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