A major international study has identified a novel gene mutation that appears to increase the risk of both inherited and sporadic cases of malignant melanoma, the most deadly form of skin cancer. The identified mutation occurs in the gene encoding MITF, a transcription factor that induces the production of several important proteins in melanocytes, the cells in which melanoma originates. While previous research has suggested that MITF may act as a melanoma oncogene, the current study identifies a mechanism by which MITF mutation could increase melanoma risk. The report from researchers from the U.S., the U.K., and Australia was published online in Nature on November 13, 2011. It is expected to appear in a print issue along with a study from French researchers finding that the same mutation increased the risk for the most common form of kidney cancer, for melanoma, or for both tumors. "We previously knew that MITF is a master regulator for production of the pigment melanin; and several years ago we identified a chemical modification, called sumoylation, that represses MITF activity," says Dr. David Fisher, chief of Dermatology at Massachusetts General Hospital (MGH), director of the MGH Cutaneous Biology Research Center and co-senior author of the Nature paper. "The currently discovered mutation appears to block sumoylation of MITF, and the resulting overactivity of MITF significantly increases melanoma risk." While approximately 10 percent of patients with melanoma report a family history of the disease, true hereditary melanoma, involving multiple cases across many generations, probably accounts for 1 percent or less of all cases, says co-senior author Dr. Hensin Tsao, of MGH Dermatology and the Wellman Center for Photomedicine.
Researchers have shown how estrogen receptor (ER)-positive breast cancer tumors become resistant to tamoxifen, the only approved hormonal therapy for premenopausal patients with this type of breast cancer. They also found that introducing a novel histone deacetylase (HDAC) inhibitor in hormone therapy treatment can overcome resistance to hormonal therapy. "We always thought that resistance was primarily an inborn or genetic effect," said Dr. Pamela N. Munster, director of the Early-Phase Clinical Trials Program at the University of California, San Francisco (UCSF). "But this is not the case. Tumors have found a way to modify their genes to become resistant. This process is called 'epigenetics,' where genes are turned on and off, but the sequence of DNA is not altered. We have also found that with this kind of breast cancer, we can prevent that resistance with histone deacetylase inhibitors." Dr. Munster presented the findings at the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics, held November 12-16, 2011 in San Francisco, California. She and her colleagues found that ER-positive breast cancer tumors alter their genes to create more AKT, a protein that spurs actions within the cell to keep it alive — the opposite of what tamoxifen is designed to do. In a preclinical study, researchers introduced the HDAC inhibitor PCI-24781 at an early phase of tamoxifen treatment and found that it reverses the tumor's survival strategy of increasing production of AKT, thus stopping the tumor cells from developing resistance and leading to higher levels of cell death. "The HDACs regulate the response of AKT to tamoxifen, and together, the effects of HDAC inhibitors and tamoxifen lead to more cell death if introduced with hormonal therapy," said Dr. Munster.