Common Inherited Gene Increases Risk for Certain Type of Deadly Melanoma
People with red hair, light skin or freckles are more likely than others to develop the deadliest skin cancer - malignant melanoma. A single gene greatly influences these traits. A new study now demonstrates that the same gene is especially likely to put individuals at risk for a particular type of melanoma that most often occurs in one's 40s or 50s - regardless of whether the gene bearers are light-complexioned.
Researchers - led by Boris Bastian, MD, of the UCSF Comprehensive Cancer Center and by Maria Teresa Landi, MD, PhD, from the National Cancer Institute - report in the July 28 issue of Science that being born with variations in a gene called MC1R results in an especially high susceptibility to a genetically distinct form of melanoma. Like freckles, variants in the MC1R gene are relatively common among whites in comparison with the entire world population.
The Science study highlights again how important it is for the fair-skinned to avoid sunburn. The results also led the study authors to the suspicion that susceptibility to damaging mutations in a gene called BRAF may peak before adulthood in individuals born with MC1R variants.
The MC1R gene is the blueprint for a protein found on specialized skin cells called melanocytes. Variants cause melanocytes to make less of a protective pigment called melanin in response to UV exposure. However, MC1R variants may contribute to melanoma risk beyond their effects on pigmentation - even dark-skinned or easily tanning persons with MC1R variants may be at increased risk.
Different Types of Melanoma
Only recently have researchers and clinicians begun to appreciate that there are different types of melanoma. This new recognition is due in large part to Bastian, a dermatologist and skin pathologist who specializes in discriminating among benign and malignant skin growths. Last November, Bastian and colleagues reported in the New England Journal of Medicine there are at least four types of melanomas. The two most common forms of the malignancy in the United States are associated with exposure to the sun's UV rays. In the Science study, Bastian and colleagues found that people with MC1R variants are most susceptible to a type of melanoma that occurs most often among people in their 40s and 50s, and that is found most often on the trunk, arms and legs - skin that normally does not show signs of chronic skin damage associated with age and long-term UV exposure. These melanomas usually have acquired BRAF mutations, which are abnormalities that help drive tumor growth. Drugs are being developed that specifically target tumors driven by BRAF mutation. However, at this time, melanomas - with or without BRAF mutations - are very difficult to treat successfully when not detected early. Another common form of melanoma occurs most often later in life on chronically damaged skin - often on the face or neck. To conduct the study reported in Science, the researchers examined genes and tissue from 197 white melanoma patients from northern Italy and the United States, with and without inherited variant MC1R genes. Among patients with melanomas that arose on skin that had not been chronically damaged, individuals who had inherited two copies of variant MC1R genes had tumors with BRAF mutations in more than 80 percent of cases. BRAF mutations were present in only 30 percent of melanomas that arose on skin that had not been chronically damaged among individuals with two copies of the common, "wild-type" MC1R. Possible Window of Vulnerability During Childhood
Not only the amount of UV exposure, but also the age at which one is exposed might be an important component of risk, Bastian suggests. "If you put it all together, it seems likely that MC1R plus UV light may make young children very vulnerable to developing these BRAF mutations," he says. Consistent with this idea is the fact that melanomas often develop from moles, and a majority of moles arise during childhood and adolescence, according to Bastian. The moles people are born with, Bastian and colleagues have found, never show BRAF mutations. The moles that arise later often have BRAF mutations. Melanomas typically take many years to develop. The earlier average age of diagnosis for BRAF-harboring melanomas on skin not chronically exposed may reflect a childhood window of vulnerability that occurred decades earlier. The best advice for the fair-skinned remains - stay out of the sun. Photo/Kaz Tsuruta
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Boris Bastian |
Only recently have researchers and clinicians begun to appreciate that there are different types of melanoma. This new recognition is due in large part to Bastian, a dermatologist and skin pathologist who specializes in discriminating among benign and malignant skin growths. Last November, Bastian and colleagues reported in the New England Journal of Medicine there are at least four types of melanomas. The two most common forms of the malignancy in the United States are associated with exposure to the sun's UV rays. In the Science study, Bastian and colleagues found that people with MC1R variants are most susceptible to a type of melanoma that occurs most often among people in their 40s and 50s, and that is found most often on the trunk, arms and legs - skin that normally does not show signs of chronic skin damage associated with age and long-term UV exposure. These melanomas usually have acquired BRAF mutations, which are abnormalities that help drive tumor growth. Drugs are being developed that specifically target tumors driven by BRAF mutation. However, at this time, melanomas - with or without BRAF mutations - are very difficult to treat successfully when not detected early. Another common form of melanoma occurs most often later in life on chronically damaged skin - often on the face or neck. To conduct the study reported in Science, the researchers examined genes and tissue from 197 white melanoma patients from northern Italy and the United States, with and without inherited variant MC1R genes. Among patients with melanomas that arose on skin that had not been chronically damaged, individuals who had inherited two copies of variant MC1R genes had tumors with BRAF mutations in more than 80 percent of cases. BRAF mutations were present in only 30 percent of melanomas that arose on skin that had not been chronically damaged among individuals with two copies of the common, "wild-type" MC1R. Possible Window of Vulnerability During Childhood
Not only the amount of UV exposure, but also the age at which one is exposed might be an important component of risk, Bastian suggests. "If you put it all together, it seems likely that MC1R plus UV light may make young children very vulnerable to developing these BRAF mutations," he says. Consistent with this idea is the fact that melanomas often develop from moles, and a majority of moles arise during childhood and adolescence, according to Bastian. The moles people are born with, Bastian and colleagues have found, never show BRAF mutations. The moles that arise later often have BRAF mutations. Melanomas typically take many years to develop. The earlier average age of diagnosis for BRAF-harboring melanomas on skin not chronically exposed may reflect a childhood window of vulnerability that occurred decades earlier. The best advice for the fair-skinned remains - stay out of the sun. Photo/Kaz Tsuruta
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"MCR1 Germline Variants Confer Risk for BRAF-Mutant Melanoma" Maria Teresa Landi, Jürgen Bauer, Ruth M. Pfeiffer, David E. Elder, Benjamin Hulley, Paola Minghetti, Donato Calista, Peter A. Kanetsky, Daniel Pinkel, Boris C. Bastian Science 2006 313(5786):521-522 Abstract | Full Text | Full Text (PDF) |
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"Distinct Sets of Genetic Alterations in Melanoma" John A. Curtin, Ph.D., Jane Fridlyand, Ph.D., Toshiro Kageshita, M.D., Hetal N. Patel, M.S., Klaus J. Busam, M.D., Heinz Kutzner, M.D., Kwang-Hyun Cho, M.D., Setsuya Aiba, M.D., Ph.D., Eva-Bettina Bröcker, M.D., Philip E. LeBoit, M.D., Dan Pinkel, Ph.D., and Boris C. Bastian, M.D. The New England Journal of Medicine 2005 353(20):2135-2147 Abstract | Full Text | Full Text (PDF) |