|Scientists Identify an Inherited Gene That Strongly Affects
Risk for the Most Common Form of Melanoma
Researchers at the National Cancer Institute (NCI), part of the National Institutes
of Health, have identified a link between inherited and acquired genetic factors
that dramatically increase the chance of developing a very common type of melanoma.
This finding appears in an online version of Science* on
June 29, 2006, and was a collaborative effort led by scientists at NCI and the
University of California San Francisco. Also involved in the study were researchers
at the University of Pennsylvania, Philadelphia, and Bufalini Hospital in Cesena,
“Knowing who is at greater risk for melanoma due to heredity, and understanding
the pathways leading to cancer, are important steps in addressing a disease which
is expected to be diagnosed in over 62,000 Americans in 2006,” said National
Institutes of Health Director Elias A. Zerhouni, M.D.
People with fair skin are generally at increased risk of developing melanoma.
Differences in skin color, or pigmentation, are due largely to the melanocortin-1
receptor (MC1R) gene. Everyone has two copies of MC1R; one inherited from the
mother and one from the father, and either can be the standard form or a variant.
Some variant forms of MC1R are responsible for traits such as fair skin, freckling,
and red hair. But MC1R may do much more than influence pigmentation.
“We previously observed that subjects who inherit one or two variant forms of
the MC1R gene had a modest increase in risk of developing melanoma, even if they
have darker pigmentation,” said Maria Teresa Landi, M.D., Ph.D., lead study investigator
at NCI. “We have now discovered that MC1R dramatically predisposes individuals
with no excessive sun exposure and variable pigmentation to developing a particular
type of melanoma.”
Melanomas, which are tumors that arise from cells which produce skin pigment,
can occur on all parts of the body where these cells are present. Caucasians
have a much higher chance than other populations of developing these tumors on
skin areas that are exposed to the sun. Sun exposure has many effects on skin,
including causing chronic sun damage, with wrinkling on areas subject to high
exposure over a lifetime. Sun exposure may also lead to mutations in cancer-causing
genes, such as BRAF, which are frequent in melanoma.
According to Boris Bastian, M.D., University of California, San Francisco, “The
relationship between BRAF mutations in melanoma and sun exposure is complex and
intriguing. On the one hand, sun exposure appears necessary for development of
BRAF mutations; melanomas on areas such as the soles of feet and palms of hands,
which have low exposure, have low mutation frequencies compared to the approximately
60 percent mutation frequency in sun-induced melanomas on skin without chronic
sun damage. On the other hand, melanomas developing in older subjects with sufficient
accumulated sun exposure to produce chronic damage also exhibit lower BRAF mutation
Because melanomas on skin areas with few signs of chronic sun-induced damage
occur in younger people and exhibit frequent mutations in BRAF, the researchers
hypothesized that there were inherited genetic factor(s) that predispose to the
development of these melanomas with BRAF mutations. An interesting candidate
for this genetic risk factor was the MC1R gene.
To determine if there was an association between inherited variant forms of
MC1R and the development of BRAF-mutant melanoma, the researchers studied the
skin surrounding the melanomas in 85 patients from the Bufalini Hospital of Cesena,
Italy, and 112 patients from the Department of Dermatology at the University
of California, San Francisco, and identified subjects with no or little signs
of chronic sun damage. They then sequenced MC1R genes in normal cells and BRAF
in tumor cells and found that BRAF mutations were more frequent in non-chronic
sun-induced melanoma cases with hereditary genetic variant forms of MC1R.
By categorizing patients into two groups, those with no variant forms of MC1R
versus those who had at least one variant, the scientists found that BRAF mutations
were six to 13 times more frequent in those with at least one MC1R variant form.
Looking more closely, the investigators found that the risk for melanoma with
BRAF mutations rose with increasing number of MC1R variant forms. Comparing data
from melanoma patients and healthy controls, the risk for melanomas with BRAF
mutations increased from seven times for individuals with one MC1R variant form,
to 17 times for those with two variant forms, when compared with individuals
with the standard MC1R.
The study results show that normal variations in the MC1R gene in Caucasians
have a very specific effect on melanoma susceptibility. Additional inherited
factors that affect susceptibility may also be present, but they have yet to
be discovered. “The mechanism by which variant forms of the MC1R gene facilitate
development of melanomas with BRAF mutations is currently unknown,” said Landi. “One
possibility is that people with MC1R variant forms and variable pigmentation
generate more reactive chemicals in their cells as a result of the ultraviolet
exposure in sunlight. These reactive chemicals can induce mutations, like those
in the BRAF gene, which may lead to cancer.”
Clinical trials for melanoma using pharmaceutical drugs directed against the
BRAF gene are ongoing. Knowledge of predisposing factors in the development of
BRAF mutations, such as MC1R, might aid prevention and therapeutic strategies
in the future.
For more information about cancer, please visit the NCI Web site at http://www.cancer.gov,
or call NCI’s Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
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agency for conducting and supporting basic, clinical and translational medical
research, and it investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs, visit www.nih.gov.