Pigment-related gene variations can reflect melanoma susceptibility

Variations in the DNA sequence of genes that play a role in determining skin pigmentation could be used to identify people at risk of developing melanoma targets for future research, the author of a recent study says.

Key Points

"The best way to reduce the incidence of mortality as a result of melanoma is to prevent the occurrence or to catch it very early," says Prashiela Manga, Ph.D., assistant professor of dermatology at New York University (NYU) School of Medicine. The only way to accomplish those goals is to identify people at risk and educate them regarding melanoma prevention and the importance of skin self-examinations, she adds.

Melanoma development

More specifically, investigators led by Iman Osman, M.D., of the NYU Interdisciplinary Melanoma Cooperative Group, prospectively enrolled 400 Caucasian patients seen at NYU Langone Medical Center for either a first diagnosis or first recurrence of melanoma. Investigators then compared the distribution of single nucleotide polymorphisms (SNPs) associated with pigmentation and DNA repair genes with the distribution of those same SNPs in an age- and gender-matched control group of 400 Caucasians. Researchers then had to determine whether the markers provided an effective measure of melanoma risk.

In addition, they analyzed Ancestry Informative Markers (AIMs), which had been developed for analyzing ancestry in European populations. These markers can be used to determine if variations in genes are better indicators of susceptibility in a particular population group or can be used as a more general measure of risk. Because ancestry plays a large role in determining skin pigmentation, Dr. Manga says, "We found that some of these AIMs actually indicated increased risk of melanoma."

Moreover, she says, "We might have inadvertently identified either new pigmentation genes or genes that may be important in development of melanoma." Researchers do not yet know whether the latter is true. "Right now, we're looking at these markers, which were chosen primarily because they are distributed differently in various European populations. We're not sure what the genes associated with these markers do yet. But we predict that they are probably involved in determining skin pigmentation."

Inheritance factors

Researchers also examined inheritance of particular genes that have been implicated either in determining skin pigmentation or repairing DNA damage. "We came up with six genes that seem to play a role in determining melanoma risk," Dr. Manga says. These include OCA4, TYR, OCA2, TYRP1, ERCC3 and ERCC5.

Investigators looked at several markers/SNPs for each gene and discovered, for example, that the rs10461928 SNP is associated with an overall melanoma risk odds ratio of 2.43. Investigators also identified two separate subpopulations within their sample. In some cases, a SNP had a stronger effect in one group versus the other.

Researchers still must determine how the genes they studied contribute to melanoma or, in some cases, melanoma resistance, Dr. Manga says. "We've used markers to trace the inheritance of a gene. But we don't know what feature of the gene is conferring a susceptibility to melanoma. That's our next step."

With pigmentation genes, she says, "It's a little easier to determine because we can use how much melanin is made as a measure." With DNA repair genes, "It's a bit trickier." To that end, she says investigators used various assays to determine the role of particular genes in melanoma protection or susceptibility.

However, Dr. Manga says, "We are starting to understand what these genes do and how they function." This will allow development of drugs targeted to them.

"If we understand why a person has extremely light skin, or a reduced capacity to repair DNA, there is the potential to target these genes individually to increase either the capacity to make melanin or to repair DNA," Dr. Manga explains. Already, she says she and her NYU colleague Seth J. Orlow, M.D., Ph.D., have identified several agents that can increase pigmentation in cells that lack OCA2.

"We don't know how these preliminary results will carry over" in subsequent testing, most likely beginning with artificial skin. "But this is a very early indication that we may be able to target these genes individually with prophylactic agents," she says.

The future

Going forward, "We have all these genes that we've implicated in melanoma. We need to understand exactly how they impact melanoma risk. We have used surrogate markers for tracing these genes, but it would be interesting to know what exactly the variant in the sequence is that confers either susceptibility or protection," Dr. Manga says.

To do this, she says she and her colleagues plan to trace down the specific DNA changes involved. "We can then look at the effects that they have on the proteins that they encode, so that we could use them as markers for genetic testing at some point, or as targets for chemical screens."

Because different sequence variants can have different effects on the proteins that they encode, "We may end up having to drug-target individual variants of these proteins. A drug may have an effect in one variant, but not another," Dr. Manga explains.

At press time, Dr. Manga says she and her colleagues had just begun sequencing the melanoma-influencing genes they have identified to try to pinpoint such variants.

Disclosures: Dr. Manga reports no relevant financial interests. Stiefel sponsored the Dermatology Research Symposium, where Dr. Manga presented her research.

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