11IN - Towards Deciphering the Genetic Landscape in Melanoma

Abstract

ABSTRACT Melanoma is the deadliest form of human skin cancer, accounting for 70% of skin-cancer related deaths although it comprises only 4% of skin cancer cases. As opposed to the steady decrease in overall rate of other cancers, the incidence of melanoma continues to rise worldwide. The median patient survival is six months following diagnosis. There is a clear need to develop improved therapy for this disease. Melanoma develops through acquired mutations in cancer genes. Cancer genome sequencing can identify recurring genetic alterations that will generate new approaches to the treatment of melanoma, enabling a more personalized approach, based on gene mutation profiles of each patient's tumor. To systematically survey mutations in melanoma, we performed whole-exome sequencing of 14 matched normal and metastatic tumor DNAs. This allowed us to discover GRIN2A, a member of the ionotropic glutamate receptor family (iGluR), to be a significantly mutated gene that had not previously been identified as playing a role in melanoma. The comprehensive nature of the acquired data in this study allowed the identification of the glutamate signaling pathway to be significantly mutated, which includes GRIN2A, GRM3 and ERBB4, found to be mutated at 25, 16 and 19 percent of melanomas, respectively GRIN2A and GRM3, a metabotropic glutamate receptor (mGluR) are regulated by glutamate. GRIN2A, which is a ligand-gated ion channel, allows cations such as calcium to pass through the plasma membrane of the cell after the binding of glutamate to the receptor. GRM3 activates pathways such as the MEK pathway upon glutamate binding. The functional interplay between GRIN2A, GRM3 and ERBB4 in melanoma will be discussed and preliminary data presented. Our findings have potential therapeutic implications, as glutamate pathway modification has previously been shown to limit tumor growth. Further investigation of the glutamate pathway in melanoma a development of glutamate pathway inhibitors is therefore warranted. Disclosure All authors have declared no conflicts of interest.