Gene Mutations May Predict Melanoma Response to Immunotherapies

Douglas Johnson, M.D.

Christine Lovly, M.D., Ph.D.

Melanoma patients whose tumors test positive for mutations in the NRAS gene were more likely to benefit from new immunotherapy drugs, according to a new study led by Vanderbilt-Ingram Cancer Center (VICC) investigators.

Douglas Johnson, M.D., assistant professor of Medicine, and Christine Lovly, M.D., Ph.D., assistant professor of Medicine and Cancer Biology, are co-first authors of the study, conducted in conjunction with colleagues from Memorial Sloan Kettering Cancer Center (MSKCC), New York, and Massachusetts General Hospital (MGH), Boston. The study was funded in part by the T.J. Martell Foundation and published in Cancer Immunology Research.

“We studied a small group of patients but the results were quite suggestive,” Johnson said. “This study highlights the need to find predictive markers that can help us understand which patients will respond to therapy.”

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Guest Blog Post – The Biologic Picture of Melanoma

Jeffrey A. Sosman, M.D., Director, Melanoma and Tumor Immunotherapy Program
Vanderbilt-Ingram Cancer Center

In the past 10 years, mutations found in melanoma (the most deadly form of skin cancer) have led directly to the development of effective therapies. One example is the BRAF mutation and its inhibitor drug vemurafenib.

The New York Times reported on a new finding uncovered in the DNA of a large number of melanomas tested with extensive DNA sequencing of the whole genome.  This new mutation found by two independent groups is actually not present in a gene that produces a functional protein or enzyme.  Instead, it is a mutation in the portion of the DNA that regulates the expression of an enzyme, telomerase. Telomerase protects the chromosomes from breakdown and the cell from death. High levels of telomerase are seen in many cancer cells, including melanoma, and it protects the cancer cells from a normal dying process.

In a mechanism previously never reported, the newly discovered mutation changes the regulatory portion of DNA so it may be very vulnerable towards activation. In this way, the mutation indirectly allows the telomerase level to increase.

This mutation is found in these exact locations in about 70 percent of melanomas. The mutation provides a link between the BRAF mutations and the regulatory portion of another gene.

The new discovery adds one more piece to the biologic puzzle of melanoma. With each additional piece we are closer to completing the biologic picture of melanoma, which will further our ability to define treatment approaches to kill this deadly cancer.