In the coming years, study of the human genome is likely to culminate in discovery of multiple genes related to melanoma. These discoveries will influence how we identify individuals at high risk of the disease. In fact, genetic testing for the presence or absence of one such high-risk melanoma gene, CDKN2A, is now commercially available.
In this issue of The Melanoma Letter, Bradley Bloom and Dr. David Polsky identify another high-risk gene called MDM2, which when mutated, and in the presence of estrogen, may increase a woman’s propensity for developing melanoma, especially at younger ages. If their findings are substantiated, it may help explain why younger women have higher melanoma incidence than younger men.
Although some melanoma-related genes may express themselves phenotypically (e.g., red hair, multiple nevi, etc.), other genes’ phenotypic expression may be minimal. Nonetheless, depending on environmental influences, these genes may also lead to melanoma. As new high-risk melanoma genes are discovered one by one, it will be interesting to observe whether targeted screening of high-risk patients will eventually shift from the current phenotypic-centric identification to genotypic-centric identification.
Another benefit of studying the human genome is identifying specific genes involved in the cell cycle. The knowledge gained from this may help researchers manipulate these genes to our advantage therapeutically. The possibility of designing drugs that attenuate or nullify the effects of a given mutated gene opens the door for targeted therapy. It is now well established that each melanoma subtype has its own unique set of mutations, which impart their influence on melanocyte proliferation, differentiation, survival, and apoptosis. Examples include c-Kit and GNAQ mutations in mucosal and ocular melanoma, respectively. Patients with melanomas expressing c-kit or GNAQ mutations may benefit therapeutically from targeted therapy. One example is the administration of Imatinib to target melanomas expressing c-kit mutations.
Another mutation frequently found in melanomas that develop on intermittently sun-exposed skin involves BRAF. It has been known for some time that the BRAF pathway is important in melanoma. However, only recently were specific BRAF mutations identified in melanoma. This finding led to the development of a drug called PLX4032, designed to target V600E, a specific BRAF mutation. Dr. Flaherty highlights the preliminary but promising results obtained with PLX4032 in the treatment of patients with metastatic melanoma.
Based on the articles in this issue of The Melanoma Letter, it is compelling to contemplate just when clinical practice will evolve from the current phenotype-based screening and disease-based therapy to molecular/genetic-based targeted screening and therapy.
Allan C. Halpern, MD
Ashfaq A. Marghoob, MD