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familial-malignant-melanoma

Familial Malignant Melanoma

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What is familial malignant melanoma?

Cancer begins when normal cells begin to change and grow uncontrollably forming a lesion called a tumor. A tumor can be benign (noncancerous) or malignant (cancerous, meaning it can spread to other parts of the body).

Familial malignant melanoma is a term usually referring to families in which two or more first-degree relatives (parent, sibling, or child) have a type of skin cancer called melanoma. Overall, about 8% of people newly diagnosed with melanoma have a first-degree relative with melanoma. A much smaller percentage, about 1%, have three or more close relatives with melanoma.

Dysplastic nevi are large, flat, irregular, asymmetric, variably pigmented moles. They occur primarily on sun-exposed skin, but they also occur in areas that are not exposed to the sun. Individuals in melanoma-prone families frequently have these moles. The moles must be monitored very carefully for any change in size, shape, and color to watch for cancer. In the United States, the average age when melanoma is diagnosed in people with familial melanoma is in the 30s; the average age when melanoma is diagnosed in the general population is in the 50s.

What causes familial melanoma?

Familial melanoma is a genetic condition. This means that the risk of melanoma can be passed from generation to generation in a family. To date, two genes have been linked to familial melanoma; they are called CDKN2Aand CDK4. A mutation (alteration) in one of these genes gives a person an increased risk of melanoma. However, alterations in these two genes only account for a small percentage of familial melanoma.

CDKN2A is unusual because it affects two separate proteins that have different functions; one is called p16, and one is called p14ARF. Both CDKN2A and CDK4 play important roles in controlling when cells divide. Studies of families with mutations in CDKN2A from Europe, North America, and Australia have shown that the risk of melanoma varies by geographic area. The reasons for these differences are not fully understood. There may be differences in the amount of sun they receive, other individual or genetic differences, or a combination of these factors.

Within melanoma-prone families with known genetic mutations dysplastic nevi and sun exposure are independent risk factors for melanoma. There is also growing evidence that variations in another gene, MC1R, alter the risk of melanoma, both in individuals with CDKN2A mutations and in individuals without CDKN2Amutations. MC1R is important in regulating pigment; variations have been associated with freckling and red hair.

Other inherited genes are associated with an increased risk of melanoma. For instance, Xeroderma pigmentosum (XP) is a rare disorder in which patients have a defect in a gene needed for repair of ultraviolet radiation (sunlight) induced DNA damage. Patients with XP have an extremely high rate of skin cancer, including melanoma. The hereditary breast cancer gene, BRCA2, is also associated with a risk of melanoma. Scientists believe that there are other genes not yet identified that also increase the risk of melanoma. Learn more about the genetics of melanoma. 

How is familial melanoma susceptibility inherited?

Normally, every cell has two copies of each gene: one inherited from the mother and one inherited from the father. Familial melanoma susceptibility follows an autosomal dominant inheritance pattern, in which case a mutation happens in only one copy of the gene. This means that a parent with a gene mutation may pass along a copy of his or her normal gene or a copy of the gene with the 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 mutation also has a 50% chance of having the same mutation.

How common is familial melanoma?

Most cases of melanoma are sporadic (occur by chance). The number of people who have an inherited risk of melanoma is unknown, but the number is thought to be low. It is estimated that about 8% of people with melanoma have a first-degree relative with melanoma and that only 1% to 2% of people with melanoma have two or more close relatives with melanoma.

How is familial melanoma diagnosed?

Familial melanoma is suspected when two or more close relatives have invasive melanomas (melanoma that has spread). In areas of higher sun exposure, like the southern United States or Australia, the frequency of sporadic melanoma is higher, so familial melanoma is not diagnosed unless three or more close relatives have invasive melanoma. Familial melanoma may also be suspected if a single family member has multiple melanomas.

Genetic testing for mutations in the CDKN2A gene is commercially available. However, genetic test results are unlikely to change screening recommendations or clinical care for people who have had melanoma or people who have a strong family history of melanoma. Most families with familial melanoma will not have a genetic mutation identified.

What are the estimated cancer risks associated with familial melanoma?

A person with a hereditary risk of melanoma has a greatly increased risk of developing melanoma during his or her lifetime.

There is also an increased risk of pancreatic cancer in families with familial melanoma and CDKN2A mutations, but this is relatively rare. Brain tumors have also been reported in a few families.

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