Abstract Background Activating BRAF gene alterations are central to melanocytic tumor pathogenesis. A small, emerging subset of melanocytic tumors driven by BRAF fusions has distinct therapeutic implications and has been described to have Spitzoid morphology patterns. However, such morphological patterns do not encompass all cases, and little is known about the functional molecular events. Materials and Methods We conducted a retrospective search through our molecular archives to identify melanocytic tumors with BRAF fusions. We reviewed clinical, histopathological, and genomic features. We further explored transcriptomic and protein‐level findings. Results Histopathologic patterns varied, with many cases without a distinctive pattern. We identified novel and diverse BRAF gene fusion partners. Differential transcriptomic analysis between low‐risk BRAF fusion tumors and reference BRAF V600E tumors showed no differentially expressed genes. However, quantitatively stronger MAPK pathway activation of BRAF fusion tumors over BRAF V600E tumors was demonstrated by statistically significant stronger staining of p‐ERK immunohistochemistry. Gene‐specific RNA analysis shows comparable BRAF transcript levels between the two groups. Discussion and Conclusion The quantitatively stronger activation of the MAPK pathway of BRAF fusion tumors, instead of qualitatively different transcriptomes, may account for the morphology difference from conventional BRAF V600E tumors. BRAF fusions likely act through dysregulated protein function rather than RNA upregulation related to the characteristics of the fusion partners.

Histopathologic, genomic, transcriptomic, and functional characteristics of eight melanocytic tumors with <i>BRAF</i> fusions showing stronger MAPK pathway activation compared to <i>BRAF V600E</i> tumors

Histopathologic, genomic, transcriptomic, and functional characteristics of eight melanocytic tumors with BRAF fusions showing stronger MAPK pathway activation compared to BRAF V600E tumors