Biographical biomarkers

Noordwijk, Netherlands - Malignant melanoma remains the leading cause of skin cancer death in industrialized countries.

The clinical and histological aspects of melanoma and its progression - well defined through internationally accepted parameters including Breslow and Clark indexes - include tumor size and ulceration as well as vascular invasion, and help the clinician in determining a prognostic framework for the patient. Though useful, histopathology must share the future of malignant melanoma diagnostics with novel biomarkers, which may tell a more detailed story.

Finding new melanoma markers

"Melanoma researchers are avidly looking for the ideal biomarkers, and to date, we have homed in on several potential candidates. Molecular markers used in melanoma diagnostics can supply us with an array of very useful information. They can differentiate between nevi and melanoma, tell us if the primary tumor has a potential to metastasize and tell us if a metastasis has already occurred.

"Also, they can tell us if a certain therapy will be effective, allowing us to choose the best possible treatment for the patient before therapy initiation, as well as inform us of the effectiveness of the therapy initiated, all influencing the prognosis of the patient," explained Dr. Bosserhoff, speaking at the Third International Melanoma Research Congress here in September.

She says biomarkers can be applied in immunohistology, serum diagnostics, detection of "minimal residual disease" and expression analysis by cDNA arrays. According to Dr. Bosserhoff, HMB45, S100 and Melan-A are used in the routine diagnostics and verify diagnosis. MIA and S100 help establish if there is a metastasis under way and if the therapy used is effective.

Though Dr. Bosserhoff admits the topic is still controversially debated, she asserts that tyrosinase, Melan-A/MART, Gp100 and MIA can provide information on the effectiveness of a given therapy and the prognosis. She supposes, however, that the future of melanoma detection, therapy and management may be in the cDNA arrays.

Genetic, molecular miasma

The analysis of the molecular profiles of melanoma has put into the spotlight several molecules that influence proliferation, invasiveness and dissemination of melanoma.

Dr. Bosserhoff studied the expression of these molecules in primary melanoma and their association with prognosis. There are a slew of new candidate genes that come under scrutiny including B-RAF, P-AKT (phosphorylated-AKT), CXCR4 (CXC chemokine receptor 4), MTAP (methylthioadenosine phosphorylase) and BMP7 (bone morphogenic protein 7).

According to Dr. Bosserhoff, B-RAF is directly related to the proliferation and aggressive growth of melanoma. Up to 80 percent of melanomas and as much as 68 percent of melanoma metastases show a B-RAF mutation. Also, approximately 82 percent of nevi carry B-RAF mutations. Dr. Bosserhoff claims that though B-RAF itself does not meet the criteria of a diagnostic marker, B-RAF inhibitors are very useful in melanoma therapy.

Dr. Bosserhoff tells Dermatology Times that MTAP is strongly downregulated in melanoma. This process has several important implications.

"In our studies, we have seen that the invasion and migration of melanoma cell clones re-expressing MTAP is strongly reduced. MTAP-expressing cell clones are sensitive to IFN (interferon) treatment. Therefore, the expression of MTAP can be seen as a putative marker for the selection of therapy," Dr. Bosserhoff says.

Dr. Bosserhoff notes that serum markers supply much-needed information concerning tumor dissemination and therapy response. The discovery and understanding of new markers gives researchers much valued information on the aggressiveness of the tumor or the best therapy to be started; however, the various gene candidates being studied must be validated carefully. Dr. Bosserhoff stresses that potential biomarkers can and should only be introduced into a clinic setting to confirm their usefulness after concerted translational and clinical research efforts.