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Mutational spectrum in clinically aggressive low-grade serous carcinoma/serous borderline tumors of the ovary—Clinical significance of BRCA2 gene variants in genomically stable tumors

  • Xiaoming Zhang
    Affiliations
    Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
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  • Author Footnotes
    1 Present address: Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
    Kyle Devins
    Footnotes
    1 Present address: Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
    Affiliations
    Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
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  • Emily M. Ko
    Affiliations
    Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
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  • Maria Carolina Reyes
    Affiliations
    Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
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  • Fiona Simpkins
    Affiliations
    Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
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  • Ronny Drapkin
    Affiliations
    Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
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  • Lauren E. Schwartz
    Affiliations
    Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
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  • Author Footnotes
    2 Present address and contact information: Division of Pathology, St. Michael's Hospital, Unity Health Toronto, 30 Bond Street, 2 Carter Wing, Toronto, Ontario, M5B-1W8, Canada.
    Ju-Yoon Yoon
    Correspondence
    Corresponding author at: The Division of Pathology, St Michael's Hospital, Unity Health Toronto, 30 Bond Street, 2 Carter Wing, Toronto, ON M5B 1W8, Canada.
    Footnotes
    2 Present address and contact information: Division of Pathology, St. Michael's Hospital, Unity Health Toronto, 30 Bond Street, 2 Carter Wing, Toronto, Ontario, M5B-1W8, Canada.
    Affiliations
    Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA

    Department of Pathology, St. Michael's Hospital, Toronto, Ontario, Canada
    Search for articles by this author
  • Author Footnotes
    1 Present address: Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
    2 Present address and contact information: Division of Pathology, St. Michael's Hospital, Unity Health Toronto, 30 Bond Street, 2 Carter Wing, Toronto, Ontario, M5B-1W8, Canada.

      Highlights

      • 17 cases of FIGO stage III low-grade serous carcinoma/serous borderline tumors underwent molecular profiling.
      • Tumor mutational burdens were generally low (range 3–10 mutations/Mb in 14 cases assessed).
      • Microsatellites were assessed to be stable in 12/12 cases.
      • The majority of tumors (11/17) harbored a clear driver mutation in forms of RTK/RAS/MAPK pathway gene mutations.
      • While BRCA2 variants were seen in 5/17 cases, further analyses suggest they are unlikely to be clinically significant.

      Abstract

      Objective

      The mutational spectra of low-grade serous carcinomas (LGSCs) and serous borderline tumors (SBTs) of the ovary are poorly characterized. We present 17 cases of advanced or recurrent LGSC/SBT patients who underwent molecular profiling.

      Methods

      Thirteen LGSCs and four SBTs underwent targeted gene panel testing by massively parallel sequencing. Microsatellite stability and tumor mutation burdens (TMBs) were determined based on panel sequencing data.

      Results

      The mean TMB was 5.2 mutations/megabase (range 3–10) in 14 cases. Twelve of twelve (12/12) cases were microsatellite stable. Clear driver mutations were identified in 11 cases, namely KRAS (5/17), BRAF (2/17), NRAS (2/17) and ERBB2 (2/17). Five cases harbored BRCA2 alterations (allele fractions: 44–51%), including two classified as likely benign/benign variants, and three classified as variants of uncertain significance (VUSs), with two variants being confirmed to be germline. The three BRCA2 VUSs were missense variants that were assessed to be of unlikely clinical significance, based on family cancer history and expected impact on protein function. Two patients received PARP inhibitors during their disease course, with neither of the patients demonstrating appreciable response.

      Conclusions

      The mutational spectra in 17 clinically aggressive SBT/LGSC cases demonstrate genomically stable tumors, frequently driven by the RTK/RAS/MAPK pathway. While BRCA2 variants were identified, our data demonstrate BRCA2 gene variants are at most VUSs and of dubious clinical significance, in contrast to disease-associated BRCA1/2 variants that may be identified in high-grade serous carcinoma. Germline testing and PARP inhibitors are thus expected to provide limited benefit to patients with LGSC/SBTs.

      Keywords

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