. 2023 Mar 1;129(5):697-713.

doi: 10.1002/cncr.34582. Epub 2022 Dec 26.

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

Eun-Young Kang¹, Ashley Weir^{2

3

4}, Nicola S Meagher^{2

5}, Kyo Farrington¹, Gregg S Nelson⁶, Prafull Ghatage⁶, Cheng-Han Lee⁷, Marjorie J Riggan⁸, Adelyn Bolithon^{3

9}, Gordana Popovic¹⁰, Betty Leung¹¹, Katrina Tang¹², Neil Lambie¹³, Joshua Millstein¹⁴, Jennifer Alsop¹⁵, Michael S Anglesio^{16

17}, Beyhan Ataseven^{18

19}, Ellen Barlow²⁰, Matthias W Beckmann²¹, Jessica Berger²², Christiani Bisinotto²³, Hans Bösmüller²⁴, Jessica Boros^{25

26

27}, Alison H Brand^{26

27}, Angela Brooks-Wilson²⁸, Sara Y Brucker²⁹, Michael E Carney³⁰, Yovanni Casablanca³¹, Alicia Cazorla-Jiménez³², Paul A Cohen^{33

34}, Thomas P Conrads³⁵, Linda S Cook^{36

37}, Penny Coulson³⁸, Madeleine Courtney-Brooks²², Daniel W Cramer^{39

40}, Philip Crowe^{11

41}, Julie M Cunningham⁴², Cezary Cybulski⁴³, Kathleen M Darcy^{44

45}, Mona A El-Bahrawy⁴⁶, Esther Elishaev⁴⁷, Ramona Erber⁴⁸, Rhonda Farrell⁴⁹, Sian Fereday^{50

51}, Anna Fischer²⁴, María J García⁵², Simon A Gayther⁵³, Aleksandra Gentry-Maharaj⁵⁴, C Blake Gilks⁵⁵; AOCS Group^{25

50

56}; Marcel Grube²⁹, Paul R Harnett^{27

57}, Shariska Petersen Harrington⁵⁸, Philipp Harter^{18

59}, Arndt Hartmann⁴⁸, Jonathan L Hecht⁶⁰, Sebastian Heikaus⁶¹, Alexander Hein²¹, Florian Heitz^{18

59

61}, Joy Hendley⁵⁰, Brenda Y Hernandez⁶², Susanna Hernando Polo⁶³, Sabine Heublein⁶⁴, Akira Hirasawa⁶⁵, Estrid Høgdall⁶⁶, Claus K Høgdall⁶⁷, Hugo M Horlings⁶⁸, David G Huntsman^{16

69}, Tomasz Huzarski^{43

70}, Andrea Jewell⁵⁸, Mercedes Jimenez-Linan⁷¹, Michael E Jones³⁸, Scott H Kaufmann⁷², Catherine J Kennedy^{25

26

27}, Dineo Khabele⁷³, Felix K F Kommoss⁷⁴, Roy F P M Kruitwagen^{75

76}, Diether Lambrechts^{77

78}, Nhu D Le⁷⁹, Marcin Lener⁸⁰, Jenny Lester⁸¹, Yee Leung^{82

83

84}, Anna Linder⁸⁵, Liselore Loverix⁸⁶, Jan Lubiński⁴³, Rashna Madan⁸⁷, G Larry Maxwell⁸⁸, Francesmary Modugno^{22

89

90}, Susan L Neuhausen⁹¹, Alexander Olawaiye²², Siel Olbrecht⁸⁶, Sandra Orsulic⁸¹, José Palacios⁹², Celeste Leigh Pearce⁹³, Malcolm C Pike^{94

95}, Carmel M Quinn⁹⁶, Ganendra Raj Mohan^{33

83}, Cristina Rodríguez-Antona^{97

98}, Matthias Ruebner²¹, Andy Ryan^{54

99}, Stuart G Salfinger³³, Naoko Sasamoto³⁹, Joellen M Schildkraut¹⁰⁰, Minouk J Schoemaker³⁸, Mitul Shah¹⁵, Raghwa Sharma¹⁰¹, Yurii B Shvetsov⁶², Naveena Singh¹⁰², Gabe S Sonke¹⁰³, Linda Steele⁹¹, Colin J R Stewart¹⁰⁴, Karin Sundfeldt⁸⁵, Anthony J Swerdlow^{38

105}, Aline Talhouk^{16

17}, Adeline Tan^{82

106}, Sarah E Taylor²², Kathryn L Terry^{39

40}, Aleksandra Tołoczko¹⁰⁷, Nadia Traficante^{50

51}, Koen K Van de Vijver^{108

109}, Maaike A van der Aa¹¹⁰, Toon Van Gorp⁸⁶, Els Van Nieuwenhuysen⁸⁶, Lilian van-Wagensveld^{75

76

110}, Ignace Vergote⁸⁶, Robert A Vierkant¹¹¹, Chen Wang¹¹², Lynne R Wilkens⁶², Stacey J Winham¹¹², Anna H Wu⁹⁵, Javier Benitez^{98

113}, Andrew Berchuck⁸, Francisco J Candido Dos Reis²³, Anna DeFazio^{5

25

26

27}, Peter A Fasching²¹, Ellen L Goode¹¹⁴, Marc T Goodman¹¹⁵, Jacek Gronwald⁴³, Beth Y Karlan⁸¹, Stefan Kommoss²⁹, Usha Menon⁵⁴, Hans-Peter Sinn⁷⁴, Annette Staebler²⁴, James D Brenton¹¹⁶, David D Bowtell^{50

51}, Paul D P Pharoah^{15

117}, Susan J Ramus^{2

3}, Martin Köbel¹

Affiliations

¹ Department of Pathology and Laboratory Medicine, University of Calgary, Foothills Medical Center, Calgary, Alberta, Canada.
² School of Clinical Medicine, UNSW Medicine and Health, University of NSW Sydney, Sydney, New South Wales, Australia.
³ Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, New South Wales, Australia.
⁴ The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
⁵ The Daffodil Centre, The University of Sydney, A Joint Venture With Cancer Council NSW, Sydney, New South Wales, Australia.
⁶ Department of Oncology, Division of Gynecologic Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
⁷ Department of Pathology and Laboratory Medicine, University of Alberta, Edmonton, Alberta, Canada.
⁸ Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University Medical Center, Durham, North Carolina, USA.
⁹ School of Women's and Children's Health, Faculty of Medicine and Health, University of NSW Sydney, Sydney, New South Wales, Australia.
¹⁰ Stats Central, Mark Wainwright Analytical Centre, University of NSW Sydney, Sydney, New South Wales, Australia.
¹¹ Prince of Wales Clinical School, UNSW Medicine and Health, University of NSW Sydney, Sydney, New South Wales, Australia.
¹² Department of Anatomical Pathology, Prince of Wales Hospital, Sydney, New South Wales, Australia.
¹³ Canterbury Health Laboratories, Christchurch, New Zealand.
¹⁴ Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
¹⁵ Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
¹⁶ Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁷ British Columbia's Gynecological Cancer Research Team (OVCARE), University of British Columbia, BC Cancer, and Vancouver General Hospital, Vancouver, British Columbia, Canada.
¹⁸ Department of Gynecology and Gynecologic Oncology, Evangelische Kliniken Essen-Mitte (KEM), Essen, Germany.
¹⁹ Department of Obstetrics and Gynecology, Ludwig Maximilian University Munich, Munich, Germany.
²⁰ Gynaecological Cancer Centre, Royal Hospital for Women, Sydney, New South Wales, Australia.
²¹ Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany.
²² Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
²³ Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
²⁴ Institute of Pathology and Neuropathology, Tuebingen University Hospital, Tuebingen, Germany.
²⁵ Centre for Cancer Research, The Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.
²⁶ Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia.
²⁷ Discipline of Obstetrics and Gynaecology, The University of Sydney, Sydney, New South Wales, Australia.
²⁸ Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, British Columbia, Canada.
²⁹ Department of Women's Health, Tuebingen University Hospital, Tuebingen, Germany.
³⁰ Department of Obstetrics and Gynecology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA.
³¹ Uniformed Services of the Health Sciences Gynecologic Cancer Center of Excellence, Bethesda, Maryland, USA.
³² Pathology Department, Fundación Jiménez Díaz, Madrid, Spain.
³³ Department of Gynaecological Oncology, St John of God Subiaco Hospital, Subiaco, Western Australia, Australia.
³⁴ Division of Obstetrics and Gynaecology, Medical School, University of Western Australia, Crawley, Western Australia, Australia.
³⁵ Women's Health Integrated Research Center, Inova Health System, Falls Church, Virginia, USA.
³⁶ Epidemiology, School of Public Health, University of Colorado, Aurora, Colorado, USA.
³⁷ Community Health Sciences, University of Calgary, Calgary, Alberta, Canada.
³⁸ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
³⁹ Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics and Gynecology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁴⁰ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
⁴¹ Department of Surgery, Prince of Wales Private Hospital, Randwick, New South Wales, Australia.
⁴² Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
⁴³ Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
⁴⁴ Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, Maryland, USA.
⁴⁵ Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, Maryland, USA.
⁴⁶ Department of Metabolism, Digestion and Reproduction, Imperial College London, Hammersmith Hospital, London, UK.
⁴⁷ Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
⁴⁸ Institute of Pathology, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany.
⁴⁹ Prince of Wales Private Hospital, Randwick, New South Wales, Australia.
⁵⁰ Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
⁵¹ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
⁵² Computational Oncology Group, Structural Biology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
⁵³ Center for Bioinformatics and Functional Genomics and the Cedars Sinai Genomics Core, Cedars-Sinai Medical Center, Los Angeles, California, USA.
⁵⁴ MRC Clinical Trials Unit, Institute of Clinical Trials & Methodology, University College London, London, UK.
⁵⁵ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
⁵⁶ QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁵⁷ Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia.
⁵⁸ Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The University of Kansas Medical Center, Kansas City, Kansas, USA.
⁵⁹ Department of Gynecology and Gynecological Oncology, HSK, Dr. Horst-Schmidt Klinik, Wiesbaden, Wiesbaden, Germany.
⁶⁰ Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
⁶¹ Center for Pathology, Evangelische Kliniken Essen-Mitte, Essen, Germany.
⁶² University of Hawaii Cancer Center, Honolulu, Hawaii, USA.
⁶³ Medical Oncology Service, Hospital Universitario Funcación Alcorcón, Alcorcón, Spain.
⁶⁴ Department of Obstetrics and Gynecology, University Hospital Heidelberg, Heidelberg, Germany.
⁶⁵ Department of Clinical Genomic Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
⁶⁶ Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
⁶⁷ Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
⁶⁸ Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
⁶⁹ Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, British Columbia, Canada.
⁷⁰ Department of Genetics and Pathology, University of Zielona Gora, Zielona Gora, Poland.
⁷¹ Department of Histopathology, Addenbrooke's Hospital, Cambridge, UK.
⁷² Division of Oncology Research and Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
⁷³ Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University in St. Louis, St. Louis, Missouri, USA.
⁷⁴ Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
⁷⁵ Department of Obstetrics and Gynecology, Maastricht University Medical Centre, Maastricht, The Netherlands.
⁷⁶ GROW - School for Oncology and Reproduction, Maastricht University Medical Center, Maastricht, The Netherlands.
⁷⁷ Department of Human Genetics, Laboratory for Translational Genetics, KU Leuven, Leuven, Belgium.
⁷⁸ VIB Center for Cancer Biology, VIB, Leuven, Belgium.
⁷⁹ Cancer Control Research, BC Cancer Agency, Vancouver, British Columbia, Canada.
⁸⁰ International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland.
⁸¹ David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, California, USA.
⁸² Division of Obstetrics and Gynaecology, Faculty of Health and Medical Sciences, University of Western Australia, Crawley, Western Australia, Australia.
⁸³ Department of Gynaecological Oncology, King Edward Memorial Hospital, Subiaco, Western Australia, Australia.
⁸⁴ Australia New Zealand Gynaecological Oncology Group, Camperdown, Australia.
⁸⁵ Department of Obstetrics and Gynecology, Inst of Clinical Science, Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden.
⁸⁶ Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, Leuven Cancer Institute, Leuven, Belgium.
⁸⁷ Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, Kansas, USA.
⁸⁸ Inova Health System Women's Service Line, Falls Church, Virginia, USA.
⁸⁹ Department of Epidemiology, University of Pittsburgh School of Public Health, Pittsburgh, Pennsylvania, USA.
⁹⁰ Women's Cancer Research Center, Magee-Womens Research Institute and Hillman Cancer Center, Pittsburgh, Pennsylvania, USA.
⁹¹ Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California, USA.
⁹² Department of Pathology, Hospital Ramón y Cajal, Instituto Ramon y Cajal de Investigación Sanitaria (IRyCIS), CIBERONC, Universidad de Alcalá, Madrid, Spain.
⁹³ Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.
⁹⁴ Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
⁹⁵ Department of Population Health and Public Health Sciences, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, USA.
⁹⁶ The Health Precincts Biobank, UNSW Biospecimen Services, Mark Wainwright Analytical Centre, University of NSW Sydney, Sydney, New South Wales, Australia.
⁹⁷ Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
⁹⁸ Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
⁹⁹ Women's Cancer, Institute for Women's Health, University College London, London, UK.
¹⁰⁰ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.
¹⁰¹ Tissue Pathology and Diagnostic Oncology, Westmead Hospital, Sydney, New South Wales, Australia.
¹⁰² Department of Pathology, Barts Health National Health Service Trust, London, UK.
¹⁰³ Department of Medical Oncology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
¹⁰⁴ School for Women's and Infants' Health, University of Western Australia, Perth, Australia.
¹⁰⁵ Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
¹⁰⁶ Gynaepath WA, Clinipath (Sonic Healthcare), Osbourne Park, Australia.
¹⁰⁷ Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
¹⁰⁸ Department of Pathology, Ghent University Hospital, Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
¹⁰⁹ Department of Pathology, Antwerp University Hospital, Antwerp, Belgium.
¹¹⁰ Department of Research, Netherlands Comprehensive Cancer Organization (IKNL), Utrecht, The Netherlands.
¹¹¹ Department of Quantitative Health Sciences, Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, Minnesota, USA.
¹¹² Department of Quantitative Health Sciences, Division of Computational Biology, Mayo Clinic, Rochester, Minnesota, USA.
¹¹³ Human Genetics Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
¹¹⁴ Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA.
¹¹⁵ Cancer Prevention and Control Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, California, USA.
¹¹⁶ Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
¹¹⁷ Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.

PMID: 36572991
PMCID: PMC10107112
DOI: 10.1002/cncr.34582

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

Eun-Young Kang et al. Cancer. 2023.

. 2023 Mar 1;129(5):697-713.

doi: 10.1002/cncr.34582. Epub 2022 Dec 26.

Authors

Affiliations

¹ Department of Pathology and Laboratory Medicine, University of Calgary, Foothills Medical Center, Calgary, Alberta, Canada.
² School of Clinical Medicine, UNSW Medicine and Health, University of NSW Sydney, Sydney, New South Wales, Australia.
³ Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, New South Wales, Australia.
⁴ The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
⁵ The Daffodil Centre, The University of Sydney, A Joint Venture With Cancer Council NSW, Sydney, New South Wales, Australia.
⁶ Department of Oncology, Division of Gynecologic Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
⁷ Department of Pathology and Laboratory Medicine, University of Alberta, Edmonton, Alberta, Canada.
⁸ Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University Medical Center, Durham, North Carolina, USA.
⁹ School of Women's and Children's Health, Faculty of Medicine and Health, University of NSW Sydney, Sydney, New South Wales, Australia.
¹⁰ Stats Central, Mark Wainwright Analytical Centre, University of NSW Sydney, Sydney, New South Wales, Australia.
¹¹ Prince of Wales Clinical School, UNSW Medicine and Health, University of NSW Sydney, Sydney, New South Wales, Australia.
¹² Department of Anatomical Pathology, Prince of Wales Hospital, Sydney, New South Wales, Australia.
¹³ Canterbury Health Laboratories, Christchurch, New Zealand.
¹⁴ Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
¹⁵ Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
¹⁶ Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁷ British Columbia's Gynecological Cancer Research Team (OVCARE), University of British Columbia, BC Cancer, and Vancouver General Hospital, Vancouver, British Columbia, Canada.
¹⁸ Department of Gynecology and Gynecologic Oncology, Evangelische Kliniken Essen-Mitte (KEM), Essen, Germany.
¹⁹ Department of Obstetrics and Gynecology, Ludwig Maximilian University Munich, Munich, Germany.
²⁰ Gynaecological Cancer Centre, Royal Hospital for Women, Sydney, New South Wales, Australia.
²¹ Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany.
²² Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
²³ Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
²⁴ Institute of Pathology and Neuropathology, Tuebingen University Hospital, Tuebingen, Germany.
²⁵ Centre for Cancer Research, The Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.
²⁶ Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia.
²⁷ Discipline of Obstetrics and Gynaecology, The University of Sydney, Sydney, New South Wales, Australia.
²⁸ Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, British Columbia, Canada.
²⁹ Department of Women's Health, Tuebingen University Hospital, Tuebingen, Germany.
³⁰ Department of Obstetrics and Gynecology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA.
³¹ Uniformed Services of the Health Sciences Gynecologic Cancer Center of Excellence, Bethesda, Maryland, USA.
³² Pathology Department, Fundación Jiménez Díaz, Madrid, Spain.
³³ Department of Gynaecological Oncology, St John of God Subiaco Hospital, Subiaco, Western Australia, Australia.
³⁴ Division of Obstetrics and Gynaecology, Medical School, University of Western Australia, Crawley, Western Australia, Australia.
³⁵ Women's Health Integrated Research Center, Inova Health System, Falls Church, Virginia, USA.
³⁶ Epidemiology, School of Public Health, University of Colorado, Aurora, Colorado, USA.
³⁷ Community Health Sciences, University of Calgary, Calgary, Alberta, Canada.
³⁸ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
³⁹ Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics and Gynecology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁴⁰ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
⁴¹ Department of Surgery, Prince of Wales Private Hospital, Randwick, New South Wales, Australia.
⁴² Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
⁴³ Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
⁴⁴ Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, Maryland, USA.
⁴⁵ Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, Maryland, USA.
⁴⁶ Department of Metabolism, Digestion and Reproduction, Imperial College London, Hammersmith Hospital, London, UK.
⁴⁷ Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
⁴⁸ Institute of Pathology, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany.
⁴⁹ Prince of Wales Private Hospital, Randwick, New South Wales, Australia.
⁵⁰ Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
⁵¹ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
⁵² Computational Oncology Group, Structural Biology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
⁵³ Center for Bioinformatics and Functional Genomics and the Cedars Sinai Genomics Core, Cedars-Sinai Medical Center, Los Angeles, California, USA.
⁵⁴ MRC Clinical Trials Unit, Institute of Clinical Trials & Methodology, University College London, London, UK.
⁵⁵ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
⁵⁶ QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁵⁷ Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia.
⁵⁸ Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The University of Kansas Medical Center, Kansas City, Kansas, USA.
⁵⁹ Department of Gynecology and Gynecological Oncology, HSK, Dr. Horst-Schmidt Klinik, Wiesbaden, Wiesbaden, Germany.
⁶⁰ Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
⁶¹ Center for Pathology, Evangelische Kliniken Essen-Mitte, Essen, Germany.
⁶² University of Hawaii Cancer Center, Honolulu, Hawaii, USA.
⁶³ Medical Oncology Service, Hospital Universitario Funcación Alcorcón, Alcorcón, Spain.
⁶⁴ Department of Obstetrics and Gynecology, University Hospital Heidelberg, Heidelberg, Germany.
⁶⁵ Department of Clinical Genomic Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
⁶⁶ Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
⁶⁷ Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
⁶⁸ Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
⁶⁹ Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, British Columbia, Canada.
⁷⁰ Department of Genetics and Pathology, University of Zielona Gora, Zielona Gora, Poland.
⁷¹ Department of Histopathology, Addenbrooke's Hospital, Cambridge, UK.
⁷² Division of Oncology Research and Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
⁷³ Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University in St. Louis, St. Louis, Missouri, USA.
⁷⁴ Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
⁷⁵ Department of Obstetrics and Gynecology, Maastricht University Medical Centre, Maastricht, The Netherlands.
⁷⁶ GROW - School for Oncology and Reproduction, Maastricht University Medical Center, Maastricht, The Netherlands.
⁷⁷ Department of Human Genetics, Laboratory for Translational Genetics, KU Leuven, Leuven, Belgium.
⁷⁸ VIB Center for Cancer Biology, VIB, Leuven, Belgium.
⁷⁹ Cancer Control Research, BC Cancer Agency, Vancouver, British Columbia, Canada.
⁸⁰ International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland.
⁸¹ David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, California, USA.
⁸² Division of Obstetrics and Gynaecology, Faculty of Health and Medical Sciences, University of Western Australia, Crawley, Western Australia, Australia.
⁸³ Department of Gynaecological Oncology, King Edward Memorial Hospital, Subiaco, Western Australia, Australia.
⁸⁴ Australia New Zealand Gynaecological Oncology Group, Camperdown, Australia.
⁸⁵ Department of Obstetrics and Gynecology, Inst of Clinical Science, Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden.
⁸⁶ Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, Leuven Cancer Institute, Leuven, Belgium.
⁸⁷ Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, Kansas, USA.
⁸⁸ Inova Health System Women's Service Line, Falls Church, Virginia, USA.
⁸⁹ Department of Epidemiology, University of Pittsburgh School of Public Health, Pittsburgh, Pennsylvania, USA.
⁹⁰ Women's Cancer Research Center, Magee-Womens Research Institute and Hillman Cancer Center, Pittsburgh, Pennsylvania, USA.
⁹¹ Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California, USA.
⁹² Department of Pathology, Hospital Ramón y Cajal, Instituto Ramon y Cajal de Investigación Sanitaria (IRyCIS), CIBERONC, Universidad de Alcalá, Madrid, Spain.
⁹³ Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.
⁹⁴ Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
⁹⁵ Department of Population Health and Public Health Sciences, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, USA.
⁹⁶ The Health Precincts Biobank, UNSW Biospecimen Services, Mark Wainwright Analytical Centre, University of NSW Sydney, Sydney, New South Wales, Australia.
⁹⁷ Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
⁹⁸ Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
⁹⁹ Women's Cancer, Institute for Women's Health, University College London, London, UK.
¹⁰⁰ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.
¹⁰¹ Tissue Pathology and Diagnostic Oncology, Westmead Hospital, Sydney, New South Wales, Australia.
¹⁰² Department of Pathology, Barts Health National Health Service Trust, London, UK.
¹⁰³ Department of Medical Oncology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
¹⁰⁴ School for Women's and Infants' Health, University of Western Australia, Perth, Australia.
¹⁰⁵ Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
¹⁰⁶ Gynaepath WA, Clinipath (Sonic Healthcare), Osbourne Park, Australia.
¹⁰⁷ Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
¹⁰⁸ Department of Pathology, Ghent University Hospital, Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
¹⁰⁹ Department of Pathology, Antwerp University Hospital, Antwerp, Belgium.
¹¹⁰ Department of Research, Netherlands Comprehensive Cancer Organization (IKNL), Utrecht, The Netherlands.
¹¹¹ Department of Quantitative Health Sciences, Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, Minnesota, USA.
¹¹² Department of Quantitative Health Sciences, Division of Computational Biology, Mayo Clinic, Rochester, Minnesota, USA.
¹¹³ Human Genetics Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
¹¹⁴ Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA.
¹¹⁵ Cancer Prevention and Control Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, California, USA.
¹¹⁶ Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
¹¹⁷ Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.

PMID: 36572991
PMCID: PMC10107112
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.

Keywords: CCNE1 amplification; cyclin E1 expression; high-grade serous carcinoma; ovarian cancer; prognosis.

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Conflict of interest statement

The authors have no relevant conflicts of interest regarding this publication. A. Hartmann has received honoraria from BMS, MSD, Roche, AstraZeneca, Boehringer Ingelheim, AbbVie, Jansen‐Cilag, and Ipsen.

T.P. Conrads is member of the Thermo Fisher Scientific Inc scientific advisory board. P.A. Cohen is a member of the Clinic IQ Scientific Advisory Board and has received honoraria from Seqirus and Astra Zeneca. D. Bowtell has research funding from AstraZeneca, Beigene, and Genentech Roche, and is an advisor to Exo Therapeutics. U. Menon has received an honorarium from the NY Obstetrical Society and held personal shares between 1 April 2011 and 30 October 2021. T. Van Gorp has received honoraria for advisory boards from Eisai Europe (to institute), OncXerna Therapeutics (to institute), Astra Zeneca (to institute), GSK (to institute), MSD (to institute), research funding from Amgen (to institute), Roche (to institute), and AstraZeneca (to institute) and travel reimbursements from MSD, Immunogen, PharmaMar, and AstraZeneca. P. Harter has received honoraria from Amgen, AstraZeneca, GSK, Roche, Sotio, Stryker, Zai Lab, MSD, Clovis, and Eisai; has served on advisory boards for AstraZeneca, Roche, GSK, Clovis, Immunogen, MSD, and Eisai; and has received research funding (to institute) from AstraZeneca, Roche, GSK, Genmab, DFG, European Union, DKH, Immunogen, and Clovis. P. Ghatage has received honoraria from AstraZeneca, GSK, and Eisai. I. Vergote has received consulting fees from Agenus, Akesobio, AstraZeneca, Bristol‐Myers Squibb, Deciphera Pharmaceuticals, Eisai, Elevar Therapeutics, F. Hoffmann‐La Roche, Genmab, GSK, Immunogen, Jazzpharma, Karyopharm, Mersana, MSD, Novocure, Novartis, Oncoinvent, OncXerna, Sanofi, Seagen, Sotio, Verastem Oncology, and Zentalis, done contracted research with Oncoinvent AS and corporate sponsored research with Amgen and Roche, and received travel expenses/accommodations from Karyopharm and Genmab. D. Bowtell has received honoraria from AstraZeneca, has a consulting role with Exo Therapeutics Research and receives funding from Roche/Genentech, AstraZeneca and BeiGene. A. DeFazio received grant funding from AstraZeneca. A.H. had an advisory role and received honoraria from BMS, MSD, Roche, Cepheid, Qiagen, Agilent, Diaceutics, Lilly, AstraZeneca, Boehringer Ingelheim, AbbVie, Jansen‐Cilag, Pfizer, and Ipsen. R. Erber has received honoraria from Roche, Eisai, Pfizer, BioNTech, Veracyte (PROCURE), Diaceutics, and Novartis. The institution of A. Hartmann and R. Erber conducts research for AstraZeneca, Roche, Janssen‐Cilag, NanoString Technologies, Biocartis, ZytoVision, Novartis, Cepheid, and BioNTech. S. Heublein received honoraria from Clovis, Merck Sharp & Dohme Corporation and Pfizer, and has received research funding from Neuer Stiftung fuer Medizische Forschung and Novartis as well as travel support from GlaxoSmithKline.

Figures

**FIGURE 1**
Kaplan–Meier overall survival analyses for (A) CISH score levels and (B) IHC score levels. CISH indicates chromogenic *in situ* hybridization; IHC, immunohistochemistry

**FIGURE 2**
(A) *CCNE1* DNA CISH and IHC combinations resulting in four groups: CCNE1^nonamp_lo CISH showing no high‐level amplification and IHC <60% positive tumor cell nuclei, CCNE1^nonammp_hi CISH showing no high‐level amplification and IHC >60% positive and >5% strongly staining tumor cell nuclei, CCNE1^amp_lo CISH showing high‐level amplification and IHC <60% positive tumor cell nuclei, CCNE1^amp_hi CISH showing high‐level amplification, and IHC >60% positive and >5% strongly staining tumor cell nuclei. (B) Kaplan–Meier overall survival analysis for four combined CISH/IHC groups. (C) Risk table indicating the number of patients within the cohort that are at risk of death, observed at a yearly. CISH, chromogenic *in situ* hybridization; IHC, immunohistochemistry

**FIGURE 3**
(A) Correlation of CCNE1 DNA CISH score with normalized mRNA expression. (B) Correlation of CCNE1 protein IHC score with normalized RNA expression. (C) Association of four combined CISH/IHC groups with normalized RNA expression. Pearson's correlation analysis given by r. *p < .05. CCNE1 indicates cyclin E1; CISH, chromogenic *in situ* hybridization; IHC, immunohistochemistry

See this image and copyright information in PMC

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

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

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