocortin-1 receptor gene variants may provide added value in detecting 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 genetic marker of melanoma risk. What's 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.
As expected, the established risk factors were strongly associated with an increased likelihood of melanoma. Red hair was associated with an adjusted threefold risk of the malignancy, as was self-reported inability to tan following repeated sun exposure. Heavy freckling was associated with a 4.1-fold increased risk, and a history of 11 or more sunburns before age 18 years carried a 2.5-fold elevated risk.
Possession of a high-risk MC1R variant such as D84E, D29H, R160W, or R151C 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 1-3 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. “This really reemphasizes the notion that there are multiple pathways to melanoma,” Dr. Kanetsky observed in an interview.
Based on his findings, Dr. Kanetsky estimated that 8%-33% of all melanomas could be detected at an early stage 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.' DR. KANETSKY