Spectrum of BRAF mutations and gene rearrangements in ovarian serous carcinoma Journal Article


Authors: Chui, M. H.; Chang, J. C.; Zhang, Y.; Zehir, A.; Schram, A. M.; Konner, J.; Drilon, A. E.; da Cruz Paula, A.; Weigelt, B.; Grisham, R. N.
Article Title: 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. © 2021 by American Society of Clinical Oncology
Journal Title: JCO Precision Oncology
Volume: 5
ISSN: 2473-4284
Publisher: American Society of Clinical Oncology  
Date Published: 2021-09-16
Start Page: 1480
End Page: 1492
Language: English
DOI: 10.1200/po.21.00055
PROVIDER: scopus
PMCID: PMC8457847
PUBMED: 34568720
DOI/URL:
Notes: Article -- Export Date: 2 November 2021 -- Source: Scopus
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MSK Authors
  1. Jason Konner
    156 Konner
  2. Rachel Nicole Grisham
    175 Grisham
  3. Ahmet Zehir
    345 Zehir
  4. Alexander Edward Drilon
    638 Drilon
  5. Alison Michele Schram
    125 Schram
  6. Britta Weigelt
    643 Weigelt
  7. Jason Chih-Peng Chang
    142 Chang
  8. Yanming Zhang
    203 Zhang
  9. Michael Herman Chui
    61 Chui