95 Investigating the Role of Concurrent NF1, BRAF, and NRAS Mutation in Melanoma

Faculty Mentor: Sheri Holmen (Surgery, University of Utah)

Melanoma is the deadliest form of skin cancer, largely due to its potential to metastasize. Utah has the highest incidence of melanoma per capita in the United States. Metastatic melanoma often has a poor prognosis, with a five-year survival rate estimated at 32%. Genetic alterations are major drivers of melanoma, and 91% of melanomas contain mutations that lead to hyperactivated MAPK/AKT pathway signaling. NF1 is the third most commonly dysregulated gene, behind BRAF and RAS, that can hyperactivate MAPK/AKT signaling. NF1 mutations are present in just under 20% of melanomas, and more than half of these are predicted to be loss of function mutations (NF1 LoF). Although previous research has established that NF1 LoF frequently co-occurs with mutations in the oncogenes BRAF and NRAS, as well as with mutations in tumor suppressors PTEN and CDKN2A, the cooperation of NF1 LoF, mutant BRAF, and mutant NRAS in the presence of altered PTEN and CDKN2A remains understudied. To address this, we used an established autochthonous in vivo mouse model of melanoma based on the RCAS/TVA avian retroviral system to assess the ability of NF1 LoF to cooperate with mutant BRAF and mutant NRAS in the presence of PTEN and CDKN2A loss to promote tumor progression and metastasis. These results demonstrated that mutant BRAF and NF1 LoF cooperate in the context of PTEN and CDKN2A loss to decrease survival from around 140 days (NF1 LoF alone) to 60 days (NF1 LoF and mutant BRAF). More research will be completed to evaluate cooperation in the presence of mutant NRAS. With 18% of melanomas exhibiting NF1 alterations, this research addresses a pressing clinical need and offers the potential to discover treatment options for a significant patient population.