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Tumor heterogeneity in the recurrence of epithelial ovarian cancer demonstrated by polycomb group proteins

Authors Gui T, Bai H, Zeng J, Zhong Z, Cao D, Cui Q, Chen J, Yang J, Shen K

Received 11 May 2014

Accepted for publication 12 July 2014

Published 25 September 2014 Volume 2014:7 Pages 1705—1716

DOI https://doi.org/10.2147/OTT.S67570

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 4


Ting Gui,1,* Huimin Bai,1,* Jianfang Zeng,1 Zhaoji Zhong,1 Dongyan Cao,1 Quancai Cui,2 Jie Chen,2 Jiaxin Yang,1 Keng Shen1

1Department of Obstetrics and Gynecology, 2Department of Pathology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
 
*These authors contributed equally to this work

Purpose: To investigate tumor heterogeneity in the recurrence of epithelial ovarian cancer demonstrated by polycomb group (PcG) proteins.
Methods: Tissue microarrays containing matched primary and recurrent ovarian tumors from the same patients were constructed for detection of PcG protein expression. Survival analyses of clinicopathological parameters and expression of PcG proteins were performed on progression-free survival (PFS) and overall survival (OS) of patients. Genetic and epigenetic heterogeneity was explored in aspects of gene copy number and microRNA (miRNA) profiling.
Results: PcG proteins were heterogeneously expressed in primary versus recurrent tumors (P<0.05). In univariate survival analysis of the ovarian carcinoma cohorts, a significant association of intensive expression of BMI1 and EZH2 in first-onset lymph node metastases with shortened PFS was demonstrated (P=0.010, P=0.019); and a significant association of intensive expression of BMI1 and EZH2 in recurrent tumors with shortened OS was demonstrated (P=0.042, P=0.047). Importantly, BMI1 and EZH2 expression provided significant independent prognostic parameters in multivariate analyses (P<0.05). Gene amplification did not always coincide with PcG protein expression. Eight miRNAs were found to be downregulated in recurrent tumors, among which miR-298 might indirectly regulate the expression of EZH2 through transcription factor ILF3.
Conclusion: Tumor heterogeneity exists in the recurrence of epithelial ovarian cancer, manifested by PcG protein expression and underlying genetic and epigenetic alterations. Intensive expression of BMI1 and EZH2 are predictors of earlier relapse and shorter OS, independent of grade and chemotherapy sensitivity. EZH2 and miR-298 have great potential to be new targets for treatment of recurrent ovarian cancer.

Keywords: PcG protein, miRNA

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