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CCNE1 copy-number gain and overexpression identify ovarian clear cell carcinoma with a poor prognosis.

CCNE1拷贝数的增加和过表达确定卵巢透明细胞癌预后差

Ayhan A,Kuhn E,Wu RC,Ogawa H,Bahadirli-Talbott A,Mao TL,Sugimura H,Shih IM,Wang TL
阅读:1940 Modern PathologyFeb 2017; 30 (2): 158 - 313:297-303 

Abstract

Ovarian clear cell carcinoma is a unique type of ovarian cancer, often derived from endometriosis, and advanced-stage disease has a dismal prognosis primarily due to the resistance to conventional chemotherapy. Previous studies have shown frequent somatic mutations in ARID1A, PIK3CA, hTERT promoter, and amplification of ZNF217; however, the molecular alterations that are associated with its aggressiveness remain largely unknown. This study examined and compared cyclin E1 expression in endometriosis-related ovarian tumors, with the aim of determining the relationship between hTERT mutations and ARID1A expression and evaluating the effects of these molecular alterations on patient survival. We performed immunohistochemistry on 207 tumors [clear cell carcinoma (n=120), endometrioid carcinoma (n=49), and seromucinous tumors (n=38)], followed by two-color fluorescence in situ hybridization (n=88) and compared with ARID1A expression and hTERT promoter mutations in the same samples. Cyclin E1 overexpression and CCNE1 copy-number gain occurred in 23.3% and 14.8% of ovarian clear cell carcinomas, respectively, but they were not detected in any of the other endometriosis-related tumors. All cases with CCNE1 copy-number gain demonstrated an intense cyclin E1 immunoreactivity (P<0.001). Cyclin E1 overexpression was positively correlated with hTERT promoter mutations (P=0.01), but not with the loss of ARID1A expression. A multivariate analysis revealed that CCNE1 overexpression predicts poor overall survival, even after adjusting for stage and age. Specifically, CCNE1 overexpression and copy-number gain were both correlated with a poor outcome in patients with stage I disease. Moreover, the subset with CCNE1 overexpression and ARID1A retention demonstrated the worst outcome. Our findings suggest that gene copy-number gain and upregulation of CCNE1 occur in ovarian clear cell carcinoma and are associated with a worse clinical outcome, dictating the survival of early-stage patients, and that these molecular alterations are unique to clear cell carcinoma among different types of endometriosis-related ovarian neoplasms.

摘要

卵巢透明细胞癌是卵巢癌的一个独特类型,通常来源于子宫内膜异位,进展期患者的预后让人沮丧主要是由于对常规化疗耐药之前的研究认为多有ARID1A、PIK3CA体细胞和hTERT启动子的基因突变以及 ZNF217的扩增。然而,与侵袭相关的分子改变在很大程度上仍不清楚。我们研究并比较细胞周期蛋白E1 在子宫内膜异位相关卵巢肿瘤中的表达,目的是确定hTERT突变与ARID1A表达之间的关系并且评估这些分子改变对患者生存的影响。

我们对207例肿瘤 [透明细胞癌(n = 120)、子宫内膜样癌(n = 49)、浆粘液性肿瘤(n = 38)]进行免疫组织化学检测,然后是双色荧光原位杂交(n = 88)并在同一个样本中比较ARID1A的表达与hTERT启动子突变的关系。细胞周期素E1过表达和CCNE1拷贝数增加分别发生在23.3%和14.8%的卵巢透明细胞癌中,但是在子宫内膜异位相关的卵巢肿瘤中并没有检测到细胞周期素E1的过表达和CCNE1拷贝数增加在CCNE1拷贝数增加的所有病例证实细胞周期素E1存在强烈免疫反应性(P < 0.001)。细胞周期素E1超表达与hTERT启动子突变呈正相关(P = 0.01),但与ARID1A的表达丢失不呈正相关。多因素分析研究揭示即使经阶段和年龄调整,CCNE1 过表达仍预示患者整体生存率不良尤其是CCNE1过度表达和拷贝数增加均与I期患者预后有关。此外CCNE1过度表达和ARID1A表达有一小部分结局最差。

我们的研究表明在卵巢透明细胞癌中CCNE1基因拷贝数增加和过表达与临床预后较差相关,影响早期患者的生存;这些分子改变在不同类型子宫内膜异位相关卵巢肿瘤中,仅见于透明细胞癌

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