BRAF Gene Fusions in Melanoma: First Kinase Domain Duplication, New Fusion Partners, and Clinical Outcomes.

Abstract

BRAF gene fusions have been well-described in Spitzoid melanocytic lesions but can also occur uncommonly in conventional melanomas. Here we report a series of 17 melanomas harboring BRAF gene fusions as their putative primary genetic driver. All but one of these tumors occurred in adults (age range 13 to 96) with a relatively even sex distribution (41% female) and a broad distribution of anatomic sites. None of the tumors showed typical Spitzoid histomorphologic features. Molecular analysis identified the first example of BRAF kinase domain duplication in melanoma, which raises interesting questions regarding the mechanism of fusion-induced BRAF activation. Although we did not identify histomorphologic features that could distinguish BRAF-fused melanomas from more conventional melanomas, we did observe a generally low tumor mutational burden and a lower rate of UV-associated mutational signatures (3/17; 18%), suggesting that BRAF-fused melanomas are molecularly and mechanistically distinct from conventional cutaneous melanomas. We report detailed treatment information and clinical outcomes for this series, with most patients having shown disease progression on systemic immunotherapy (8/12; 67%). Our results highlight the need for continued molecular subclassification to yield a comprehensive understanding of melanoma pathogenesis and have potential implications for therapeutic selection in BRAF-fused and perhaps other unconventional forms of melanoma.