A candidate precursor to serous carcinoma that originates in the distal fallopian tube

Authors

  • Y Lee,

    1. Division of Women's and Perinatal Pathology, Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
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    • The authors of this article declared they have no conflicts of interest.

    • Both authors contributed equally to this work and are considered co-first authors.

  • A Miron,

    1. Department of Cancer Biology, Dana-Farber Cancer Institute, USA
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    • The authors of this article declared they have no conflicts of interest.

    • Both authors contributed equally to this work and are considered co-first authors.

  • R Drapkin,

    1. Division of Women's and Perinatal Pathology, Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
    2. Department of Medical Oncology, Dana-Farber Cancer Institute, USA
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    • The authors of this article declared they have no conflicts of interest.

  • MR Nucci,

    1. Division of Women's and Perinatal Pathology, Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
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    • The authors of this article declared they have no conflicts of interest.

  • F Medeiros,

    1. Division of Women's and Perinatal Pathology, Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
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    • The authors of this article declared they have no conflicts of interest.

  • A Saleemuddin,

    1. Division of Women's and Perinatal Pathology, Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
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    • The authors of this article declared they have no conflicts of interest.

  • J Garber,

    1. Department of Medical Oncology, Dana-Farber Cancer Institute, USA
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    • The authors of this article declared they have no conflicts of interest.

  • C Birch,

    1. Division of Women's and Perinatal Pathology, Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
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    • The authors of this article declared they have no conflicts of interest.

  • H Mou,

    1. Department of Cell Biology, Harvard Medical School, USA
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    • The authors of this article declared they have no conflicts of interest.

  • RW Gordon,

    1. Department of Cancer Biology, Dana-Farber Cancer Institute, USA
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  • DW Cramer,

    1. Obstetrical and Gynecologic Epidemiology, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, MA, USA
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  • FD McKeon,

    1. Department of Cell Biology, Harvard Medical School, USA
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  • CP Crum

    Corresponding author
    1. Division of Women's and Perinatal Pathology, Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
    • Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
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    • The authors of this article declared they have no conflicts of interest.


Abstract

The tubal fimbria is a common site of origin for early (tubal intraepithelial carcinoma or TIC) serous carcinomas in women with familial BRCA1 or 2 mutations (BRCA+). Somatic p53 tumour suppressor gene mutations in these tumours suggest a pathogenesis involving DNA damage, p53 mutation, and progressive loss of cell cycle control. We recently identified foci of strong p53 immunostaining—termed ‘p53 signatures’—in benign tubal mucosa from BRCA+ women. To examine the relationship between p53 signatures and TIC, we compared location (fimbria vs ampulla), cell type (ciliated vs secretory), evidence of DNA damage, and p53 mutation status between the two entities. p53 signatures were equally common in non-neoplastic tubes from BRCA+ women and controls, but more frequently present (53%) and multifocal (67%) in fallopian tubes also containing TIC. Like prior studies of TIC, p53 signatures predominated in the fimbriae (80–100%) and targeted secretory cells (HMFG2 + /p73−), with evidence of DNA damage by co-localization of γ-H2AX. Laser-capture microdissected and polymerase chain reaction-amplified DNA revealed reproducible p53 mutations in eight of 14 fully-analysed p53 signatures and all of the 12 TICs; TICs and their associated ovarian carcinomas shared identical mutations. In one case, a contiguous p53 signature and TIC shared the same mutation. Morphological intermediates between the two, with p53 mutations and moderate proliferative activity, were also seen. This is the first report of an early and distinct alteration in non-neoplastic upper genital tract mucosa that fulfils many requirements for a precursor to pelvic serous cancer. The p53 signature and its malignant counterpart (TIC) underline the significance of the fimbria, both as a candidate site for serous carcinogenesis and as a target for future research on the early detection and prevention of this disease. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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