SF3B1 and EIF1AX mutations occur in primary leptomeningeal melanocytic neoplasms; yet another similarity to uveal melanomas

INTRODUCTION: Like uveal melanomas, primary leptomeningeal melanocytic neoplasms (LMNs) frequently carry GNAQ and GNA11 mutations. However, it is currently unknown whether these LMNs harbor mutations in BAP1, SF3B1 and/or EIF1AX like uveal melanomas as well. In this study, we used Sanger sequencing for the detection of mutations in SF3B1 (hotspots in exon 14 and 15) and EIF1AX (exon 1 and 2 and flanking intronic regions) in a series of 24 primary LMNs. Additionally, BAP1 immunohistochemistry was used as a surrogate marker for the detection of inactivating mutations in the BAP1 gene.

RESULTS: Mutations in either SF3B1 or EIF1AX were identified in 8 out of 24 primary LMNs (33 %). The presence of these mutations was mutually exclusive and occurred in primary LMNs of different malignancy grades (melanocytomas, intermediate-grade melanocytic tumors, melanomas). Complete absence of nuclear BAP1 staining as is typically seen in BAP1-mutated tumors was not observed.

CONCLUSIONS: Our finding that an SF3B1 or EIF1AX mutation is present in a substantial subset of primary LMNs underscores that these tumors genetically resemble uveal melanoma and are different from cutaneous melanoma at the genetic level. This information may not only aid in the differential diagnosis of primary versus metastatic melanocytic tumor in/around the central nervous system, but also in the identification of more promising therapeutic approaches targeting the molecular pathways involved in the oncogenesis of LMNs. As none of the primary LMNs in our series showed complete loss of nuclear BAP1 protein, it is unlikely that BAP1 mutations are frequent in these tumors but the role of this gene warrants further investigation.