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Red Hair-Linked Gene Variants Also Associated With Increased Skin Cancer Mutations

NEW YORK (GenomeWeb) – The gene linked to having red hair is also associated with an increased somatic mutation load in melanoma, according to a study led by researchers at the Wellcome Trust Sanger Institute.

The Sanger Institute's David Adams and his colleagues examined the somatic mutational landscape of some 400 people with melanoma from The Cancer Genome Atlas and the Yale Melanoma Genome Project and correlated that with the melanocortin 1 receptor (MC1R) alleles the patients harbored. MC1R encodes a G-protein coupled receptor found on melanocyte surfaces and has been linked to melanoma risk.

As the researchers reported today in Nature Communications, melanoma patients with one or two R alleles — an allele that, when present as two copies, is associated with red hair, freckles, and a tendency to burn after being in the sun — had higher mutational loads than people without an R allele. These patients harbored mutational signatures that suggested the mutations arose after sun exposure.

"It has been known for a while that a person with red hair has an increased likelihood of developing skin cancer, but this is the first time that the gene has been proven to be associated with skin cancers with more mutations," Adams said in a statement.

He and his colleagues examined SNVs present in the TCGA and Yale cohorts of melanoma patients, and classified for each patient all non-synonymous and nonsense MC1R variants as R, r, or wild type. Some 8 percent of the TCGA cohort had two R alleles, while 41 percent had one, and 51 percent had none. Similarly, 4 percent of patients in the Yale cohort had two R alleles, 41 percent had one, and 55 percent had none.

The researchers also categorized the SNVs they uncovered by the type of nucleotide change, such as whether it was a cytosine-to-thymine transition or a thymine-to-adenine transversion. Then, using a negative binomial regression, they modeled the relationship between the expected SNV burden and the presence of MC1R alleles.

For all six mutation types, the researchers noted an increased burden of SNVs in patients with one or two R alleles. After correcting for testing six mutation classes, they reported statistically significant differences in the expected and observed SNV counts for all six mutation classes in the combined dataset. Adams and his colleagues further calculated that harboring one or more R alleles was linked with a 42 percent increase in expected somatic SNV count.

"Unexpectedly … people with only a single copy of the gene variant still have a much higher number of tumor mutations than the rest of the population," Adams added. "This is one of the first examples of a common genetic profile having a large impact on a cancer genome and could help better identify people at higher risk of developing skin cancer."

He and his colleagues also reported that eight mutational signatures accounted for nearly 98 percent of the mutations present in the combined dataset, and that sun exposure-associated cytosine-to-thymine substitutions were the most common mutation, across all genotypes.

By knocking down MC1R in a cell line of primary human melanocytes — which reduced but didn't eliminate MC1R expression — and exposing those cells to increasing amounts of UV light, the researchers found that reduced MC1R expression affected survival and DNA repair and led to increased cyclobutane pyrimidine dimers, which occur in response to sun exposure and lead to cytosine to thymine substitutions

The findings also emphasize the need for people to protect themselves from sun exposure, Julie Sharp, head of health and patient information at Cancer Research UK, said in a statement. "[It] isn't just people with red hair who need to protect themselves from too much sun," she added. "People who tend to burn rather than tan, or who have fair skin, hair or eyes, or who have freckles or moles are also at higher risk."

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