Gene amplification CCNE1 is related to poor survival and potential therapeutic target in ovarian cancer

Naomi Nakayama, Kentaro Nakayama, Yeasmin Shamima, Masako Ishikawa, Atsuko Katagiri, Kouji Iida, Khoji Miyazaki
Cancer 2010 June 1, 116 (11): 2621-34

BACKGROUND: This study examined the clinical significance of CCNE1 (Cyclin E1) amplification and assessed whether CCNE1 is a potential therapeutic target in ovarian cancer.

METHODS: CCNE1 expression and amplification in ovarian cancer was assessed by immunohistochemistry, fluorescence in situ hybridization and clinical data collected by retrospective chart review. CCNE1 gene knockdown using silencing RNA and a CCNE1 gene transfection system were used to asses CCNE1 function in tissue samples of ovarian cancer.

RESULTS: Gene amplification was identified in 18 (20.4%) of 88 ovarian carcinomas. CCNE1 copy number significantly correlated with CCNE1 protein expression (r = 0.522, P < .0001). CCNE1 amplification significantly correlated with shorter disease-free survival and overall survival (P < .001). There were nonsignificant trends between high protein expression and poor disease-free survival (P = .2865) and overall survival (P = .1248). Multivariate analysis showed gene amplification was an independent prognostic factor for disease-free survival and overall survival after standard platinum-taxane chemotherapy (P = .0274, P = .0023). Profound growth inhibition and apoptosis were observed in silencing RNA-treated cancer cells with gene amplification compared with results in cancer cells with CCNE1 moderate expression without gene amplification or with low CCNE1 expression. CCNE1 overexpression stimulated proliferation in ovarian cancer cell lines ES2 and TOV-21G, which have lower endogenous CCNE1 expression.

CONCLUSIONS: These findings indicate that CCNE1 overexpression is critical to growth and survival of ovarian cancer tumors with CCNE1 gene amplification. Furthermore, they suggest that CCNE1 silencing RNA-induced phenotypes depend on amplification status of ovarian cancers. Therefore, CCNE1-targeted therapy may benefit ovarian cancer patients with CCNE1 amplification.

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