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Loss of ARID1A Expression Is an Early Molecular Event in Tumor Progression From Ovarian Endometriotic Cyst to Clear Cell and Endometrioid Carcinoma
  1. Ayse Ayhan, MD, PhD*,,
  2. Tsui-Lien Mao, MD,
  3. Tamer Seckin, MD§,
  4. Chen-Hsuan Wu, MD*,,
  5. Bin Guan, PhD*,
  6. Hiroshi Ogawa, MD,
  7. Masayuki Futagami, MD,
  8. Hiroki Mizukami, MD,
  9. Yoshihito Yokoyama, MD,
  10. Robert J. Kurman, MD, PhD* and
  11. Ie-Ming Shih, MD, PhD*
  1. *Departments of Pathology, Oncology and Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, Maryland;
  2. Department of Pathology, Seirei Mikatahara General Hospital, Hamamatsu, Japan;
  3. Department of Pathology, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan;
  4. §North Shore LIJ-Lenox Hill Hospital, New York, NY; and theDepartments of
  5. Obstetrics and Gynecology, and
  6. Pathology & Molecular Medicine, Hirosaki University Graduate School of Medicine, Japan.
  1. Address correspondence and reprint requests to Ie-Ming Shih, MD, PhD. E-mail: ishih{at}jhmi.edu and Ayse Ayhan, MD, PhD. E-mail: ayseayhanjp{at}gmail.com.

Abstract

Objectives ARID1A is a recently identified tumor suppressor participating in chromatin remodeling. Somatic inactivating mutations of ARID1A and loss of its expression occur frequently in ovarian clear cell and endometrioid carcinomas and in uterine endometrioid carcinomas. Because endometriotic epithelium is thought to be the cell of origin of most ovarian clear cell and endometrioid carcinomas, we undertook an analysis of ARID1A expression of these tumors arising within an endometriotic cyst (endometrioma).

Materials and Methods Our immunohistochemical study set consisted of 47 endometriotic cysts containing clear cell carcinoma in 24 cases, well-differentiated ovarian endometrioid carcinoma in 20 cases, and mixed clear cell and endometrioid carcinoma in 3 cases.

Results ARID1A loss was observed in 31 (66%) of 47 carcinomas; and therefore, these cases were informative for determining the temporal sequence of loss of ARID1A expression in tumor progression. In 16 of the 47 cases, ARID1A immunoreactivity was retained in both the endometriotic cyst and the carcinoma; and thus, these cases were not informative. All of the 31 informative cases showed loss of ARID1A immunoreactivity in the carcinoma and in the endometriotic cyst epithelium in direct continuity with the carcinoma but not in the cyst epithelium that was not adjacent to the tumor.

Conclusions Loss of ARID1A function as shown by loss of expression, presumably due to mutations, is an early molecular event in the development of most ovarian clear cell and endometrioid carcinomas arising in endometriomas.

  • ARID1A
  • Chromatin remodeling gene
  • Endometriosis
  • Endometriotic cyst
  • Initiation
  • Ovarian clear cell carcinoma
  • Ovarian endometrioid carcinoma
  • Tumor suppressor
  • Carcinogenesis

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Footnotes

  • This study was supported by an NIH/NCI grant R21CA165807, an OSB1 grant from HERA Women’s Cancer Foundation, NSC grant 100-2320-B-002-081, and a grant from Endometriosis Foundation of America (EFA).

  • The authors declare no conflict of interest.

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