Red hair gene variants associated with increased mutations in skin cancer

Skin cancer patients who have variations in the MC1R gene, linked to red hair and freckles, have more mutations in their tumors, according to a study in Nature Communications. The results, based on analysis of genetic data from previously published reports, may explain why people with red hair are at a higher risk for skin cancer, according to the authors of the study.


Dr. Brian P. Pollack, Assistant Professor of Dermatology, Pathology and Laboratory Medicine, Research Member, Winship Cancer Institute, Emory University School of Medicine (webpage):

Expertise: clinical dermatology, dermatopathology, basic research related to understanding how oncogenic events influence interactions between tumor cells and the immune system

“It is well established that individuals with red hair and light skin are at increased risk for melanoma, a potentially aggressive form of skin cancer. Red hair results due to variations called R alleles in a gene called the melanocortin 1 receptor (MC1R). While individuals with red hair have two R alleles, those with a single R allele (or no R alleles) usually do not.

“The authors characterized the types and number of DNA mutations as well as R allele status in melanoma samples and found that patients with just one R allele had the same number of mutations as those with two R alleles. This suggests that having just a single R allele impacts the ability of melanocytes to respond to ultraviolet radiation and DNA damage.

“Overall, the methods used were appropriate and justify the conclusions made by the authors. One caveat is that the authors looked at the number of mutations in established tumors and not the risk of developing melanoma. Thus, while the data suggest that having a single R allele promotes DNA damage and/or prevents the repair of DNA damage in tumors, it does not tell us if patients with one R allele are at increased risk for developing melanoma in the first place. This is a very important question raised by this study. For example, should dermatologists and other health care providers ask patients if they have a parent with red hair as a way to determine if they carry an R allele?

“Another important caveat relates to outcome. It is unclear if having a large number of mutations in a patient’s tumor impacts their prognosis; though this is a very active area of research. This is because with the expansion of immune-based anti-cancer treatments, mutations need to be considered in multiple contexts. For example, DNA mutations can be cancer causing events because they change the function of key proteins within cells. However, we’re beginning to understand that mutations can also influence the ability of the immune system to recognize tumor cells by creating altered proteins that are recognized as foreign.”


Dr.Raymond J. Cho, Assistant Professor, Department of Dermatology, University of California, San Francisco (webpage):

Expertise: Understanding how DNA changes accumulate across the genome during the development of skin and other cancers

“Past epidemiological research has shown that individuals born with certain genetic variants giving rise to red hair develop skin cancer more often.

People with red hair usually show low levels of natural skin pigmentation. Skin pigment is known to protect against ultraviolet damage and mutation of DNA. Therefore it has been natural to presume that red-haired individuals frequently get skin cancer because their skin cells are less pigment-protected and accumulate more DNA damage.

“This new report confirms that mutation accumulation occurs much more rapidly, relative to age, in skin cancers of people with certain genetic causes of red hair. It suggests that even non-cancerous cells in individuals with such MC1R alleles may accrue mutations far more easily.

“Surprisingly, some other types of mutations not strongly associated with sunlight were also found in this study to be elevated with in persons with red hair. These data suggest genetics behind differing pigment levels may adjust cancer risk through some mechanisms we do not yet fully understand.”


Declared interests (see GENeS register of interests policy):

No interests declared



‘Germline MC1R status influences somatic mutation burden in melanoma’, published in Nature Communications on Tuesday, 11 July 2016



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