Genetic and Epigenetic Biomarkers in Melanoma Prognosis and Treatment

^1,2

Because early identification of melanoma lesions is associated with improved outcomes, the identification of blood biomarkers of disease could potentially improve survival rates through earlier detection—even in the absence of novel treatments.^1,2

Epigenetic Biomarkers

For many years, scientists have known that cancer cells manifest both genetic mutations and epigenetic changes. For melanoma in particular, detection of these epigenetic changes may serve an important role in uncovering predictive biomarkers to detect melanoma, determining the prognosis of melanoma, and assessing each patient’s response to therapy.¹DNA methyltransferases (DNMT) are important in the epigenetic modification of cancer DNA. These enzymes tend to methylate certain short cytosinerich strands of DNA in the promoter region of genes. Promoter regions for tumor suppressor genes that normally suppress the formation of tumors may be silenced through methylation, increasing the probability of formation and growth (Figure 1).^1,3

Figure 1. Mechanism of epigenetic tumor suppressor silencing. Overexpression of methyltransferase leads to methylation of promoters, suppressing production of tumor suppressor proteins.

Current strategies for measuring the level of methylation include use of antibodies to target and measure cytosine-rich regions of DNA, electrophoresis, and other techniques that involve breakdown and sequencing of DNA.^4,5

One important recent finding in epigenetic modification of tumors is the correlation between the level of methylation at the RASSF1A locus and the likelihood of melanoma progression. Changes in expression at the RASSF1A locus can be identified using peripheral blood by analyzing changes in tumor-related genes found in strands of cellfree circulating nucleic acids (cfCNAs).^1,6

Use of these biomarkers may also be useful in gauging individual patients’ response to treatment. For example, methylation of the RASSF1A locus of cfCNA has been associated with a poorer response to biochemotherapy in patients with stage IV melanoma.⁶

Similarly, higher levels of 2 DNA methyltransferases, DNMT3A and DNMT3B, have been associated with more advanced melanoma and poorer survival. Methyltransferases have been proposed as a therapeutic target in melanoma using decitabine, which is a global demethylator, as well as temozolomide, which targets an enzyme involved in DNA repair called methylguanine methyltransferase (MGMT).^1,4

Genetic Biomarkers

Because changes in histone expression in melanoma cells has been linked to uncontrolled proliferation and formation of immortal cancer cells, medications that inhibit histone expression are being evaluated in melanoma. Specifically, the histone deacetylase (HDAC) inhibitors vorinostat, pivanex, panobinostat, and valproic acid are in ongoing trials.¹Genetic analysis of melanoma is already playing a role in the treatment of patients with melanoma in the case of BRAF inhibitors, which require a genetic test before initiation of therapy to confirm the presence of BRAF mutations in cancer cells. Medications and tests are expected to take advantage of information about loss of function mutations and gain of function mutations to help physicians predict the prognosis of melanoma and treat it in an individualized manner.⁷

Loss of function mutations are common in melanoma, and in some cases may be helpful in predicting the prognosis of the disease. For example, in ocular melanoma, loss of chromosomes— particularly chromosome 3—is associated with poorer survival. Patients with a deletion of 1 copy of chromosome 3 have a 75.1% rate of mortality versus 13% in melanomas in which both copies of chromosome 3 are intact.^7,8

In addition, PTEN, which is involved in the PI3K/AKT signaling pathway, is lost in 40% to 70% of melanomas. Epigenetic silencing of PTEN losses may occur more frequently in BRAF- and NRASmutant melanomas.⁷

Along with loss of function mutations, gain of function mutations are also common in melanoma. For example, amplification of KIT, BRAF, and RAS are more frequent in melanomas and other human cancers than in ordinary body cells.⁷

Summary

Mutations are a target for therapeutic interventions in melanoma. Already, agents exist to target BRAF and MEK mutations. Future targets of therapy under investigation in clinical trials include NRAS, KIT, programmed cell death 1 (PD-1), and programmed cell death 1 ligand (PD-L1).⁷Epigenetic and genetic biomarkers are potential methods of early detection of melanoma and other types of skin cancer. Earlier diagnosis alone would improve survival, even in the absence of novel therapies. Fortunately, genetic mutations may be targeted with mutation-specific therapies, including therapies that target BRAF and MEK, which are already available. With earlier treatment, biomarker- based detection and therapeutic response determination in melanoma, and therapies that target genetic pathways, the future of melanoma treatment offers hope to patients and the health care professional teams who treat them.

References

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2. Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27(36):6199-6206.
3. Schinke C, Mo Y, Yu Y, et al. Aberrant DNA methylation in malignant melanoma. Melanoma Res. 2010;20(4):253- 265.
4. Sigalotti L, Covre A, Fratta E, et al. Epigenetics of human cutaneous melanoma: setting the stage for new therapeutic strategies. J Transl Med. 2010;8:56.
5. Fazzari MJ, Greally JM. Introduction to epigenomics and epigenome-wide analysis. Methods Mol Biol. 2010;620:243-265.
6. Hoon DS, Spugnardi M, Kuo C, Huang SK, Morton DL, Taback B. Profiling epigenetic inactivation of tumor suppressor genes in tumors and plasma from cutaneous melanoma patients. Oncogene. 2004;23(22):4014-4022.
7. Griewank KG, Scolyer RA, Thompson JF, Flaherty KT, Schadendorf D, Murali R. Genetic alterations and personalized medicine in melanoma: progress and future prospects. J Natl Cancer Inst. 2014;106(2):djt435.
8. Thomas S, Pütter C, Weber S, Bornfeld N, Lohmann DR, Zeschnigk M. Prognostic significance of chromosome 3 alterations determined by microsatellite analysis in uveal melanoma: a long-term follow-up study. Br J Cancer. 2012;106(6):1171-1176.