CCNE1 and survival of patients with tubo‐ovarian high‐grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study
Authors: Kang Eun‐Young , Weir Ashley , Meagher Nicola S. , Farrington Kyo , Nelson Gregg S. , Ghatage Prafull , Lee Cheng‐Han , Riggan Marjorie J. , Bolithon Adelyn , Popovic Gordana , Leung Betty , Tang Katrina , Lambie Neil , Millstein Joshua , Alsop Jennifer , Anglesio Michael S. , Ataseven Beyhan , Barlow Ellen , Beckmann Matthias W. , Berger Jessica , Bisinotto Christiani , Bösmüller Hans , Boros Jessica , Brand Alison H. , Brooks‐Wilson Angela , Brucker Sara Y. , Carney Michael E. , Casablanca Yovanni , Cazorla‐Jiménez Alicia , Cohen Paul A. , Conrads Thomas P. , Cook Linda S. , Coulson Penny , Courtney‐Brooks Madeleine , Cramer Daniel W. , Crowe Philip , Cunningham Julie M. , Cybulski Cezary , Darcy Kathleen M. , El‐Bahrawy Mona A. , Elishaev Esther , Erber Ramona , Farrell Rhonda , Fereday Sian , Fischer Anna , García María J. , Gayther Simon A. , Gentry‐Maharaj Aleksandra , Gilks C. Blake ,   AOCS Group, Grube Marcel , Harnett Paul R. , Harrington Shariska Petersen , Harter Philipp , Hartmann Arndt , Hecht Jonathan L. , Heikaus Sebastian , Hein Alexander , Heitz Florian , Hendley Joy , Hernandez Brenda Y. , Polo Susanna Hernando , Heublein Sabine , Hirasawa Akira , Høgdall Estrid , Høgdall Claus K. , Horlings Hugo M. , Huntsman David G. , Huzarski Tomasz , Jewell Andrea , Jimenez‐Linan Mercedes , Jones Michael E. , Kaufmann Scott H. , Kennedy Catherine J. , Khabele Dineo , Kommoss Felix K. F. , Kruitwagen Roy F. P. M. , Lambrechts Diether , Le Nhu D. , Lener Marcin , Lester Jenny , Leung Yee , Linder Anna , Loverix Liselore , Lubiński Jan , Madan Rashna , Maxwell G. Larry , Modugno Francesmary , Neuhausen Susan L. , Olawaiye Alexander , Olbrecht Siel , Orsulic Sandra , Palacios José , Pearce Celeste Leigh , Pike Malcolm C. , Quinn Carmel M. , Mohan Ganendra Raj , Rodríguez‐Antona Cristina , Ruebner Matthias , Ryan Andy , Salfinger Stuart G. , Sasamoto Naoko , Schildkraut Joellen M. , Schoemaker Minouk J. , Shah Mitul , Sharma Raghwa , Shvetsov Yurii B. , Singh Naveena , Sonke Gabe S. , Steele Linda , Stewart Colin J. R. , Sundfeldt Karin , Swerdlow Anthony J. , Talhouk Aline , Tan Adeline , Taylor Sarah E. , Terry Kathryn L. , Tołoczko Aleksandra , Traficante Nadia , Van de Vijver Koen K. , van der Aa Maaike A. , Van Gorp Toon , Van Nieuwenhuysen Els , van‐Wagensveld Lilian , Vergote Ignace , Vierkant Robert A. , Wang Chen , Wilkens Lynne R. , Winham Stacey J. , Wu Anna H. , Benitez Javier , Berchuck Andrew , Candido dos Reis Francisco J. , DeFazio Anna , Fasching Peter A. , Goode Ellen L. , Goodman Marc T. , Gronwald Jacek , Karlan Beth Y. , Kommoss Stefan , Menon Usha , Sinn Hans‐Peter , Staebler Annette , Brenton James D. , Bowtell David D. , Pharoah Paul D. P. , Ramus Susan J. , Köbel Martin 
Published: December 2022

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.