Clues to melanoma treatments lie in profiles of disease subtypes

UV damage

The melanomas that occur when the skin is chronically exposed to ultraviolet light occur on sites such as lower dorsal arms or the head and neck, and they tend to occur in individuals who are older than 50 or 60, according to Dr. Bastian.

"They (the melanomas) develop through a different genetic pathway than BRAF, and we found c-KIT mutations in about 20 percent to 30 percent of mutations in these melanomas," he says. BRAF is infrequent in these melanomas, he says.

"NRAS represents about another 15 percent of the mutations. Almost half of these melanomas don't have a specific, known oncogene driver assigned to them yet. Thus, these melanomas arise in later life, have a specific anatomic distribution and different genetics," Dr. Bastian says.

The c-KIT mutations also occur in up to 30 percent of acral melanomas. These melanomas occur on the palms, soles and nails, sites that are not exposed to ultraviolet light. Acral melanomas represent up to 5 percent of all melanomas in the U.S. They are the most common type of melanoma in African-Americans and Asian-Americans.

"Acral sites are usually protected by a thick layer of the skin," he says. "Sunlight is unlikely to play a role in their formation."

Other melanomas

Mucosal melanomas that develop in the paranasal sinuses, anogenital region and oropharynx are somewhat similar to acral melanomas in that they also harbor KIT mutations, but they also have genetic alterations that separate them from acral melanomas.

"They share commonalities with acral melanomas, but they are regarded as distinct," Dr. Bastian says.

Another type of melanoma is uveal melanoma, which is the most common intraocular cancer. It is estimated that 40 percent of uveal melanomas contain mutations in GNAQ, which encodes an alpha subunit of heterotrimeric G proteins that act downstream of G-protein coupled receptors.

A recent study that Dr. Bastian published examined the genetic composition of uveal melanomas, and he and co-investigators found that 83 percent had somatic mutations in GNAQ or GNA11, a closely related gene, concluding that the two genes appear to be major contributors to uveal melanoma. (Herlyn M, Nathanson KL. N Eng J Med. 2010;363(23):2256-2257).

They are two oncogenes that are mutated in mutually exclusive patterns. Like BRAF, the mutations need to be followed by additional genetic alterations to make a melanoma.

"The uvea of the eye has melanocytes in the iris, ciliary body and choroid," Dr. Bastian says. "There are typically no mutations in BRAF, c-KIT or NRAS in melanocytic neoplasia arising from these sites."

Based on the finding of mutations in GNAQ and GNA11 and the observation that they activate the MAP-kinase pathway, there is a trial using MEK inhibitors to treat uveal melanoma, says Dr. Bastian. There are also ongoing studies on treating melanomas arising from c-KIT mutations.

"The recognition of these biological subtypes is essential to make progress in the field," Dr. Bastian says. "We cannot lump all of the melanomas together. If we do, all of the therapeutic benefits in subgroups will be washed out and missed."