Genetics research is leading to identification of melanoma susceptibility genes and an understanding of the mechanisms by which alterations in those genes drive tumor development and progression. Technological advances are expected to enable individual genome sequencing and "hyperphenotyping" of suspicious pigmented lesions and will enhance the melanoma risk determination and diagnosis.
"Genetics links cancer predisposition and progression, and selection operates in both human and tumor populations but in different time domains. The key to understanding melanoma genetics lies in understanding selection pressure, and we can look forward to sophisticated molecular imaging tools that will allow us to visualize or sense the invisible. Over time, individual phenotyping will become hyperphenotyping, and with this information, we will be able to better serve our patients," says Dr. Tsao, assistant professor of dermatology, Harvard Medical School.
Currently, clinicians can make some fundamental assessments of melanoma risk based on phenotype. Thanks to ongoing research, biology is converging on genetics to explain the phenotypes and provide an understanding of how genetic mutations, polymorphisms and variants drive tumor development and progression.
MC1R variations are common in the population but associated with a low to moderate risk of melanoma. Melanoma susceptibility genes associated with a high risk of malignancy include p16, cyclin-dependent kinase 4 (CDK4) and p14ARF. Mutations or variations in those genes appear to be more rare. Of the three melanoma risk genes, alterations in p16 appear to be the most common in the population.
"Risk associated with p16 mutations varies depending on ambient sun exposure and behavior. However, according to one study, Australians with an inherited mutation of p16 have a 96 percent lifetime risk of getting melanoma compared with a 1.5 percent risk in the general population," Dr. Tsao tells Dermatology Times.
The increased risk for melanoma in persons with xeroderma pigmentosum (XP) is also understood through knowledge of the function of the disease-related genes. XP is caused by mutations in a family of genes that play a role in nucleotide excision repair and therefore in maintaining the genetic homeostasis in the melanocyte nucleus, Dr. Tsao explains.
Researchers have also been studying UVB signature changes to determine if and how UV exposure plays a role in melanoma risk. The findings indicate there are few UV-induced oncogenes, whereas at least half of all reported mutations for melanoma involve tumor suppressor genes.
"As the Human Genome Project has been completed, we stand at the dawn of a second phase of characterizing disease-causing genes. The Melanoma Genome Project aims to tell us what genetic alterations, including mutations, variants in polymorphisms, or variations in gene copies, predispose individuals to melanoma. The next phase will be the personal genome project in which an individual's genome will be characterized to define that person's disease risks," Dr. Tsao says.
The ability to better identify melanoma and melanoma risk through clinical examination is another frontier. Currently, epiluminescence dermoscopy is helpful for discriminating benign nevi from malignant lesions, but much more sophisticated technology has much greater diagnostic potential.
Now available, optical coherence tomography gives architectural detail in vivo, and in vivo confocal microscopy takes the resolution to a higher level in providing cellular detail. Even beyond that, studies in animal models indicate feasibility of using fluorescently tagged antibodies to characterize expression of individual proteins. In addition, comparative genomic hybridization is emerging as a potential clinical tool with the capability of marking out features of the melanoma genome within the melanocyte nucleus.
"These approaches will provide physicians with unprecedented information," Dr. Tsao says.