A multidisciplinary team has defined a subgroup of genetic mutations present in a significant number of melanoma skin cancer cases. Their findings shed light on an important mutation in this deadly disease, and may lead to more targeted anticancer therapies. The study was published in Nature Genetics (2015; doi:10.1038/ng.3361).

The role of mutations in numerous genes and genomic changes in the development of melanoma is well established and continues to be the focus of intense research. Yet in approximately 30% of cases the genetic abnormalities are unclear. To deepen understanding of mutations in melanoma cases, the research team conducted a comprehensive analysis using whole-exome sequencing of more than 200 melanoma samples from patients with the disease.

The multidisciplinary team from Yale University and Yale Cancer Center in New Haven, Connecticut, drew on their expertise in genetics, cancer, computational biology, pharmacology, and other disciplines. They also tested the response of tumor cells with specific mutations to anticancer drugs.

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The researchers confirmed that the NF1 gene is a major player in the development of skin cancer.

“The key finding is that roughly 45% of melanomas that do not harbor the known BRAF or NRAS mutations display loss of NF1 function, which leads to activation of the same cancer-causing pathway,” said Michael Krauthammer, MD, associate professor of pathology and the study’s corresponding author.

Additionally, the researchers observed that melanoma patients with the NF1 mutation were older and had a greater number of mutations in the tumors. These include mutations in the same pathway, collectively known as RASopathy genes.

Yet mutations in NF1 are not sufficient to cause skin cancer, said lead author Ruth Halaban, PhD, senior research scientist in dermatology, a member of Yale Cancer Center.

“Loss of NF1 requires more accompanying changes to make a tumor,” Halaban explained. “Our study identified changes in about 100 genes that are present only in the malignant cells and are likely to be causative. This panel of genes can now be used in precision medicine to diagnose malignant lesions and can be applied to personalized cancer treatment.”

The researchers tested the response of the melanoma samples to two cancer drugs and determined that multiple factors, in addition to loss of NF1, need to be tested to predict the response to the drugs. “It opens the door to more research,” said Halaban, who is also principal investigator at Yale SPORE in Skin Cancer.