PMID- 34568720
OWN - NLM
STAT- MEDLINE
DCOM- 20220404
LR  - 20230404
IS  - 2473-4284 (Electronic)
IS  - 2473-4284 (Linking)
VI  - 5
DP  - 2021
TI  - Spectrum of BRAF Mutations and Gene Rearrangements in Ovarian Serous Carcinoma.
LID - PO.21.00055 [pii]
LID - 10.1200/PO.21.00055 [doi]
AB  - 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 BRAF (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 
      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). BRAF(V600E) 
      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 BRAF (V600E) 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.
CI  - (c) 2021 by American Society of Clinical Oncology.
FAU - Chui, M Herman
AU  - Chui MH
AUID- ORCID: 0000-0002-7220-3996
AD  - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
FAU - Chang, Jason C
AU  - Chang JC
AUID- ORCID: 0000-0002-1705-1870
AD  - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
FAU - Zhang, Yanming
AU  - Zhang Y
AD  - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
FAU - Zehir, Ahmet
AU  - Zehir A
AUID- ORCID: 0000-0001-5406-4104
AD  - Department of Computational Biology, Memorial Sloan Kettering Cancer Center, New 
      York, NY.
FAU - Schram, Alison M
AU  - Schram AM
AUID- ORCID: 0000-0002-6070-2413
AD  - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
AD  - Department of Medicine, Weill Cornell Medical College, New York, NY.
FAU - Konner, Jason
AU  - Konner J
AUID- ORCID: 0000-0002-0720-2719
AD  - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
AD  - Department of Medicine, Weill Cornell Medical College, New York, NY.
FAU - Drilon, Alexander E
AU  - Drilon AE
AUID- ORCID: 0000-0001-6806-9061
AD  - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
AD  - Department of Medicine, Weill Cornell Medical College, New York, NY.
FAU - Da Cruz Paula, Arnaud
AU  - Da Cruz Paula A
AD  - Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
FAU - Weigelt, Britta
AU  - Weigelt B
AUID- ORCID: 0000-0001-9927-1270
AD  - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
FAU - Grisham, Rachel N
AU  - Grisham RN
AD  - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
AD  - Department of Medicine, Weill Cornell Medical College, New York, NY.
LA  - eng
GR  - P30 CA008748/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20210916
PL  - United States
TA  - JCO Precis Oncol
JT  - JCO precision oncology
JID - 101705370
RN  - EC 2.7.11.1 (BRAF protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
MH  - *Carcinoma/genetics
MH  - Female
MH  - Gene Rearrangement/genetics
MH  - Humans
MH  - In Situ Hybridization, Fluorescence
MH  - Mutation
MH  - Neoplasm Grading
MH  - *Ovarian Neoplasms/genetics
MH  - Proto-Oncogene Proteins B-raf/genetics
MH  - Retrospective Studies
PMC - PMC8457847
COIS- The following represents disclosure information provided by authors of this 
      manuscript. All relationships are considered compensated unless otherwise noted. 
      Relationships are self-held unless noted. I = Immediate Family Member, Inst = My 
      Institution. Relationships may not relate to the subject matter of this 
      manuscript. For more information about ASCO's conflict of interest policy, please 
      refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a 
      public database containing information reported by companies about payments made 
      to US-licensed physicians (Open Payments).
EDAT- 2021/09/28 06:00
MHDA- 2021/09/28 06:01
PMCR- 2022/09/16
CRDT- 2021/09/27 06:22
PHST- 2021/02/07 00:00 [received]
PHST- 2021/05/28 00:00 [revised]
PHST- 2021/07/27 00:00 [accepted]
PHST- 2021/09/27 06:22 [entrez]
PHST- 2021/09/28 06:00 [pubmed]
PHST- 2021/09/28 06:01 [medline]
PHST- 2022/09/16 00:00 [pmc-release]
AID - PO.21.00055 [pii]
AID - 10.1200/PO.21.00055 [doi]
PST - epublish
SO  - JCO Precis Oncol. 2021 Sep 16;5:PO.21.00055. doi: 10.1200/PO.21.00055. 
      eCollection 2021.