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Loss of function germline mutations in RAD51D in women with ovarian carcinoma

  • Author Footnotes
    1 These authors contributed equally to the work.
    Anneka Wickramanyake
    Footnotes
    1 These authors contributed equally to the work.
    Affiliations
    Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA 98195, USA
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  • Author Footnotes
    1 These authors contributed equally to the work.
    Greta Bernier
    Footnotes
    1 These authors contributed equally to the work.
    Affiliations
    Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA

    Department of Surgery, University of Washington School of Medicine, Seattle, WA 98195, USA
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  • Christopher Pennil
    Affiliations
    Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA 98195, USA
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  • Silvia Casadei
    Affiliations
    Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA
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  • Kathy J. Agnew
    Affiliations
    Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA 98195, USA
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  • Sunday M. Stray
    Affiliations
    Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA
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  • Jessica Mandell
    Affiliations
    Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA
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  • Rochelle L. Garcia
    Affiliations
    Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA
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  • Tom Walsh
    Affiliations
    Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA
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  • Mary-Claire King
    Affiliations
    Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA
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  • Elizabeth M. Swisher
    Correspondence
    Corresponding author at: University of Washington Medical Center, Department of Obstetrics and Gynecology, Box 356460, Seattle, WA 98195-6460, USA. Fax: +1 206 543 3915.
    Affiliations
    Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA 98195, USA

    Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to the work.

      Abstract

      Objective

      RAD51D, a gene in the Fanconi Anemia–BRCA homologous recombination pathway, has recently been shown to harbor germline mutations responsible for ovarian carcinoma in multiply affected families. We aimed to extend these results to ovarian carcinoma in the general population.

      Methods

      We sequenced RAD51D in germline DNA from 360 individuals with primary ovarian, peritoneal or fallopian tube carcinoma who were not selected for age of cancer onset or family history. We also sequenced RAD51D in 459 probands from 226 high risk breast cancer families who were wild type for 21 breast and ovarian cancer genes.

      Results

      Of 360 cases, three (0.8%) carried loss-of-function mutations in RAD51D. All three subjects had ovarian carcinoma; one was also diagnosed with a synchronous endometrial carcinoma. Only one of the three subjects had a family history of breast or ovarian cancer. Combined with previous data for this series, 23.9% of women with unselected ovarian, fallopian tube, or peritoneal carcinoma carried a germline loss-of-function mutation in any of 13 tumor suppressor genes. Among the 449 women and 10 men with familial breast cancer, none carried a loss of function mutation in RAD51D.

      Conclusions

      These data support the previous observation that loss-of-function mutations in RAD51D predispose to ovarian carcinoma but not to breast carcinoma. We conclude that inherited ovarian cancer is highly heterogeneous genetically, and that approximately one in four ovarian carcinoma patients carry a germline mutation in a known tumor suppressor gene that confers high risk.

      Highlights

      • RAD51D loss-of-function mutations are present in 1% of unselected women with ovarian cancer.
      • Ovarian cancer risk assessment should include evaluation of RAD51D in a multigene panel.
      • Women with ovarian cancer should be evaluated for hereditary risk without selection for family history.

      Keywords

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