Genetic research is putting a new complexion on melanoma risk.
It has long been known that people with red hair, fair skin, freckles, and an inability to tan are at the highest risk for melanoma. But a new mouse study published in the journal Nature suggests they are at greater risk even if they never go out in the sun -- thanks to a genetic mechanism that's linked to their fair coloring.
"We've known for a long time that people with red hair and fair skin have the highest melanoma risk of any skin type," study author Dr. David Fisher of Massachusetts General Hospital said in a statement. "The risk for people with this skin type has not changed, but now we know that blocking UV radiation -- which continues to be essential -- may not be enough."
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The key appears to be the gene for the melanocortin 1 receptor, MC1R, whose genetic variations lead to different levels of two variants of melanin -- the brown-black eumelanin and the red-yellow form, pheomelanin.
So-called RHC polymorphisms -- named after the red hair color associated with them -- lead to lower levels of eumelanin and higher levels of pheomelanin, the researchers noted.
Pheomelanin is less able to protect against ultraviolet light, which is at least part of the reason redheads have a higher risk of skin cancer in general.
But for melanoma, that can't be the whole answer, Fisher and colleagues noted, because -- unlike other skin cancers -- melanomas appear on skin that is not exposed to sunlight and mutations that drive the disease are only rarely related to UV damage.
To investigate the issue, they turned to mice that were genetically identical except that one strain did not have a complete MC1R gene and so produced relatively high levels of pheomelanin and another had a mutation that prevented any pigment from being synthesized although the MC1R gene was normal.
The three strains -- dubbed black, red, and white because of their coat color -- were crossed with mice that expressed BRafV600E, one of the most common gene mutations in melanoma, in their pigment-producing melanocytes.
In the absence of UV light, less than a quarter of both the black and the white mice developed melanoma after a year. In contrast, half the red mice had developed cancer by year's end, Fisher and colleagues found.
Put another way, animals with high levels of pheomelanin -- the red mice -- were more susceptible to melanoma than those with relatively low levels or none at all.
The experiment suggests, the researchers concluded, that there may be "intrinsic carcinogenic features" of pheomelanin synthesis and perhaps even the substance itself.
One possibility is damage caused by reactive oxygen species, the researchers noted, since there is evidence that pheomelanin amplifies ultraviolet-A-induced reactive oxygen species.
They cautioned that the study doesn't "diminish the importance of sun exposure" as a key contributing factor in the pathogenesis of melanoma.
On the other hand, Fisher said, the findings may lead to better sunscreens and other measures "that directly address this pigmentation-associated risk while continuing to protect against UV radiation."
Indeed, decreasing the risk is "perhaps the most pertinent question," commented Drs. Meenhard Herlyn and Mizuho Fukunaga-Kalabis of the Wistar Institute in Philadelphia.
In an accompanying News & Views article, they said it's possible that, in the black mice and presumably their human counterparts, the abundant eumelanin scavenges the reactive oxygen species spawned by pheomelanin.
If so, researchers should look at topical compounds that increase eumelanin synthesis as well as oral antioxidants to see if they reduce melanoma risk in redheads, they argued.
In the meantime, they concluded, redheads should continue to get regular skin check-ups to catch melanoma early.