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Incidence of Germline Variants in Familial Bladder Cancer and Among Patients With Cancer Predisposition Syndromes

  • Author Footnotes
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    Matthew Mossanen
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    Affiliations
    Department of Urology, Brigham and Women's Hospital, Boston, MA

    Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA
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  • Author Footnotes
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    Amin H. Nassar
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    Affiliations
    Department of Medicine, Brigham and Women's Hospital, Boston, MA

    Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA
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  • Author Footnotes
    # Equal credit as first authors
    Samantha M. Stokes
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    Affiliations
    Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA

    Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA
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  • Author Footnotes
    # Equal credit as first authors
    Nieves Martinez-Chanza
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    Affiliations
    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA

    Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA
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    Vivek Kumar
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    Affiliations
    Department of Medicine, Brigham and Women's Hospital, Boston, MA

    Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA
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    Pier Vitale Nuzzo
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    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA

    Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA
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    David J. Kwiatkowski
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    Department of Medicine, Section of Medical Oncology, Brigham and Women's Hospital, Boston, MA

    Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA
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    Judy E. Garber
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    Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA

    Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA
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    Catherine Curran
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    Affiliations
    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA

    Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA
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    Dory Freeman
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    Affiliations
    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA

    Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA
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    Mark Preston
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    Department of Urology, Brigham and Women's Hospital, Boston, MA

    Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA
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    Kent W. Mouw
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    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA

    Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA
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    Adam Kibel
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    Department of Urology, Brigham and Women's Hospital, Boston, MA

    Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA
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  • Author Footnotes
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    Toni K. Choueiri
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    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA

    Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA
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    Guru Sonpavde
    Correspondence
    Address for correspondence: Guru Sonpavde, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215.
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    # Equal credit as first authors
    Affiliations
    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA

    Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA
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    Huma Q. Rana
    Correspondence
    Address for correspondence: Huma Q. Rana. Department of Medical Oncology, Division of Population Sciences, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215,.
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    # Equal credit as first authors
    Affiliations
    Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA

    Department of Radiation Oncology, Brigham and Women's Hospital, Boston, MA
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Published:August 28, 2022DOI:https://doi.org/10.1016/j.clgc.2022.08.009

      Abstract

      Background

      The familial aggregation of bladder cancers has been observed, but the incidence and association of familial bladder cancer with germline pathogenic and likely pathogenic (P/LP) variants is unknown.

      Patients and Methods

      A retrospective analysis was conducted of patients with bladder cancer treated at the Dana-Farber Cancer Institute to identify those with a first-degree relative with bladder cancer. A second cohort of patients referred to DFCI for suspicion of a cancer predisposition syndrome was analyzed for candidate P/LP germline variants. Descriptive statistics were generated.

      Results

      Among 885 patients with bladder cancer, 38 patients (4.3%) had a family history of bladder cancer in a first-degree relative. No significant association of age of diagnosis was observed between patients with and without a first-degree family history of bladder cancer (P = .3). In the second cohort, 27 of 80 (34%) patients with bladder cancer evaluated for cancer predisposition syndromes harbored a P/LP germline variant. P/LP variants were identified most commonly in the following genes: BRCA1 (n = 5), MSH2 (n = 5), MLH1 (n = 4), ATM (n = 3), and CHEK2 (n = 2). Of the 27 patients with identified germline P/LP variants, 20 (74%) had a family history of a tumor component syndrome in a first- or second-degree relative and 3 were subsequently diagnosed with another genetically-linked associated cancer.

      Conclusion

      Familial bladder cancer defined as bladder cancer in the proband and a first-degree relative, was present in 4.3% of patients with bladder cancer and was not associated with age of diagnosis. Additionally, among patients suspected to have a familial cancer syndrome, one-third harbored a germline P/LP variant. Further study of germline variants in patients with familial bladder cancer including somatic testing for loss of heterozygosity may provide insights regarding disease pathogenesis and inform therapy.

      Keywords

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