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Pale Melanoma Susceptibility Linked to Albinism-Related Genes

NEW YORK – New research suggests so-called "pale melanomas," marked by melanin pigment-poor, flesh-toned tumors in individuals with light-colored skin and hair, may be more common in individuals with inherited germline or somatic changes in albinism-related genes.

As they reported in PLOS One on Wednesday, researchers from the University of Queensland, QIMR Berghofer Medical Research Institute, and elsewhere used exome sequence data to search for suspicious mutations in more than 300 individuals with pigmented melanoma, including 28 individuals with amelanotic or hypomelanotic melanoma, comparing the protein-coding sequences to those from more than 1,100 population controls from Australia. In particular, they scrutinized gene-coding sequences for half a dozen genes linked to albinism in past studies.

After incorporating array-based genotypes or hundreds more pigmented or amelanotic/hypomelanotic cases or controls, the team saw an over-representation of rare alterations affecting one copy of albinism-related genes such as TYR or OCA2 in the individuals with pale melanoma.

"These people may be more prone to developing pale-colored melanomas, called amelanotic, because tumors accumulate new mutations, and they already have a mutated albinism gene," first author Jenna Rayner, a dermatologist and researcher at the University of Queensland, said in a statement, noting that these and other findings from the new study "could optimize early intervention and consequently improve patient outcomes."

The researchers highlighted an OCA2 allele called V443I that was enriched across all of the melanoma cases, but was particularly common in individuals with amelanotic/hypomelanotic forms of melanoma. On the other hand, they noted more than 7 percent of individuals with pigmented melanoma and 9.4 percent of unaffected controls had an OCA2 haplotype associated with darker skin or eye color — a haplotype that was not found in the amelanotic/hypomelanotic melanoma cases considered.

"These results clearly demonstrate that rare albinism-associated variants in TYR, and the OCA2 p.V443I variant, are more frequent in individuals with melanoma compared to controls," the authors wrote.

From their findings, the authors suggested that both germline variants and somatic loss-of-function changes in OCA2 or TYR may produce forms of melanoma with little or no pigmentation — consistent with the uptick in somatic mutations in TYR and OCA2 that have been identified in amelanotic/hypomelanotic melanoma tumors profiled for the Cancer Genome Atlas project.

Together, these and other findings suggested that the presence of such alterations may help to track down melanoma-susceptible individuals and pale melanoma cases that might otherwise by missed, since amelanotic/hypomelanotic melanomas can be difficult to detect compared to pigmented melanoma. 

"Amelanotic melanomas are normally diagnosed in advanced stage, compared with darker melanomas, causing patients to often miss out on early treatment and their best chance of a cure," senior and corresponding author Rick Sturm, a dermatology researcher at the University of Queensland's Diamantina Institute, said in a statement.

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