Spectrum of <i>BRAF</i> Mutations and Gene Rearrangements in Ovarian Serous Carcinoma.

Abstract

Low-grade serous carcinoma (LGSC) is a rare type of ovarian cancer, which commonly arises from serous borderline tumor (SBT) and is characterized by frequent activating mutations in the mitogen-activated protein kinase pathway, including <i>BRAF</i>. The <i>BRAF</i> ^V600E mutation is associated with improved prognosis in SBT and LGSC, and responses to BRAF inhibitor therapy have been reported. We sought to characterize the clinicopathologic and molecular features of <i>BRAF</i>-driven tubo-ovarian and primary peritoneal serous tumors. Retrospective analysis of our institutional cohort of SBTs (n = 22), LGSCs (n = 119) and high-grade serous carcinomas (HGSCs, n = 1,290) subjected to targeted massively parallel sequencing was performed to identify cases with <i>BRAF</i> genetic alterations. Putative <i>BRAF</i> rearrangements were confirmed using targeted RNA sequencing and/or fluorescence in situ hybridization (FISH). BRAF^V600E oncoprotein expression was assessed by immunohistochemistry on selected cases. <i>BRAF</i> somatic genetic alterations were identified in 29 of 1,431 (2%) serous tumors and included mutations (n = 24), gene rearrangements (n = 3), and amplification (n = 2). <i>BRAF</i> mutations were more frequent in SBTs (7 of 22; 32%) compared with LGSCs (11 of 119; 9%, <i>P</i> = .009) and HGSCs (6 of 1,290; 0.5%; <i>P</i> < .0001, SBT/LGSC <i>v</i> HGSC). The <i>BRAF</i> ^V600E hotspot mutation was most common (n = 16); however, other <i>BRAF</i> driver mutations were also detected (n = 8). <i>BRAF</i> mutations were often clonal or truncal in SBTs and LGSCs, but subclonal in most HGSCs. Pathogenic <i>BRAF</i> gene fusions were identified in LGSCs (n = 2) and HGSC (n = 1) and involved distinct fusion partners (<i>AGK, MKRN1</i>, and <i>AGAP3</i>). Three patients with BRAF-mutant LGSC were treated with targeted mitogen-activated protein kinase inhibitors, one of whom was maintained on therapy for over 3 years with clinical benefit. Recognition of <i>BRAF</i> alterations beyond V600E mutation in LGSC may have clinical implications for appropriate targeted therapy selection.