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GENETICS OF MELANOMA 1
Melanoma is considered to be a family disease when two or
more first-degree relatives (parents, brothers, sisters, children)
are diagnosed with melanoma. This is sometimes referred to
as familial melanoma. Since sun exposure is a known risk factor
for developing melanoma, people living in the southern United
States or other parts of the world with high sun exposure,
familial melanoma is defined as three or more first-degree
relatives with melanoma.
There are other important signs that suggest possible cases
of heritable melanoma, including:
- More than one case of melanoma
in the same person
- Melanoma diagnosed in early adulthood.
- Multiple atypical or dysplastic nevi (Dysplastic nevi are large
(larger than 5 mm) clinically abnormal flat moles with
an indistinct irregular border and uneven color that can occur in areas without
much sun exposure. They identify individuals at increased
risk
of melanoma. Although dysplastic nevi are likely to be
related to altered genes, the specific genes involved have not been
identified.)
If a person has a first-degree relative with melanoma,
his or her risk of developing melanoma is two to three
times
greater than the general population risk.
People who are concerned about their family history
of melanoma can consult a genetic counselor. Genetic
counselors are trained
to assess the potential for hereditary cancer risk
in a family and can identify appropriate genetic
testing or research
studies.
There are a growing number of genes thought to be associated
with an increased risk of melanoma. However, more research
is needed to better understand how these genes impact the risk
of melanoma. Below is a discussion of some of the possible
diseases that lead to an increase in the risk of melanoma and
their associated genetic defects. Having a particular genetic
mutation linked to melanoma does not yet accurately predict
that a person will develop cancer. Research is underway to
clarify these risks.
Hereditary melanoma. At least three genes have been linked
to hereditary melanoma. Families with mutations in these genes
may have multiple dysplastic nevi. The association of familial
melanoma and multiple dysplastic nevi is also sometimes called
familial atypical multiple mole melanoma (FAMMM) or atypical
nevus syndrome.
Mutations in the CDKN2A gene (also called p16 and MST1) are
thought to account for approximately 25% of hereditary melanoma
cases. People who have mutations in the CDKN2A gene have a
nearly 70% risk of developing melanoma during their lifetime,
but the risk varies by geographic location. Some families with
these mutations also have an increased risk (up to 17%) of
developing pancreatic cancer. Pancreatic cancer, however, is
much less frequent than melanoma in these families.
The CDKN2A gene is called a tumor suppressor gene. Tumor suppressor
genes make proteins that suppress tumor formation by limiting
cell growth. Mutations in tumor suppressor genes result in
a loss of the ability to restrict tumor growth and, as a result,
cancer can develop. CDKN2A is a rather unique gene, in that
it can produce two different proteins, p16 and p14ARF, depending
on how the gene is "read." Mutations affecting p16
are known to be associated with an increased risk of melanoma
and pancreatic cancer. The cancer risk associated with mutations
affecting p14ARF is not as well understood, although there
appears to be some increased risk for melanoma, and possibly
other cancers, in a small number of families.
Genetic testing for mutations in CDKN2A is available, but
such testing is not being routinely performed outside of a
research setting since researchers do not fully understand
the implications of certain types of mutations. In addition,
several types of melanoma that run in families do not yet have
clearly defined genetic causes.
Mutations in the CDK4 gene are responsible for an increased
risk of melanoma in a very small number of families. The cancer
risks associated with mutations in CDK4 are thought to be similar
to those in families with mutations in CDKN2A. The CDK4 gene
is called a proto-oncogene. Proto-oncogenes make proteins that
promote normal cell growth. Mutations in proto-oncogenes result
in too much cell growth and can lead to cancer. Genetic testing
for mutations in the CDK4 gene is not available. Based on limited
data, the clinical characteristics of melanomas occurring in
families with CDK4 mutations are quite similar to those in
families with CDKN2A mutations.
Recently, a third area on chromosome 1 (1p22) has been shown
to possibly contain another melanoma susceptibility gene that
has not yet been identified. There is also evidence that additional
genes associated with hereditary melanoma exist. This is a
very active area of research.
People at risk for hereditary melanoma should examine their
skin carefully each month to look for changes in the appearance
of moles. Screening should begin by age 10 in children at risk.
Skin examinations by a trained health-care provider should
be performed yearly or more frequently if necessary.
Melanoma-astrocytoma syndrome. People with this rare condition
have an increased risk of melanoma and astrocytoma (a type
of brain tumor). The specific gene for this condition is thought
to be located on chromosome 9. Families with both melanoma
and neural tumors have been described with alterations in CDKN2A
that affect the p14ARF protein.
Other genetic conditions that are associated with an increased
risk of melanoma include xeroderma pigmentosum, retinoblastoma,
Li-Fraumeni syndrome, ataxia-telangiectasia, and Werner syndrome.
Environmental Factors
A risk factor is anything that increases a person's risk of
developing a disease.
In addition to family history, there are other environmental
and lifestyle factors that may increase the risk of melanoma.
Discussing family history and personal risk factors, especially
the type (dysplastic nevi) and number of moles, complexion,
and extensive freckling with a doctor may help someone better
understand his or her risk. People with risk factors for melanoma
are encouraged to see their doctor at least once a year for
skin examination. In general all people but particularly people
with a higher than average risk may benefit from sun-protective
behavior and early detection strategies.
Whereas, a person’s genetic makeup is out of that person’s
control, controllable risk factors also play a large role in
risk of melanoma and can be avoided or minimized. Sun or other
types of ultraviolet light exposure (such as tanning beds)
are the most important controllable risk factors for melanoma.
Currently, to prevent melanoma, it is recommended that people
limit sun exposure, particularly at mid-day, seek shade when
outdoors, wear protective clothing, and use sunscreens as directed.
Tanning parlors and sun beds should not be used. Consult a
doctor for more information.
1 Acknowledgement to American Society
of Clinical Oncology
EDUCATIONAL LINKS
American Society of Clinical Oncology http://www.asco.org
FDA, Food and Drug Administration http://www.fda.gov/
CEDR, Center for Drug Evaluation and Research http://www.fda.gov/cder/
NCI melanoma website http://www.cancer.gov/cancertopics/types/melanoma
MedlinePlus melanoma http://www.nlm.nih.gov/medlineplus/melanoma.html
American Cancer Society http://www.cancer.org/docroot/home/index.asp
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