Abstract

Activating BRAF gene alterations are central to melanocytic tumor pathogenesis. A small, emerging subset of melanocytic tumors driven by BRAF fusions displays distinct clinical presentation, histopathology, and therapeutic implications. Herein, we report a series of 7 melanocytic tumors with BRAF Fusions. The patients presented at various ages (26-62) with various clinical outcomes (from no recurrence to fatal). Histopathologic patterns include previously described “buck-shot fibrosis”, “whorled fibrosis”, “fascicular”, and conventional malignant epithelioid pattern. The high-risk/melanoma group (n=4) shows unequivocal worrisome features (high mitotic count, sheet-like growth, pagetoid spread), while the low-risk/nevus group (n=3) lacks such findings. Immunohistochemical studies of p16, Ki-67, and PRAME corroborate the above classification. Next-generation sequencing identifies a wide range of BRAF gene fusion partners: AKAP9, TRIM33, RUFY3, FMN1, SEPT7, and MYO5A. Additional pathogenic genetic alterations are mostly found in high-risk/melanoma groups, including TERT promotor mutation, PTEN loss, and CDKN2A loss. High tumor mutation burden correlates with age in sun-exposed areas (p<0.001, t-test). Differential transcriptomic analysis between the low-risk/nevus group and 5 reference BRAF V600E atypical nevi shows comparable mRNA profiles, with similar BRAF transcript levels across different exons. The findings may suggest the BRAF fusions act through alteration of protein function, rather than RNA upregulation. Our study further expands the growing literature on this class of melanocytic tumors, demonstrates novel fusion partners, and provides novel insight on the transcriptomic level.