Molecular genetics of melanoma

Philadelphia - Understanding the clinical behavior and the biological mechanisms of malignant melanoma in its earlier stages may be the key to developing optimal treatment and management strategies for this deadly skin cancer.

At the 2006 annual meeting of the Society for Investigative Dermatology, Hensin Tsao M.D., Ph.D., director of the Massachusetts General Hospital (MGH) Melanoma & Pigmented Lesion Center and the MGH Melanoma Genetics Program, Massachusetts General Hospital, and assistant professor of dermatology, Harvard Medical School, discussed research on the disease. He spoke on his past and ongoing studies of the molecular genetics of cutaneous melanoma, and reported on how far we have come in the last 10 years and how close we are to achieving a "global" view of this devastating tumor.

Dr. Tsao says that innately, cancer is a genetic disease and that most cancers are sporadic in nature.

There are a series of mutations in critical genes that lead to changes in the rate of proliferation or survivability of the cell. Tumors emerge as a result of selection for cellular growth and survival. Mutations can accumulate from either low background errors or from ultraviolet radiation due to solar exposure. According to Dr. Tsao, rare familial skin cancer syndromes also exist, including melanoma. A small group of individuals inherit germline mutations and may develop hereditary cancer. These cancers may occur earlier than in other individuals, and may develop in multiplicity.

The investigator says that past studies have shown that a cell cycle regulator is potentially involved in the genesis of many types of tumors, and that in 60 percent of melanoma cell lines and in nearly half of all cancers, p16/CDKN2A is homozygously deleted. Furthermore, specific deleterious point mutations were also detected in melanoma cell lines without evidence of p16 deletion.

Genetic specifics of melanoma

Dr. Tsao says that, "Two growth inhibitory hurdles that must be overcome by the evolving cancer cell include pathways regulated by RB and p53. In human melanoma cells, inactivation of a single locus, CDKN2A, can lead to abrogation of both RB and p53 functionality through loss of the two CDKN2A cognate transcripts - p16 and p14ARF, respectively. Recent data from our laboratory showed that the melanoma cell thwarts both pathways through discrete but recurrent mechanisms that may play into the unique genetic vulnerabilities of this tumor type."

Germline CDKN2A mutations have also been reported in many melanoma-prone families worldwide. According to the investigator, when the p16 transcript of CDKN2A is mutated, the phenotype is one of familial melanoma and pancreatic cancer. However, when the ARF transcript of CDKN2A is inactivated, the phenotype is familial melanoma and neural system tumors.

Recently, Dr. Tsao and his group published a logistic regression model, termed MELPREDICT, that estimates the likelihood that an individual, based on number of melanomas in the family and age of onset, harbors a p16 mutation. Since commercial testing for p16 is available, this model will hopefully guide cancer risk counselors in their discussions regarding p16 genetic testing.

Mutations not inherited

In melanoma tumors, there are also many "somatic" mutations that arise within the cancer cell but are not inherited.