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

Kang EY, Weir A, Meagher NS, Farrington K, Nelson GS, Ghatage P, Lee CH, Riggan MJ, Bolithon A, Popovic G, Leung B, Tang K, Lambie N, Millstein J, Alsop J, Anglesio MS, Ataseven B, Barlow E, Beckmann M, Berger J, Bisinotto C, Bösmüller H, Boros J, Brand AH, Brooks-Wilson A, Brucker SY, Carney ME, Casablanca Y, Cazorla-Jiménez A, Cohen PA, Conrads TP, Cook LS, Coulson P, Courtney-Brooks M, Cramer DW, Crowe P, Cunningham JM, Cybulski C, Darcy KM, El-Bahrawy MA, Elishaev E, Erber R, Farrell R, Fereday S, Fischer A, García MJ, Gayther SA, Gentry-Maharaj A, Gilks CB, Grube M, Harnett PR, Harrington SP, Harter P, Hartmann A, Hecht JL, Heikaus S, Hein A, Heitz F, Hendley J, Hernandez BY, Polo SH, Heublein S, Hirasawa A, Høgdall E, Høgdall CK, Horlings HM, Huntsman DG, Huzarski T, Jewell A, Jimenez-Linan M, Jones ME, Kaufmann SH, Kennedy CJ, Khabele D, Kommoss FK, Kruitwagen RF, Lambrechts D, Le ND, Lener M, Lester J, Leung Y, Linder A, Loverix L, Lubiński J, Madan R, Maxwell GL, Modugno F, Neuhausen SL, Olawaiye A, Olbrecht S, Orsulic S, Palacios J, Pearce CL, Pike MC, Quinn CM, Mohan GR, Rodríguez-Antona C, Rübner M, Ryan A, Salfinger SG, Sasamoto N, Schildkraut JM, Schoemaker MJ, Shah M, Sharma R, Shvetsov YB, Singh N, Sonke GS, Steele L, Stewart CJ, Sundfeldt K, Swerdlow AJ, Talhouk A, Tan A, Taylor SE, Terry KL, Tołoczko A, Traficante N, Van de Vijver KK, van der Aa MA, Van Gorp T, Van Nieuwenhuysen E, van-Wagensveld L, Vergote I, Vierkant RA, Wang C, Wilkens LR, Winham SJ, Wu AH, Benitez J, Berchuck A, Candido dos Reis FJ, DeFazio A, Fasching P, Goode EL, Goodman MT, Gronwald J, Karlan BY, Kommoss S, Menon U, Sinn HP, Staebler A, Brenton JD, Bowtell DD, Pharoah PD, Ramus SJ, Köbel M (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Book Volume: 129

Pages Range: 697-713

Journal Issue: 5

DOI: 10.1002/cncr.34582

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.

Authors with CRIS profile

Involved external institutions

Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) Poland (PL) University of Kansas Medical Center United States (USA) (US) Addenbrooke's Hospital United Kingdom (GB) University of São Paulo / Universidade de São Paulo (USP) Brazil (BR) University of Sydney (USYD) Australia (AU) Mayo Clinic United States (USA) (US) Okayama University / 岡山大学 Japan (JP) University of Copenhagen Denmark (DK) University of Hawaii (U.H.) United States (USA) (US) Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI / NKI-AVL) Netherlands (NL) University of British Columbia Canada (CA) Keck School of Medicine of USC United States (USA) (US) Ciber de Enfermedades Raras (CIBERER) Spain (ES) Duke University United States (USA) (US) The Institute of Cancer Research (ICR) United Kingdom (GB) Mayo Clinic College of Medicine and Science (MCCMS) United States (USA) (US) Universitätsklinikum Heidelberg Germany (DE) Cedars-Sinai Medical Center United States (USA) (US) University of California Los Angeles (UCLA) United States (USA) (US) Maastricht University Netherlands (NL) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven Belgium (BE) British Columbia Cancer Agency Canada (CA) Universitätsklinikum Tübingen Germany (DE) University College London (UCL) United Kingdom (GB) University of Cambridge United Kingdom (GB) Peter MacCallum Cancer Centre Australia (AU) University of New South Wales (UNSW) Australia (AU) University of Calgary Canada (CA) Universidad de Alcalá (UAH) Spain (ES) University of Michigan United States (USA) (US) Westmead Hospital Australia (AU) Memorial Sloan Kettering Cancer Center United States (USA) (US) St John of God Health Care Australia (AU) Uniformed Services University United States (USA) (US) Fundación Jiménez Díaz Spain (ES) Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) Spain (ES) Inova Health System United States (USA) (US) University of Colorado Anschutz Medical Campus United States (USA) (US) Brigham and Women's Hospital (BWH) United States (USA) (US) Emory University United States (USA) (US) University of Pittsburgh United States (USA) (US) Walter Reed National Military Medical Center United States (USA) (US) Washington University in St. Louis United States (USA) (US) Barts Health NHS Trust United Kingdom (GB) City of Hope Medical Center United States (USA) (US) Hammersmith Hospital United Kingdom (GB) Prince of Wales Hospital (POWH) Australia (AU) University of Gothenburg / Göteborgs universitet Sweden (SE) University of Alberta Canada (CA) Kliniken Essen-Mitte Germany (DE) Harvard University United States (USA) (US) University Hospital Ghent Belgium (BE) Netherlands Comprehensive Cancer Organisation / Integraal Kankercentrum Nederland (IKNL) Netherlands (NL) Canterbury Health Laboratories New Zealand (NZ) Royal Hospital for Women Australia (AU) Hospital Universitario Fundación Alcorcón (HUFA) Spain (ES)

How to cite

APA:

Kang, E.Y., Weir, A., Meagher, N.S., Farrington, K., Nelson, G.S., Ghatage, P.,... Köbel, M. (2023). CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study. Cancer, 129(5), 697-713. https://doi.org/10.1002/cncr.34582

MLA:

Kang, Eun Young, et al. "CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study." Cancer 129.5 (2023): 697-713.

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