Comparative analysis of the GNAQ, GNA11, SF3B1, and EIF1AX driver mutations in melanoma and across the cancer spectrum

Abstract

Uveal melanoma is characterized by recurrent mutations in GNAQ, GNA11, SF3B1, and EIF1AX, as well as a low total mutational burden. The frequency and clinical significance of these mutations in non-uveal melanoma and other cancers is not well described. We identified that GNAQ/GNA11 mutations occur in 0.5–1% of non-uveal melanomas and are essentially melanoma-specific. Further, these mutations are associated with a lack of other typical melanoma mutations (BRAF, NRAS, KIT, NF1), a low mutational burden, and, in a small subset, lack of response to immunotherapy. We suggest that GNAQ/GNA11 mutations characterize an uncommon but distinct subtype of non-uveal melanomas.

Figure 1

Co-occurring genetic alterations in non-uveal melanomas harboring mutations in GNAQ, GNA11, SF3B1, and EIF1AX. Note: No mutations were identified in NF1, KRAS, MAP2K1, AKT1, CTNNB1, or CDK4 ^ATCGA: The Cancer Genome Atlas, whole exome sequencing, 278 melanomas. ^BBroad: whole exome sequencing, 121 melanomas (mutations only) performed at the Broad Institute. ^CYale: Whole exome sequencing, 91 melanomas (mutations only) performed at Yale. ^DClinical Samples: Next generation sequencing or hotspot mutation testing performed at VICC or MDACC. *NRAS^A83V mutation identified. #Co-occurring mutations in KIT^V559D, BRAF^G469V