Spectrum of BRAF Mutations and Gene Rearrangements in Ovarian Serous Carcinoma

Abstract

PURPOSE 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 BRAF. The BRAFV600E 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 BRAF-driven tubo-ovarian and primary peritoneal serous tumors. METHODS 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 BRAF genetic alterations. Putative BRAF rearrangements were confirmed using targeted RNA sequencing and/or fluorescence in situ hybridization (FISH). BRAFV600E oncoprotein expression was assessed by immunohistochemistry on selected cases. RESULTS BRAF 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). BRAF mutations were more frequent in SBTs (7 of 22; 32%) compared with LGSCs (11 of 119; 9%, P = .009) and HGSCs (6 of 1,290; 0.5%; P < .0001, SBT/LGSC v HGSC). The BRAFV600E hotspot mutation was most common (n = 16); however, other BRAF driver mutations were also detected (n = 8). BRAF mutations were often clonal or truncal in SBTs and LGSCs, but subclonal in most HGSCs. Pathogenic BRAF gene fusions were identified in LGSCs (n = 2) and HGSC (n = 1) and involved distinct fusion partners ( AGK, MKRN1, and AGAP3). 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. CONCLUSION Recognition of BRAF alterations beyond V600E mutation in LGSC may have clinical implications for appropriate targeted therapy selection.

The Evolution of Ovarian Carcinoma Subclassification

“…Data from a large study integrating mutational data from targeted sequencing and IHC in LGSC suggest five molecular subtypes, and, listed in order of decreasing aggressiveness, they are CDKN2A IHC alteration > PR loss/high fraction of genome altered > MAPK pathway mutations ( KRAS , NRAS , BRAF ) ~ USP9X mutations ~ NSMP [ 98 ]. This could provide context for molecularly informed treatment decisions, such as CDK4/6 inhibitors for cases with CDKN2A loss versus hormonal therapy plus MEK inhibitors for MAPK-mutated cases with retained hormone receptor expression [ 63 , 90 , 99 , 100 , 101 ]. However, these findings require further validation in preclinical models and clinical trials.…”

Molecular mechanisms of platinum‑based chemotherapy resistance in ovarian cancer (Review)

“…Epithelia cancers include serous [high-grade serous carcinoma (HGSC) and low-grade serous carcinoma (LGSC)], endometrioid (high-grade endometrioid carcinoma and low-grade endometrioid carcinoma), clear-cell and mucinous carcinomas ( 2 , 4 ). LGSCs usually contain KRAS and BRAF mutations ( 5 , 6 ), whereas most HGSCs have TP53 mutations and exhibit severe aneuploidy genome aberrations. Clear cell carcinoma is characterized by mutations in the ARID1A, PIK3CA, PTEN and KRAS genes, while endometrioid carcinoma, similar to its uterine counterpart, has mutations in ARID1A, CTNNB1, and PTEN, as well as microsatellite instability ( 7 , 8 ).…”

AGAP3: A novel BRAF fusion partner in pediatric pancreatic‐type acinar cell carcinoma

“…The protein is mainly physiologically expressed in brain cortex, while overexpression has been reported in colorectal carcinoma and adenoma 16 . The AGAP3::BRAF fusion has previously been reported in a few cases from various tumor origins: colorectal carcinoma, lung adenocarcinoma, ovarian serous carcinoma, melanoma, and gastrointestinal stromal tumor 17–19 . The detection of this AGAP3::BRAF fusion seems important for the choice of a targeted treatment since it has been described to confer resistance to EGFR‐targeted and BRAF‐targeted therapies, in colorectal carcinoma and melanoma, respectively 20,21 .…”

“… 16 The AGAP3::BRAF fusion has previously been reported in a few cases from various tumor origins: colorectal carcinoma, lung adenocarcinoma, ovarian serous carcinoma, melanoma, and gastrointestinal stromal tumor. 17 , 18 , 19 The detection of this AGAP3::BRAF fusion seems important for the choice of a targeted treatment since it has been described to confer resistance to EGFR‐targeted and BRAF‐targeted therapies, in colorectal carcinoma and melanoma, respectively. 20 , 21 Fusion genes involving BRAF , RAF1 , and RET are mutually exclusive in PACC.…”