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Cutaneous Melanoma Clues Found From Risky SNPs, Related Traits Analyses

NEW YORK – An international team led by investigators at the National Cancer Institute, the University of Leeds, and QIMR Berghofer Medical Research Institute has tracked down dozens of loci linked to cutaneous melanoma susceptibility by considering the genetics of melanoma diagnoses as well as related traits or phenotypes.

As they reported in Nature Genetics on Monday, the researchers narrowed in on risk loci related to melanoma in general, along with still other secondary risk sites associated with cutaneous melanoma — a dangerous form of skin cancer related to ultraviolet (UV) light exposure that is more common in individuals with light skin and eye color.

"The discovery of new loci and genes augments our understanding of cutaneous melanoma risk and provides many new insights into cutaneous melanoma etiology," co-senior author Matthew Law, a statistical genetic researcher with QIMR Berghofer Medical Research Institute, and Mark Iles, a data analytics researcher at the University of Leeds, and their colleagues wrote.

Iles, Law, and colleagues started with a genome-wide association meta-analysis of array- and imputation-based genotyping profiles for 36,760 individuals with melanoma and 375,188 unaffected control individuals from the US, UK, Australia, Northern Europe, Western Europe, and the Mediterranean, including research-consented 23andMe customers and participants in the UK Biobank project.

The study participants included 30,134 individuals with clinically confirmed cutaneous melanoma diagnoses and 6,626 self-reported cutaneous melanoma cases, they noted, and the meta-analysis highlighted 68 SNPs with significant ties to melanoma at 54 genomic loci — a set that encompassed 19 of the 21 loci implicated in cutaneous melanoma in the past.

When it came to secondary traits contributing to cutaneous melanoma, meanwhile, the team analyzed data from the GWAS meta-analysis — in combination with a complementary transcriptome-wide association analysis (TWAS) using available melanocyte cell expression data, hair color clues, and "nevus," or mole, counts — to find dozens more candidate loci with ties to secondary, cutaneous melanoma-related traits.

"Many of the loci previously associated with nevus count or pigmentation are also associated with cutaneous melanoma, confirming the close relationship between these traits," the authors reported, adding that "combined analysis of cutaneous melanoma, nevus, and hair color GWAS data, and use of expression data through TWAS, identified 31 secondary, potential loci."

Together with population risk data, information on the cutaneous melanoma subtypes present in the study participants, individuals' age at diagnosis, and polygenic risk score analyses, the researchers saw signs that the risk of at least one cutaneous melanoma subtype known as acral  melanoma does not appear to be related to an individual's pigmentation.

With the data on hand, the team was also able to take a closer look at the biological pathways that may contribute to cutaneous melanoma risk, the tissue types involved, cutaneous melanoma heritability, and more. The investigators noted that additional data is needed to confirm and expand on the current findings.

"While the biological mechanisms underlying many of the existing and new cutaneous melanoma risk loci remain to be confirmed or discovered by post-GWAS functional studies and even larger GWAS, these data suggest potential pathways new to melanoma susceptibility," the authors concluded, "and highlight nevus formation, pigmentation, and telomere maintenance, the three pathways that appear to dominate the landscape of melanoma susceptibility."

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