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 BergerChristiani 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, Estrid Høgdall, Claus K Høgdall, AOCS group, Martin Köbel*

*Corresponding author for this work

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 languageEnglish
JournalCancer
Volume129
Issue number5
Pages (from-to)697-713
Number of pages17
ISSN0008-543X
DOIs
Publication statusPublished - 1 Mar 2023

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