TY - JOUR

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

T2 - An Ovarian Tumor Tissue Analysis consortium study

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 - Høgdall, Estrid

AU - Høgdall, Claus K.

AU - AOCS Group

N1 - Funding Information: S. Ramus is supported by National Health and Medical Research Council of Australia (NHMRC) grant APP2009840. N.S. Meagher is supported by the NSW Ministry of Health and UNSW Sydney under the NSW Health PhD Scholarship Program, and the Translational Cancer Research Network, a translational cancer research center program funded by the Cancer Institute NSW. J. Millstein is funded by NCI grant P30CA014089. S. Heublein was funded by Heuer Stiftung für medizinische Forschung. M.S. Anglesio is funded through a Michael Smith Foundation for Health Research Scholar Award and the Janet D. Cottrelle Foundation Scholars program managed by the BC Cancer Foundation. BC's Gynecological Cancer Research team (OVCARE) receives support through the BC Cancer Foundation and The VGH+UBC Hospital Foundation. L. Loverix is predoctoral researcher of the Fund for Scientific Research‐Flanders (FWO Vlaanderen 1S41921). T. Van Gorp is a Senior Clinical Investigator of the Fund for Scientific Research‐Flanders (FWO Vlaanderen 18B2921N). The funding for K.M. Darcy and preparation of tumor samples and clinical samples are from awards HU0001‐16‐2‐0006 and HU0001‐21‐2‐0027 from the Uniformed Services University of the Health Sciences from the Defense Health Program to the Henry M Jackson Foundation (HJF) for the Advancement of Military Medicine Inc. Gynecologic Cancer Center of Excellence Program (PI: Yovanni Casablanca, Co‐PI: G. Larry Maxwell). D. Khabele is supported by NIH NCI grants R01CA243511 and R21CA210210. A. Staebler received funding by Deutsche Forschungsgemeinschaft as part of the CRC 685. R.E. was supported by the Interdisciplinary Center for Clinical Research (IZKF; Clinician Scientist Program) of the Medical Faculty FAU Erlangen‐Nürnberg. U. Menon and A. Gentry‐Maharaj are supported by salary contributions through MRC core funding (MC_UU_00004/01). Funding Information: The study was funded by Alberta Precision Laboratory research support fund (RS17‐601, RS10‐526). This work was funded by the National Institutes of Health/National Cancer Institute (NCI) grants to S.J. Ramus (grant number R01CA172404). The Australian Ovarian Cancer Study (AOCS) was supported by the U.S. Army Medical Research and Materiel Command under DAMD17‐01‐1‐0729, The Cancer Council Victoria, Queensland Cancer Fund, The Cancer Council New South Wales, The Cancer Council South Australia, The Cancer Foundation of Western Australia, The Cancer Council Tasmania and the National Health and Medical Research Council of Australia (NHMRC; ID199600; ID400413 and ID400281). The AOCS gratefully acknowledges additional support from the Peter MacCallum Foundation and Ovarian Cancer Australia. BGS: Breast Cancer Now and the Institute of Cancer Research (ICR). ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. BRZ: Brazilian National Council for Scientific and Technological Development, grant No. 478416/2009‐1; CAL: Cancer Research Society (19319) and CLS Internal Research support RS14‐508; CNI: CNI funded by Instituto de Salud Carlos Tercero (AES grant PI19/01730) and Fondo Europeo de Desarrollo Regional, FEDER. Instituto de Salud Carlos III (PI 12/01319); Ministerio de Economía y Competitividad (SAF2012); HOP: Department of Defense (DAMD17‐02‐1‐0669) and NCI (K07‐CA080668, R01‐CA95023, MO1‐RR000056). This project used the UPMC Hillman Cancer Center and Tissue and Research Pathology/Pitt Biospecimen Core shared resource which is supported in part by award P30CA047904. LAX: American Cancer Society Early Detection Professorship (SIOP‐06‐258‐01‐COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124; MAY: National Institutes of Health (R01‐CA122443, R01‐CA243483, P30‐CA15083, P50‐CA136393); Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; NCT: Parts of the study at the NCT were funded by “Heuer Stiftung für medizinische Forschung”; POC: Pomeranian Medical University; SEA: Cancer Research UK C490/A16561, the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Cambridge Cancer Centre. The University of Cambridge has received salary support for Paul D.P. Pharoah from the NHS in the East of England through the Clinical Academic Reserve. TVA: This work was supported by Canadian Institutes of Health Research grant (MOP‐86727) and by NIH/NCI 1 R01CA160669‐01A1; UKO: The UKOPS study was funded by The Eve Appeal (The Oak Foundation) with contribution to author’s salary through MRC core funding (MC_UU_00004/01) and the National Institute for Health Research University College London Hospitals Biomedical Research Centre; VAN: BC's Gynecological Cancer Research Team (OVCARE) receives core funding from The BC Cancer Foundation and the VGH and UBC Hospital Foundation; WMH: National Health and Medical Research Council of Australia, Enabling Grants ID 310670 and ID 628903. Cancer Institute NSW Grants 12/RIG/1‐17 and 15/RIG/1‐16. The Westmead GynBiobank acknowledges financial support from the Sydney West Translational Cancer Research Centre, funded by the Cancer Institute NSW; COE: The GYN‐COE program, T.P. Conrads, Y. Cassablanca, G.L. Maxwell, and K.M. Darcy are funded by the U.S. Defense Health Program (grants HU0001‐16‐2‐0006 and HU0001‐19‐2‐0031); The Health Science Alliance (HAS) Biobank, UNSW Sydney, Australia, is funded by the Translational Cancer Research Network (TCRN), a Translational Cancer Research Centre supported by the Cancer Institute NSW. The SWE cohort is funded by the Swedish Cancer Foundation (CAN 2018/384). Publisher Copyright: © 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.

PY - 2023

Y1 - 2023

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

U2 - 10.1002/cncr.34582

DO - 10.1002/cncr.34582

M3 - Journal article

C2 - 36572991

AN - SCOPUS:85147569563

VL - 129

SP - 697

EP - 713

JO - Cancer

JF - Cancer

SN - 0008-543X

IS - 5

ER -