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

Ayse Ayhan, Elisabetta Kuhn, Ren Chin Wu, Hiroshi Ogawa, Asli Bahadirli-Talbott, Tsui Lien Mao, Haruhiko Sugimura, Ie Ming Shih, Tian-Li Wang

Research output: Contribution to journalArticle

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.Modern Pathology advance online publication, 21 October 2016; doi:10.1038/modpathol.2016.160.

Original languageEnglish (US)
JournalModern Pathology
DOIs
StateAccepted/In press - Oct 21 2016

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Cyclins
Endometriosis
Carcinoma
Mutation
Ovarian Neoplasms
Survival
Neoplasms
Endometrioid Carcinoma
Gene Dosage
Fluorescence In Situ Hybridization
Publications
Up-Regulation
Multivariate Analysis
Color
Immunohistochemistry
Pathology
Drug Therapy

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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CCNE1 copy-number gain and overexpression identify ovarian clear cell carcinoma with a poor prognosis. / Ayhan, Ayse; Kuhn, Elisabetta; Wu, Ren Chin; Ogawa, Hiroshi; Bahadirli-Talbott, Asli; Mao, Tsui Lien; Sugimura, Haruhiko; Shih, Ie Ming; Wang, Tian-Li.

In: Modern Pathology, 21.10.2016.

Research output: Contribution to journalArticle

Ayhan, Ayse ; Kuhn, Elisabetta ; Wu, Ren Chin ; Ogawa, Hiroshi ; Bahadirli-Talbott, Asli ; Mao, Tsui Lien ; Sugimura, Haruhiko ; Shih, Ie Ming ; Wang, Tian-Li. / CCNE1 copy-number gain and overexpression identify ovarian clear cell carcinoma with a poor prognosis. In: Modern Pathology. 2016.
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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.Modern Pathology advance online publication, 21 October 2016; doi:10.1038/modpathol.2016.160.",
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AU - Ayhan, Ayse

AU - Kuhn, Elisabetta

AU - Wu, Ren Chin

AU - Ogawa, Hiroshi

AU - Bahadirli-Talbott, Asli

AU - Mao, Tsui Lien

AU - Sugimura, Haruhiko

AU - Shih, Ie Ming

AU - Wang, Tian-Li

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N2 - 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.Modern Pathology advance online publication, 21 October 2016; doi:10.1038/modpathol.2016.160.

AB - 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.Modern Pathology advance online publication, 21 October 2016; doi:10.1038/modpathol.2016.160.

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