Melanoma genetics need focus, more research

July 1, 2005

Dr. Peris explained that the melanoma genetics consortium, which was founded in 1977, investigates inherited melanoma susceptibility.

Speaking about melanoma genetics at the Congress, Dr. Ketty Peris, a professor of dermatology in the department of dermatology at the University of L'Aquila in Italy, noted that the genetics of the condition is an area that demands more focus and research.

"We still don't know the genetic alterations that occur in 60 percent of cases of melanoma," Dr. Peris says. "We can now only explain about 40 percent of the cases of familial melanoma. We have to focus on finding other genes. The development of melanoma depends on the genetics of the family as well as things like sun exposure."

Globally, the presence of the CDKN2A germline mutation accounts for 25 percent of cases of familial melanoma, which are families where there are multiple cases of CMM. CDKN2A is located at 9p21 while CDK4 is located at chromosome 12q13.

A British study published in the Journal of the National Cancer Institute in 2002 explored the frequency of germline mutations and familial melanoma by geographic region. Researchers studied 80 families where there were documented mutations of CDKN2A and multiple cases of CMM.

The study's investigators sampled families in Europe, the United States, and Australia. They found the rate of frequency of the mutations was 13 percent among Europeans at age 50 who had CMM, 50 percent among Americans at age 50 and 32 percent of Australians at age 50.

They also found the frequency of the mutation to be 58 percent among Europeans aged 80 who had CMM, 76 percent among Americans aged 80 who had CMM and were sampled, and 91 percent of Australians at age 80 who had CMM and were part of the sample. The rates of CMM, associated with the CDKN2A mutation, rise precipitously with age.

Predictors Germline mutations such as CDKN2A are predictive of family history of melanoma, multiple primary melanomas, the occurrence of other tumors within family members and atypical mole syndrome.

The presence of germline mutations such as CDKN2A also is indicative of increased risk of other kinds of tumors such as pancreatic cancer, gastric cancer and breast cancer, Dr. Peris explains. Variants of the melanocortin receptor 1 gene (MC1R) have been demonstrated to have low penetrance. However, a study published in 2001 found that MC1R could be a modifier allele, which increases the penetrance of mutations in CDKN2A.

A study published in the American Journal of Human Genetics in 2003 established a localized region on chromosome one which was found to have some genetic loci that may give rise to the development of CMM in a vast minority of cases.

"There might be, for instance, another gene or genes that are important in the chromosomal region 1p," Dr. Peris says. She adds that studies with animal models have shown that five chromosomal regions may be associated with the development of melanoma.

Genetic testing Dr. Peris spoke of the issue of genetic testing for melanoma, but cautioned that it should occur only in the context of research projects.

"We cannot say exactly which individuals will develop melanoma and when," Dr. Peris says.

Dr. Peris explained that the melanoma genetics consortium, which was founded in 1977, investigates inherited melanoma susceptibility. One of the consortium's first objectives has been the examination of the penetrance of CDKN2A mutations related to melanoma, particularly in families with multiple cases of the disease. The consortium will enhance studies of melanoma etiology through improved documentation of the role of the CDKN2A gene to melanoma incidence.