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DNA Damage Signaling and Apoptosis in Preinvasive Tubal Lesions of Ovarian Carcinoma

Chene, Gautier MD, PhD*†‡; Ouellet, Veronique PhD*†; Rahimi, Kurosh MD†§; Barres, Veronique*†; Caceres, Katia*†; Meunier, Liliane*†; Cyr, Louis*†; De Ladurantaye, Manon*†; Provencher, Diane MD, PhD*†∥; Mes Masson, Anne Marie MD, PhD*†

International Journal of Gynecological Cancer: June 2015 - Volume 25 - Issue 5 - p 761–769
doi: 10.1097/IGC.0000000000000196
Basic Science

Objective: High-grade serous ovarian cancer (HGSC) is the most life-threatening gynecological malignancy despite surgery and chemotherapy. A better understanding of the molecular basis of the preinvasive stages might be helpful in early detection and diagnosis. Genetic instability is 1 of the characteristics shared by most human cancers, and its level is variable through precancerous lesions to advanced cancer. Because DNA damage response (DDR) has been described as 1 of the first phases in genomic instability, we investigated the level of DDR activation and the apoptosis pathway in serous tubal intraepithelial carcinoma (STIC), the potential precursor of HGSC.

Methods/Materials: A tissue microarray including 21 benign fallopian tubes, 21 STICs, 17 HGSCs from patients with STICs (associated ovarian cancer [AOC]) from the same individuals, and 30 HGSCs without STICs (non-AOC) was used in this study.

Immunohistochemistry was performed to evaluate the level of DDR proteins (pATM, pChk2, γH2AX, 53BP1, and TRF2), apoptosis proteins (Bcl2, BAX, and BIM), and cyclin E.

Results: The expression of all DDR proteins increased from benign fallopian tubes to STICs. The level of expression of pATM, pChk2, γH2AX, and TRF2 was also increased in STICs in comparison with AOC. BAX, BIM, and cyclin E expressions were high in STICs, whereas Bcl2 expression was low. Immunohistochemical profiles of AOC and non-AOC were also different.

Conclusions: These results suggest an activation of the DDR and apoptosis pathways in STICs, indicating that genomic instability may occur early in the precancerous lesions of HGSC.

*Centre de Recherche du Centre hospitalier de l’Université de Montréal; †Institut du Cancer de Montréal, Montreal, Quebec, Canada; ‡Department of Gynecology, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France; Departments of §Pathology, and ∥Gynecology, Centre hospitalier de l’Université de Montréal, Montreal, Quebec, Canada.

Address correspondence and reprint requests to Gautier Chene, MD, PhD, Department of Gynecology, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, 59 boulevard Pinel, 69677 Bron cedex, France. E-mail: chenegautier@yahoo.fr.

This work was supported by a grant from La Fondation de France.

Tumor banking was supported by the Banque de tissus et données of the Réseau de recherche sur le cancer of the Fond de Recherche du Québec-Santé, associated with the Canadian Tumor Repository Network.

The authors declare no conflicts of interest.

Received January 10, 2014

Received in revised form May 5, 2014

Accepted May 5, 2014

© 2015 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.