OSUCCC – James study identifies molecular factors driving melanoma development

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Researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute identified key features of a gene mutation responsible for 15-20% of all melanomas.

Using a preclinical laboratory model, the team established that the frequency at which a specific NRAS gene mutation occurs in human melanoma is directly related to the ability of that gene mutation to initiate spontaneous melanoma formation.

The findings were published in Nature Communications

“This means that properties of the mutant itself—rather than the ease at which that specific gene mutation occurs—is the cause of cancer formation,” corresponding author Christin Burd, associate professor of molecular genetics in The Ohio State University College of Arts and Sciences, Department of Molecular Genetics and member of the OSUCCC – James Molecular Carcinogenesis and Chemoprevention Program, said in a statement. 

The researchers developed genetically engineered models that allowed them to activate one of nine different NRAS-mutant variations in melanocytes.

“Amazingly, when we activated these gene mutations, only those found in the human disease caused melanoma to develop,” Burd said. “Some mutants never led to melanoma, yet we know that they cause leukemia. This finding shows that selection of NRAS mutations is specific to each tumor type and occurs during cancer initiation, rather than in response to a specific mutagenic event like sun exposure.”

Collaborating with NIH, Burd’s team found that slight variances in the outward-facing structure of NRAS mutants capable of initiating melanoma made these proteins better able to interact with the signaling pathways that drive melanoma growth.

The team also generated eight new and publicly available genetically engineered mouse models that can be used to activate and study the role of NRAS in other relevant cancer types, such as colon cancer, leukemia, myeloma, and thyroid cancer. 

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