Genomic analysis reveals low tumor mutation burden which may be associated with GNAQ/11 alteration in a series of primary leptomeningeal melanomas

Primary central nervous system melanoma is rare and characterized by a variable prognosis, and no current treatment guidelines exist. We describe the clinical course of a 70‐year‐old female patient diagnosed with primary leptomeningeal melanoma (LMN) whose case represents the diagnostic and management challenges of this tumor. Targeted genomic sequencing of 315 genes from this tumor revealed GNAQ Q209L mutation and low (4 mutations/Megabase) tumor mutation burden (TMB). Wild‐type NRAS, KIT, and BRAF were also observed. A cohort of 4,787 melanomas was subsequently analyzed to identify additional primary central nervous system melanomas, of which 10 additional tumors met pathologic criteria (0.21% of total melanoma cohort). These tumors were genomically assessed according to the same targeted sequencing panel, and 6 of the tumors were also found to harbor a GNAQ mutation. All 10 tumors had low (less than or equal to 2 mutations/Megabase) TMB indicating a potential trend between G‐protein‐coupled receptor (GPCR) alterations and low TMB in LMNs. GPCR alterations were found to significantly correlate with TMB across the cohort of 4,787 melanomas, supporting this potential finding in the limited LMN subset.