Melanoma: more than just the genetics

By Ana Miletic Sedy
March 22, 2012

Melanoma is a type of skin cancer in which melanocytes, the pigment-producing cells in the skin, keep growing even when they shouldn’t. More than 100,000 new cases of melanoma are diagnosed each year in the U.S. and almost 80 percent of melanoma patients die from their disease, making melanoma the most deadly type of cancer. Because melanoma can spread very quickly, early detection and treatment give patients the best chance for survival.

The development of melanoma involves a complex interplay between environmental factors and alterations in gene expression (the way genes are turned on or off). While exposure to UV radiation is a key risk factor for melanoma development, it’s unclear how UV radiation influences which genes are turned on or off in skin cells—a process known as gene expression. This is exactly the question that interests Ranjan J. Perera, Ph.D., scientific director of Analytical Genomics and Bioinformatics and associate professor in the Diabetes and Obesity Research Center at Sanford-Burnham in Lake Nona, Orlando.

Perera’s lab studies how epigenetics—changes in gene expression caused by modifications to the DNA in the genome rather than by the actual DNA sequence—lead to melanoma. Typically, epigenetic regulation of genes involves the linking of small molecules to DNA (such as methylation, which adds a methyl group) or the removal of small molecules to DNA-associated proteins, both of which serve to alter the expression of targeted coding genes (those that hold the recipe for proteins) and noncoding genes (DNA that doesn’t encode proteins).

The questions Perera wants to answer are, “Can we use epigenetic changes or methylation signatures as prognostic or diagnostic markers to differentiate early melanoma from benign growths? And can we also use these markers for disease staging of advanced tumors?”

To answer these questions, Perera and Joseph Mazar, Ph.D., a postdoctoral researcher in his lab, looked very carefully into how many microRNAs (miRs) are being epigenetically regulated in melanoma compared to melanocytes, melanoma’s normal counterpart cells. MiRs—small pieces of genetic material that regulate the expression of target genes—are involved in the growth and function of normal cells, and growing evidence is showing that the dysregulation of miRs is associated with diseases such as cancer.

The researchers found that the levels of two miRs, miR-375 and miR-34b, were decreased in melanoma cell lines compared to melanocytes and keratinocytes, another type of cell found in the skin. Specifically, they found that methylation affecting miR-375 and miR-34b was absent in normal melanocytes, keratinocytes, and in stage 1 melanoma cell lines. In contrast, stage 2 melanoma, stage 3 melanoma, and stage 4 melanoma cell lines showed high levels of methylation of both miRs. Perera, Mazar, and colleagues found similar patterns of methylation when they examined samples taken from melanoma patients. These studies were recently published in the journal FEBS Letters (miR-375) and in PloS ONE (miR-34b), along with a review article in the journal Epigenomics that provides additional insight regarding epigenetics and melanoma.

“This is an early indication that we have something interesting,” Perera said. Perera’s lab also recently completed a study to look at the melanoma “methylome” (a global look at all methylation in the cell) and they anticipate identifying other melanoma-specific methylated regions in the genome that could be used as epigenetic prognostic markers in future.

Each person’s epigenetic markers are unique. Knowing the epigenetic signature of a patient’s cancer can allow doctors to tailor treatments for that person. This type of personalized medicine—the idea that health care can be customized to the individual patient using his or her genetic information—is something that Perera thinks will be possible in the near future. He envisions a day when researchers and medical doctors can “clinically classify melanoma for a more personalized approach for diagnosis and treatment of melanoma. That is exactly where we are going. One day, we may have a whole list of signatures that we can actually compare to someone’s personal genome to see any areas that we need to watch out for.”

Original papers:

Mazar J, DeBlasio D, Govindarajan SS, Zhang S, & Perera RJ (2011). Epigenetic regulation of microRNA-375 and its role in melanoma development in humans. FEBS letters, 585 (15), 2467-76 PMID: 21723283

Mazar J, Khaitan D, DeBlasio D, Zhong C, Govindarajan SS, Kopanathi S, Zhang S, Ray A, & Perera RJ (2011). Epigenetic regulation of microRNA genes and the role of miR-34b in cell invasion and motility in human melanoma. PloS one, 6 (9) PMID: 21949788

Perera RJ, & Ray A (2012). Epigenetic regulation of miRNA genes and their role in human melanomas. Epigenomics, 4 (1), 81-90 PMID: 22332660

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