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Senior Citizen Health & Medicine
Inherited Gene Found to Increase Melanoma Risk
About 7,910 Americans are expected to die of
melanomas during 2006
June 30, 2006 The most common cancer is skin
cancer melanoma. Although about half of all cases occur in people
older than 56, it is unusual for a cancer to appear in so many younger
people. New research by the National Cancer Institute has found a link
between inherited and acquired genetic factors that dramatically
increase the chance of developing a very common type of melanoma. It is
information that may be of particular interest to senior citizens that
need to alert their children and grandchildren.
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This finding appears in an online version of
Science on June 29, 2006, and was a collaborative effort led by
scientists at NCI, part of the National Institutes of Health, 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, Italy.
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.
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Key Melanoma Statistics |
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By  American
Cancer Society
Cancer of the skin is the most common of
all cancers, probably accounting for more than 50% of all
cancers. Melanoma accounts for about 4% of skin cancer cases but
causes a large majority of skin cancer deaths.
Melanoma tends to occur at a younger age
than most cancers. Half of all melanomas are found in people
under age 57. Adolescents can have melanoma also. About 1 of
every 30,000 girls aged 15 to 19 will develop melanoma. For boys
of this age, the rate is about 1 of every 15,000.
The American Cancer Society estimates
that about 62,190 new melanomas will be diagnosed in the United
States during 2006. The number of new melanomas diagnosed in the
United States is increasing. Among white men and women in the
United States, incidence rates for melanoma increased sharply at
about 6% per year from 1973 until the early 1980s. Since 1981,
however, the rate of increase slowed to little less than 3% per
year. For the last 2 years in which there is information, this
increase may have slowed even further.
About 7,910 people in the United States
are expected to die of melanomas during 2006. Since 1973, the
mortality rate for melanoma has increased by 50%. Much of this
increase has been in older people, mostly white men. More
recently, the death rate from melanoma has leveled off for men
and dropped slightly in women.
>>
More at American Cancer Society |
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On the other hand, melanomas developing
in older subjects with sufficient accumulated sun exposure to produce
chronic damage also exhibit lower BRAF mutation frequencies.
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 NCIs Cancer Information Service at 1-800-4-CANCER
(1-800-422-6237).
The National Institutes of Health (NIH) The
Nation's Medical Research Agency includes 27 Institutes and Centers
and is a component of the U.S. Department of Health and Human Services.
It is the primary federal 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.
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