What are genes?

Genes carry small individual collections of information within each cell of the human body. Each gene is made of a unique sequence of DNA. Researchers working on the Human Genome Project have estimated that there are as many as 30,000 different genes in each cell. Genes are packaged onto chromosomes. There are 23 pairs of chromosomes in each cell. One chromosome of each pair is inherited from the person's father and one from the person's mother.

Genes control how a cell functions, including how quickly it grows, how often it divides, and how long it lives. To control these functions, genes produce proteins that perform specific tasks and act as messengers for the cell. Therefore, it is essential that each gene have the correct instructions or "code" for making its protein so that the protein can perform the proper function for the cell.

What role do genes play in melanoma?

Cancer begins when one or more genes in a cell are mutated (changed), creating an abnormal protein or no protein at all. The information provided by an abnormal protein is different from that of a normal protein, which can cause cells to multiply uncontrollably and become cancerous.

A person may either be born with a genetic mutation in all of their cells (germline mutation) or acquire a genetic mutation in a single cell during his or her lifetime. An acquired mutation is passed on to all cells that develop from that single cell (called a somatic mutation). Most melanomas (about 90%) are considered sporadic, meaning that the damage to the genes occurs by chance after a person is born. An increased risk of melanoma occurs when specific gene mutations are passed within a family from generation to generation. Keep in mind that melanoma itself is not inherited, it is an increase in risk of developing melanoma that is inherited. Many people who have an increased risk of melanoma never develop the disease. Although 10% of melanoma is familial (runs in the family), known genetic variations only account for 1% of all melanoma diagnoses.

What are the chances a mutated gene is inherited?

Every cell usually has two copies of each gene: one inherited from a person’s mother and one inherited from a person’s father. Hereditary melanoma follows an autosomal dominant inheritance pattern, in which a mutation needs to happen in only one copy of the gene for the person to have an increased risk of getting the disease. This means that a parent with a gene mutation may pass on a copy of the normal gene or a copy of the gene with a mutation. Therefore, a child who has a parent with a mutation has a 50% chance of inheriting that mutation. A brother, sister, or parent of a person who has a gene mutation also has a 50% chance of having the same mutation.

What is a person's average risk for melanoma?

A person at average risk for melanoma has a 2% chance of developing melanoma during his or her lifetime. More specifically, the average risk for women is 1.6% and the average risk for men is 2.3%.

How common is melanoma?

In 2008, an estimated 62,480 adults (34,950 men and 27,530 women) in the United Stated will be diagnosed with melanoma. It is estimated that 8,420 deaths (5,400 men and 3,020 women) from this disease will occur this year. People with inherited traits, such as dysplastic nevi (large, flat, irregular, asymmetric, variably pigmented moles), fair skin and light-colored eyes, and skin that burns easily, tans poorly, or freckles, have an increased risk of developing melanoma. Although these characteristics are genetically controlled, how they are controlled is not yet fully understood.

How can a person know if he or she has inherited a genetic mutation that increases his or her risk of melanoma?

Only genetic testing can determine whether a person has a genetic mutation. Genetic testing for melanoma risk is available on a limited basis. Doctors suggest that families with multiple cases of melanoma consider participating in genetic research studies, so that more can be learned about how genetic mutations influence the melanoma risk. Even in families with several people who have melanoma, an altered gene is often not identified.

For more information, read Genetic Testing and What to Expect When Meeting With a Genetic Counselor.

How does a person know if melanoma runs in the family?

An inherited risk of melanoma is suspected if two or more first-degree relatives (parents, brothers, sisters, children) are diagnosed with melanoma and is sometimes referred to as familial melanoma. For people living in the southern United States or other parts of the world with high sun exposure, familial melanoma is suspected if three or more first-degree relatives develop melanoma.

There are other important signs that suggest possible cases of inherited melanoma, including:

• More than one case of melanoma in the same person
  
  
• Melanoma diagnosed in early adulthood. Inherited melanoma in American families often develops around 35. Most women develop melanoma before age 50.
  
  
• Multiple atypical or dysplastic nevi, which are more common for people who have an increased risk of melanoma.

Most experts strongly recommend that people concerned about their family history of melanoma 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.

What is a person's risk if melanoma runs in the family?

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 average risk. The risk is higher if there are multiple family members in various geographic locations with melanoma.

Which inherited genetic mutations raise the risk of melanoma?

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 affect the risk of melanoma.

Hereditary melanoma. At least three genes have been linked to hereditary melanoma. Families with mutations in these genes may have multiple dysplastic nevi. Although dysplastic nevi are likely to be related to altered genes, the specific genes involved have not been identified. 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 melanomas. People who have mutations in the CDKN2A gene have about a 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. Pancreatic cancer also varies by geographic location, with much higher rates in Europe than in the United States, and extremely low rates in Australia.

The CDKN2A gene is a tumor suppressor gene. A tumor suppressor gene makes proteins that prevent tumor formation by limiting cell growth. Mutations in a tumor suppressor gene result in a loss of the ability to restrict tumor growth, which can cause cancer to develop. CDKN2A produces two different proteins, p16 and p14ARF, depending on how the gene is "read." Mutations affecting p16 are 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 may be some increased risk for melanoma, and possibly other cancers, in a small number of families.

There is also growing evidence that variations in another gene, MC1R, alters the risk of melanoma for people with CDKN2A mutations and for people without CDKN2A mutations. MC1R is important in regulating pigment; variations have been associated with freckling and red hair.

Genetic testing for mutations in CDKN2A is available, but the American Society of Clinical Oncology’s (ASCO’s) Task Force on Genetic Testing recommends that such testing not be routinely performed outside of a research study 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. ASCO bases its clinical recommendations for identifying melanoma risk on family history, skin type, and environmental factors, regardless of the presence or absence of known mutations.

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 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 because this genetic mutation is thought to be rare. Based on limited data, the characteristics of melanomas occurring in families with CDK4 mutations are similar to those in families with CDKN2A mutations.

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, and this topic is an 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.

For more information, read the Cancer.Net Guide to Familial Malignant Melanoma.

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 brain tumors have been shown to have alterations in CDKN2A that affect the p14ARF protein. 

Are there other genetic conditions associated with an increased risk of melanoma?

Other genetic conditions that are associated with an increased risk of melanoma include xeroderma pigmentosum, retinoblastoma, Li-Fraumeni syndrome, ataxia-telangiectasia, and Werner syndrome.

Xeroderma pigmentosum. Xeroderma pigmentosum (XP) is a group of rare conditions whereby a person’s cells cannot repair DNA damage caused by ultraviolet (UV) exposure, such as sunshine. Signs of XP are caused by the increased sensitivity to UV light, and include dry skin, abnormal pigmentation, severe freckling, and blistering after minimal sun exposure. There is a high rate of skin cancer, including melanoma (over a thousand times more frequent than in the general population), and noncancerous skin abnormalities in people who have XP. People with XP also have an increased risk of other types of cancers including leukemia, brain tumors, and stomach, lung, breast, uterine, and testicular cancers.

There are several different forms of XP, but each is inherited as an autosomal recessive condition. In autosomal recessive inheritance, a person needs to have two copies of a gene mutation in order to have the disease. This means that each parent must have one mutated gene and one normal gene. If both parents carry a gene mutation for XP, each of their children will have a 25% chance of inheriting both gene mutations and having XP. Several genes have been linked to the different forms of XP, but genetic testing is not available.

For more information, read the Cancer.Net Guide to Xeroderma Pigmentosum.

Retinoblastoma. Retinoblastoma is a childhood eye tumor. Tumors may develop in one or both eyes, but inherited retinoblastoma most often occurs in both eyes. Nearly all cases of retinoblastoma are found in children under age 5, and inherited retinoblastoma occurs most often in children younger than one. Approximately 30% to 40% of retinoblastoma cases are hereditary. Children with hereditary retinoblastoma have an increased risk of developing other cancers as they grow older, including osteosarcoma (a type of bone cancer), other sarcomas, leukemia, lymphoma, melanoma (50 times more than the general population), lung cancer, and bladder cancer.

Retinoblastoma is inherited as an autosomal dominant condition. The gene associated with hereditary retinoblastoma is called RB1. However, many children with hereditary retinoblastoma have new mutations in the RB1 gene, meaning that there is no other family history of the condition. People with new gene mutations can pass the mutation to their children. Genetic testing for the RB1 gene is available.

For more information, read the Cancer.Net Guide to Retinoblastoma.

Li-Fraumeni syndrome. People with Li-Fraumeni syndrome (LFS) have up to a 50% chance of developing cancer by age 40 and a 90% chance of developing cancer by age 60. Some of the cancers most commonly associated with LFS are osteosarcoma (a type of bone cancer), soft tissue sarcoma, leukemia, breast cancer, brain cancer, and adrenal cortical tumors. Melanoma has occasionally been reported in such families, but the risk of developing melanoma is not known.

LFS is a rare condition. The gene associated with LFS is called p53. The p53 gene is a tumor suppressor gene. Testing for p53 gene mutations is available for families meeting the diagnostic criteria for LFS. More research is needed to better understand LFS. Another gene, CHEK2, may be responsible for LFS in some families. Testing for mutations in the CHEK2 gene is only available as part of a research study.

For more information, read the Cancer.Net Guide to Li-Fraumeni syndrome.

Werner syndrome. Werner syndrome is a rare condition characterized by premature aging and an increased risk of cancer. The first sign of Werner syndrome may be the lack of a growth spurt in puberty. People with Werner syndrome develop the signs of aging in early adulthood, including graying hair and hair loss, cataracts, and osteoporosis. The risk of developing cancer is approximately 10%. The most common types of cancer seen in people with Werner syndrome are osteosarcoma (a type of bone cancer), other sarcomas, melanoma, and thyroid cancer.

Werner syndrome is inherited as an autosomal recessive condition. The gene associated with Werner syndrome is called WRN. Genetic testing for the WRN gene is currently available only as part of a research study.

For more information, read the Cancer.Net Guide to Werner Syndrome.

Hereditary breast and ovarian cancer. An increased risk of melanoma has also been identified in people with hereditary breast and ovarian cancer (HBOC). HBOC is a genetic condition that follows an autosomal dominant inheritance pattern. Two genes are associated with HBOC: BRCA1 and BRCA2 (BRCA stands for BReast CAncer). A mutation in either of these genes gives a woman an increased lifetime risk of developing breast and ovarian cancers. Men with these gene mutations have an increased risk of breast cancer and prostate cancer. A genetic mutation on the BRCA2 gene is more commonly associated with an increased risk of melanoma.

For more information, read the Cancer.Net Guide to Hereditary Breast and Ovarian Cancer.

Cowden syndrome. Melanoma has been reported in association with Cowden syndrome (CS). Cowden syndrome is a rare genetic condition that follows an autosomal dominant inheritance pattern. It is caused by a mutation on the PTEN gene. People with CS have a high risk of both noncancerous and cancerous tumors of the breast, thyroid, and endometrium (lining of the uterus). Also, people with CS often have small growths on the face or in the mouth and a larger than average head size. Although people with CS have developed melanoma, it is not known whether having CS increases a person’s risk of developing melanoma.

For more information, read the Cancer.Net Guide to Cowden Syndrome.

What is a person's risk level?

In addition to family history, other environmental and lifestyle factors may increase the risk of melanoma. Discussing family history and personal risk factors, especially the type and number of moles (such as dysplastic nevi), complexion, and extensive freckling with a doctor may help a person 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 examinations. The ABCDE (Asymmetry, Border, Color, Dimension, Evolution) criteria are most commonly used in the diagnosis of early melanoma. People with a higher than average risk may benefit from sun-protective behavior and early detection strategies.

A risk factor is anything that increases a person's risk of developing cancer. Having a particular genetic mutation linked to melanoma cannot predict that a person will develop cancer. Research is underway to clarify these risks. Controllable risk factors also play a large role in the development of melanoma. Sun or other types of ultraviolet light exposure (such as tanning beds) are the most important controllable risk factors for melanoma. 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. Talk with a doctor for more information about melanoma screening and prevention. Talk with a doctor for more information about risk factors, prevention, and screening for melanoma.

More Information

Genetics

Cancer.Net Guide to Melanoma

ASCO Expert Corner: Treatment and Research Update for Melanoma

Cancer.Net Feature: Protecting Your Skin From the Sun