Original Paper

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

  1. Y Lee1,†,‡,
  2. A Miron2,†,‡,
  3. R Drapkin1,3,†,
  4. MR Nucci1,†,
  5. F Medeiros1,†,
  6. A Saleemuddin1,†,
  7. J Garber3,†,
  8. C Birch1,†,
  9. H Mou4,†,
  10. RW Gordon2,†,
  11. DW Cramer5,†,
  12. FD McKeon4,†,
  13. CP Crum1,†,*

Article first published online: 20 NOV 2006

DOI: 10.1002/path.2091

Issue

The Journal of Pathology

The Journal of Pathology

Volume 211, Issue 1, pages 26–35, January 2007

Additional Information

How to Cite

Lee, Y., Miron, A., Drapkin, R., Nucci, M., Medeiros, F., Saleemuddin, A., Garber, J., Birch, C., Mou, H., Gordon, R., Cramer, D., McKeon, F. and Crum, C. (2007), A candidate precursor to serous carcinoma that originates in the distal fallopian tube. J. Pathol., 211: 26–35. doi: 10.1002/path.2091

Author Information

  1. 1

    Division of Women's and Perinatal Pathology, Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA

  2. 2

    Department of Cancer Biology, Dana-Farber Cancer Institute, USA

  3. 3

    Department of Medical Oncology, Dana-Farber Cancer Institute, USA

  4. 4

    Department of Cell Biology, Harvard Medical School, USA

  5. 5

    Obstetrical and Gynecologic Epidemiology, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, MA, USA

  1. †

    The authors of this article declared they have no conflicts of interest.

  2. ‡

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

*Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.

  1. †

    The authors of this article declared they have no conflicts of interest.

  2. ‡

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

Publication History

  1. Issue published online: 29 NOV 2006
  2. Article first published online: 20 NOV 2006
  3. Manuscript Accepted: 26 SEP 2006
  4. Manuscript Revised: 22 SEP 2006
  5. Manuscript Received: 9 AUG 2006

Funded by

  • NIH. Grant Number: CA 83944
  • NCI. Grant Numbers: P50 CA10500, K08 CA 108748
  • Ovarian Cancer Research Fund
  • Francis Ward Paine and TSA Pemberton Funds of the Division of Women's and Perinatal Pathology
  • Department of Pathology, Brigham and Women's Hospital
  • Columbia Hospital for Women Research Foundation, Washington, DC

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Keywords:

  • BRCA;
  • p53;
  • fallopian tube neoplasms;
  • serous carcinoma;
  • ovarian neoplasms;
  • fimbria

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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