CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study

AOCS Group

doi:10.1002/cncr.34582

CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study

AOCS Group

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

Background: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. Methods: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. Results: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p =.034, and HR, 1.18; 95% CI, 1.05-1.32, p =.015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p =.033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p =.58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. Conclusion: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

Original language	English
Pages (from-to)	697-713
Number of pages	17
Journal	Cancer
Volume	129
Issue number	5
DOIs	https://doi.org/10.1002/cncr.34582
State	Published - Mar 1 2023

Keywords

CCNE1 amplification
cyclin E1 expression
high-grade serous carcinoma
ovarian cancer
prognosis

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10.1002/cncr.34582

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@article{f77ca37c3c9144928ef40636d168b7dd,

title = "CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study",

abstract = "Background: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. Methods: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. Results: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p =.034, and HR, 1.18; 95% CI, 1.05-1.32, p =.015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p =.033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p =.58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. Conclusion: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.",

keywords = "CCNE1 amplification, cyclin E1 expression, high-grade serous carcinoma, ovarian cancer, prognosis",

author = "{AOCS Group} and Kang, {Eun Young} and Ashley Weir and Meagher, {Nicola S.} and Kyo Farrington and Nelson, {Gregg S.} and Prafull Ghatage and Lee, {Cheng Han} and Riggan, {Marjorie J.} and Adelyn Bolithon and Gordana Popovic and Betty Leung and Katrina Tang and Neil Lambie and Joshua Millstein and Jennifer Alsop and Anglesio, {Michael S.} and Beyhan Ataseven and Ellen Barlow and Beckmann, {Matthias W.} and Jessica Berger and Christiani Bisinotto and Hans B{\"o}sm{\"u}ller and Jessica Boros and Brand, {Alison H.} and Angela Brooks-Wilson and Brucker, {Sara Y.} and Carney, {Michael E.} and Yovanni Casablanca and Alicia Cazorla-Jim{\'e}nez and Cohen, {Paul A.} and Conrads, {Thomas P.} and Cook, {Linda S.} and Penny Coulson and Madeleine Courtney-Brooks and Cramer, {Daniel W.} and Philip Crowe and Cunningham, {Julie M.} and Cezary Cybulski and Darcy, {Kathleen M.} and El-Bahrawy, {Mona A.} and Esther Elishaev and Ramona Erber and Rhonda Farrell and Sian Fereday and Anna Fischer and Garc{\'i}a, {Mar{\'i}a J.} and Gayther, {Simon A.} and Aleksandra Gentry-Maharaj and Gilks, {C. Blake} and Marcel Grube and Harnett, {Paul R.} and Harrington, {Shariska Petersen} and Philipp Harter and Arndt Hartmann and Hecht, {Jonathan L.} and Sebastian Heikaus and Alexander Hein and Florian Heitz and Joy Hendley and Hernandez, {Brenda Y.} and Polo, {Susanna Hernando} and Sabine Heublein and Akira Hirasawa and Estrid H{\o}gdall and H{\o}gdall, {Claus K.} and Horlings, {Hugo M.} and Huntsman, {David G.} and Tomasz Huzarski and Andrea Jewell and Mercedes Jimenez-Linan and Jones, {Michael E.} and Kaufmann, {Scott H.} and Kennedy, {Catherine J.} and Dineo Khabele and Kommoss, {Felix K.F.} and Kruitwagen, {Roy F.P.M.} and Diether Lambrechts and Le, {Nhu D.} and Marcin Lener and Jenny Lester and Yee Leung and Anna Linder and Liselore Loverix and Jan Lubi{\'n}ski and Rashna Madan and Maxwell, {G. Larry} and Francesmary Modugno and Neuhausen, {Susan L.} and Alexander Olawaiye and Siel Olbrecht and Sandra Orsulic and Jos{\'e} Palacios and Pearce, {Celeste Leigh} and Pike, {Malcolm C.} and Quinn, {Carmel M.} and Mohan, {Ganendra Raj} and Cristina Rodr{\'i}guez-Antona and Matthias Ruebner and Andy Ryan and Salfinger, {Stuart G.} and Naoko Sasamoto and Schildkraut, {Joellen M.} and Schoemaker, {Minouk J.} and Mitul Shah and Raghwa Sharma and Shvetsov, {Yurii B.} and Naveena Singh and Sonke, {Gabe S.} and Linda Steele and Stewart, {Colin J.R.} and Karin Sundfeldt and Swerdlow, {Anthony J.} and Aline Talhouk and Adeline Tan and Taylor, {Sarah E.} and Terry, {Kathryn L.} and Aleksandra To{\l}oczko and Nadia Traficante and {Van de Vijver}, {Koen K.} and {van der Aa}, {Maaike A.} and {Van Gorp}, Toon and {Van Nieuwenhuysen}, Els and Lilian van-Wagensveld and Ignace Vergote and Vierkant, {Robert A.} and Chen Wang and Wilkens, {Lynne R.} and Winham, {Stacey J.} and Wu, {Anna H.} and Javier Benitez and Andrew Berchuck and {Candido dos Reis}, {Francisco J.} and Anna DeFazio and Fasching, {Peter A.} and Goode, {Ellen L.} and Goodman, {Marc T.} and Jacek Gronwald and Karlan, {Beth Y.} and Stefan Kommoss and Usha Menon and Sinn, {Hans Peter} and Annette Staebler and Brenton, {James D.} and Bowtell, {David D.} and Pharoah, {Paul D.P.} and Ramus, {Susan J.} and Martin K{\"o}bel",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.",

year = "2023",

month = mar,

day = "1",

doi = "10.1002/cncr.34582",

language = "English",

volume = "129",

pages = "697--713",

journal = "Cancer",

issn = "0008-543X",

number = "5",

}

TY - JOUR

T1 - CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma

T2 - An Ovarian Tumor Tissue Analysis consortium study

AU - AOCS Group

AU - Kang, Eun Young

AU - Weir, Ashley

AU - Meagher, Nicola S.

AU - Farrington, Kyo

AU - Nelson, Gregg S.

AU - Ghatage, Prafull

AU - Lee, Cheng Han

AU - Riggan, Marjorie J.

AU - Bolithon, Adelyn

AU - Popovic, Gordana

AU - Leung, Betty

AU - Tang, Katrina

AU - Lambie, Neil

AU - Millstein, Joshua

AU - Alsop, Jennifer

AU - Anglesio, Michael S.

AU - Ataseven, Beyhan

AU - Barlow, Ellen

AU - Beckmann, Matthias W.

AU - Berger, Jessica

AU - Bisinotto, Christiani

AU - Bösmüller, Hans

AU - Boros, Jessica

AU - Brand, Alison H.

AU - Brooks-Wilson, Angela

AU - Brucker, Sara Y.

AU - Carney, Michael E.

AU - Casablanca, Yovanni

AU - Cazorla-Jiménez, Alicia

AU - Cohen, Paul A.

AU - Conrads, Thomas P.

AU - Cook, Linda S.

AU - Coulson, Penny

AU - Courtney-Brooks, Madeleine

AU - Cramer, Daniel W.

AU - Crowe, Philip

AU - Cunningham, Julie M.

AU - Cybulski, Cezary

AU - Darcy, Kathleen M.

AU - El-Bahrawy, Mona A.

AU - Elishaev, Esther

AU - Erber, Ramona

AU - Farrell, Rhonda

AU - Fereday, Sian

AU - Fischer, Anna

AU - García, María J.

AU - Gayther, Simon A.

AU - Gentry-Maharaj, Aleksandra

AU - Gilks, C. Blake

AU - Grube, Marcel

AU - Harnett, Paul R.

AU - Harrington, Shariska Petersen

AU - Harter, Philipp

AU - Hartmann, Arndt

AU - Hecht, Jonathan L.

AU - Heikaus, Sebastian

AU - Hein, Alexander

AU - Heitz, Florian

AU - Hendley, Joy

AU - Hernandez, Brenda Y.

AU - Polo, Susanna Hernando

AU - Heublein, Sabine

AU - Hirasawa, Akira

AU - Høgdall, Estrid

AU - Høgdall, Claus K.

AU - Horlings, Hugo M.

AU - Huntsman, David G.

AU - Huzarski, Tomasz

AU - Jewell, Andrea

AU - Jimenez-Linan, Mercedes

AU - Jones, Michael E.

AU - Kaufmann, Scott H.

AU - Kennedy, Catherine J.

AU - Khabele, Dineo

AU - Kommoss, Felix K.F.

AU - Kruitwagen, Roy F.P.M.

AU - Lambrechts, Diether

AU - Le, Nhu D.

AU - Lener, Marcin

AU - Lester, Jenny

AU - Leung, Yee

AU - Linder, Anna

AU - Loverix, Liselore

AU - Lubiński, Jan

AU - Madan, Rashna

AU - Maxwell, G. Larry

AU - Modugno, Francesmary

AU - Neuhausen, Susan L.

AU - Olawaiye, Alexander

AU - Olbrecht, Siel

AU - Orsulic, Sandra

AU - Palacios, José

AU - Pearce, Celeste Leigh

AU - Pike, Malcolm C.

AU - Quinn, Carmel M.

AU - Mohan, Ganendra Raj

AU - Rodríguez-Antona, Cristina

AU - Ruebner, Matthias

AU - Ryan, Andy

AU - Salfinger, Stuart G.

AU - Sasamoto, Naoko

AU - Schildkraut, Joellen M.

AU - Schoemaker, Minouk J.

AU - Shah, Mitul

AU - Sharma, Raghwa

AU - Shvetsov, Yurii B.

AU - Singh, Naveena

AU - Sonke, Gabe S.

AU - Steele, Linda

AU - Stewart, Colin J.R.

AU - Sundfeldt, Karin

AU - Swerdlow, Anthony J.

AU - Talhouk, Aline

AU - Tan, Adeline

AU - Taylor, Sarah E.

AU - Terry, Kathryn L.

AU - Tołoczko, Aleksandra

AU - Traficante, Nadia

AU - Van de Vijver, Koen K.

AU - van der Aa, Maaike A.

AU - Van Gorp, Toon

AU - Van Nieuwenhuysen, Els

AU - van-Wagensveld, Lilian

AU - Vergote, Ignace

AU - Vierkant, Robert A.

AU - Wang, Chen

AU - Wilkens, Lynne R.

AU - Winham, Stacey J.

AU - Wu, Anna H.

AU - Benitez, Javier

AU - Berchuck, Andrew

AU - Candido dos Reis, Francisco J.

AU - DeFazio, Anna

AU - Fasching, Peter A.

AU - Goode, Ellen L.

AU - Goodman, Marc T.

AU - Gronwald, Jacek

AU - Karlan, Beth Y.

AU - Kommoss, Stefan

AU - Menon, Usha

AU - Sinn, Hans Peter

AU - Staebler, Annette

AU - Brenton, James D.

AU - Bowtell, David D.

AU - Pharoah, Paul D.P.

AU - Ramus, Susan J.

AU - Köbel, Martin

PY - 2023/3/1

Y1 - 2023/3/1

N2 - Background: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. Methods: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. Results: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p =.034, and HR, 1.18; 95% CI, 1.05-1.32, p =.015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p =.033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p =.58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. Conclusion: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

AB - Background: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. Methods: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. Results: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p =.034, and HR, 1.18; 95% CI, 1.05-1.32, p =.015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p =.033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p =.58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. Conclusion: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

KW - CCNE1 amplification

KW - cyclin E1 expression

KW - high-grade serous carcinoma

KW - ovarian cancer

KW - prognosis

UR - http://www.scopus.com/inward/record.url?scp=85147569563&partnerID=8YFLogxK

U2 - 10.1002/cncr.34582

DO - 10.1002/cncr.34582

M3 - Article

C2 - 36572991

AN - SCOPUS:85147569563

SN - 0008-543X

VL - 129

SP - 697

EP - 713

JO - Cancer

JF - Cancer

IS - 5

ER -

CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study

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Keywords

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