Loss of neurofibromin accelerates uveal and dermal melanoma formation driven by GNAQ

Abstract

ABSTRACTNeurofibromin is a very large and complex tumor suppressor, whose loss can synergize with other MAPK pathway mutations to promote melanoma in the skin. In this paper, we investigated whetherNF1loss has a role in other melanomas, such as those that form in the dermis or eye (uveal tract). We found that heterozygous 17q11.2 loss that includes theNF1locus is an uncommon, but recurrent phenomenon in human dermal and uveal melanomas described previously. We studied the effects ofNf1haploinsufficiency in mice expressing oncogenic GNAQQ209Lin melanocytes and Schwann cells of peripheral nerves using thePlp1-creERTtransgene, with tamoxifen given at 5 weeks of age.Nf1haploinsufficiency accelerated dermal and uveal melanoma formation. We studied the effects ofNf1loss in these melanomas using RNAseq. Many of the differentially expressed genes were homologous to genes whose expression correlates with prognosis in human uveal melanoma. Of particular interest was the up-regulation of cAMP signaling and its connection to protein kinase A, which is mutant in malignant melanotic nerve sheath tumors (MMNSTs). An unexpected finding was that oncogenic GNAQ was sufficient by itself to drive peripheral nerve sheath-like neoplasms in the mice. Hence, these studies reveal new insight into both melanocyte and Schwann cell transformation.