Prognostic gene expression signature for high-grade serous ovarian cancer

J Millstein; T Budden; E L Goode; M S Anglesio; A Talhouk; M P Intermaggio; H S Leong; S Chen; W Elatre; B Gilks; T Nazeran; M Volchek; R C Bentley; C Wang; D S Chiu; S Kommoss; S C Y Leung; J Senz; A Lum; V Chow; H Sudderuddin; R Mackenzie; J George; AOCS Group; S Fereday; J Hendley; N Traficante; H Steed; J M Koziak; M Köbel; I A McNeish; T Goranova; D Ennis; G Macintyre; D Silva De Silva; T Ramón Y Cajal; J García-Donas; S Hernando Polo; G C Rodriguez; K L Cushing-Haugen; H R Harris; C S Greene; R A Zelaya; S Behrens; R T Fortner; P Sinn; E Herpel; J Lester; J Lubiński; O Oszurek; A Tołoczko; C Cybulski; J Menkiszak; C L Pearce; M C Pike; C Tseng; J Alsop; V Rhenius; H Song; M Jimenez-Linan; A M Piskorz; A Gentry-Maharaj; C Karpinskyj; M Widschwendter; N Singh; C J Kennedy; R Sharma; P R Harnett; B Gao; S E Johnatty; R Sayer; J Boros; S J Winham; G L Keeney; S H Kaufmann; M C Larson; H Luk; B Y Hernandez; P J Thompson; L R Wilkens; M E Carney; B Trabert; J Lissowska; L Brinton; M E Sherman; C Bodelon; S Hinsley; L A Lewsley; R Glasspool; S N Banerjee; E A Stronach; P Haluska; I Ray-Coquard; S Mahner; B Winterhoff; D Slamon; D A Levine; L E Kelemen; J Benitez; J Chang-Claude; J Gronwald; A H Wu; U Menon; M T Goodman; J M Schildkraut; N Wentzensen; R Brown; A Berchuck; G Chenevix-Trench; A deFazio; S A Gayther; M J García; M J Henderson; M A Rossing; A Beeghly-Fadiel; P A Fasching; S Orsulic; B Y Karlan; G E Konecny; D G Huntsman; D D Bowtell; J D Brenton; J A Doherty; P D P Pharoah; S J Ramus

doi:10.1016/j.annonc.2020.05.019

Prognostic gene expression signature for high-grade serous ovarian cancer

Ann Oncol. 2020 Sep;31(9):1240-1250. doi: 10.1016/j.annonc.2020.05.019. Epub 2020 May 28.

Authors

J Millstein¹, T Budden², E L Goode³, M S Anglesio⁴, A Talhouk⁵, M P Intermaggio⁶, H S Leong⁷, S Chen⁸, W Elatre⁹, B Gilks¹⁰, T Nazeran¹¹, M Volchek¹², R C Bentley¹³, C Wang¹⁴, D S Chiu¹¹, S Kommoss¹⁵, S C Y Leung¹¹, J Senz¹⁰, A Lum¹¹, V Chow¹¹, H Sudderuddin¹¹, R Mackenzie¹¹, J George¹⁶; AOCS Group¹⁷; S Fereday¹⁸, J Hendley¹⁸, N Traficante¹⁸, H Steed¹⁹, J M Koziak²⁰, M Köbel²¹, I A McNeish²², T Goranova²³, D Ennis²², G Macintyre²³, D Silva De Silva²³, T Ramón Y Cajal²⁴, J García-Donas²⁵, S Hernando Polo²⁶, G C Rodriguez²⁷, K L Cushing-Haugen²⁸, H R Harris²⁹, C S Greene³⁰, R A Zelaya³¹, S Behrens³², R T Fortner³², P Sinn³³, E Herpel³⁴, J Lester³⁵, J Lubiński³⁶, O Oszurek³⁶, A Tołoczko³⁶, C Cybulski³⁶, J Menkiszak³⁷, C L Pearce³⁸, M C Pike³⁹, C Tseng⁴⁰, J Alsop⁴¹, V Rhenius⁴¹, H Song⁴¹, M Jimenez-Linan⁴², A M Piskorz²³, A Gentry-Maharaj⁴³, C Karpinskyj⁴³, M Widschwendter⁴⁴, N Singh⁴⁵, C J Kennedy⁴⁶, R Sharma⁴⁷, P R Harnett⁴⁸, B Gao⁴⁸, S E Johnatty⁴⁹, R Sayer⁵⁰, J Boros⁴⁶, S J Winham¹⁴, G L Keeney⁵¹, S H Kaufmann⁵², M C Larson¹⁴, H Luk⁵³, B Y Hernandez⁵³, P J Thompson⁵⁴, L R Wilkens⁵³, M E Carney⁵⁵, B Trabert⁵⁶, J Lissowska⁵⁷, L Brinton⁵⁶, M E Sherman⁵⁸, C Bodelon⁵⁶, S Hinsley⁵⁹, L A Lewsley⁵⁹, R Glasspool⁶⁰, S N Banerjee⁶¹, E A Stronach⁶², P Haluska⁶³, I Ray-Coquard⁶⁴, S Mahner⁶⁵, B Winterhoff⁶⁶, D Slamon⁶⁷, D A Levine⁶⁸, L E Kelemen⁶⁹, J Benitez⁷⁰, J Chang-Claude⁷¹, J Gronwald³⁶, A H Wu⁴⁰, U Menon⁴³, M T Goodman⁵⁴, J M Schildkraut⁷², N Wentzensen⁵⁶, R Brown⁷³, A Berchuck⁷⁴, G Chenevix-Trench⁴⁹, A deFazio⁴⁶, S A Gayther⁷⁵, M J García⁷⁶, M J Henderson⁷⁷, M A Rossing²⁹, A Beeghly-Fadiel⁷⁸, P A Fasching⁷⁹, S Orsulic³⁵, B Y Karlan³⁵, G E Konecny⁶⁷, D G Huntsman⁸⁰, D D Bowtell¹⁸, J D Brenton²³, J A Doherty⁸¹, P D P Pharoah⁸², S J Ramus⁸³

Collaborators

AOCS Group:
D Bowtell, G Chenevix-Trench, A Green, P Webb, A DeFazio, D Gertig, N Traficante, S Fereday, S Moore, J Hung, K Harrap, T Sadkowsky, N Pandeya, M Malt, A Mellon, R Robertson, T Vanden Bergh, M Jones, P Mackenzie, J Maidens, K Nattress, Y E Chiew, A Stenlake, H Sullivan, B Alexander, P Ashover, S Brown, T Corrish, L Green, L Jackman, K Ferguson, K Martin, A Martyn, B Ranieri, J White, V Jayde, P Mamers, L Bowes, L Galletta, D Giles, J Hendley, K Alsop, T Schmidt, H Shirley, C Ball, C Young, S Viduka, Hoa Tran, Sanela Bilic, Lydia Glavinas, Julia Brooks, R Stuart-Harris, F Kirsten, J Rutovitz, P Clingan, A Glasgow, A Proietto, S Braye, G Otton, J Shannon, T Bonaventura, J Stewart, S Begbie, M Friedlander, D Bell, S Baron-Hay, A Ferrier A, G Gard, D Nevell, N Pavlakis, S Valmadre, B Young, C Camaris, R Crouch, L Edwards, N Hacker, D Marsden, G Robertson, P Beale, J Beith, J Carter, C Dalrymple, R Houghton, P Russell, M Links, J Grygiel, J Hill, A Brand, K Byth, R Jaworski, P Harnett, R Sharma, G Wain, B Ward, D Papadimos, A Crandon, M Cummings, K Horwood, A Obermair, L Perrin, D Wyld, J Nicklin, M Davy, M K Oehler, C Hall, T Dodd, T Healy, K Pittman, D Henderson, J Miller, J Pierdes, P Blomfield, D Challis, R McIntosh, A Parker, B Brown, R Rome, D Allen, P Grant, S Hyde, R Laurie, M Robbie, D Healy, T Jobling, T Manolitsas, J McNealage, P Rogers, B Susil, E Sumithran, I Simpson, K Phillips, D Rischin, S Fox, D Johnson, S Lade, M Loughrey, N O'Callaghan, W Murray, P Waring, V Billson, J Pyman, D Neesham, M Quinn, C Underhill, R Bell, L F Ng, R Blum, V Ganju, I Hammond, Y Leung, A McCartney, M Buck, I Haviv, D Purdie, D Whiteman, N Zeps

Affiliations

¹ Division of Biostatistics, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, USA.
² School of Women's and Children's Health, Faculty of Medicine, University of NSW Sydney, Sydney, Australia; CRUK Manchester Institute, The University of Manchester, Manchester, UK.
³ Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, USA.
⁴ British Columbia's Ovarian Cancer Research (OVCARE) Program, BC Cancer, Vancouver General Hospital, and University of British Columbia, Vancouver, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada; Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, Canada.
⁵ British Columbia's Ovarian Cancer Research (OVCARE) Program, BC Cancer, Vancouver General Hospital, and University of British Columbia, Vancouver, Canada; Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, Canada.
⁶ School of Women's and Children's Health, Faculty of Medicine, University of NSW Sydney, Sydney, Australia.
⁷ Peter MacCallum Cancer Center, Melbourne, Australia.
⁸ Center for Cancer Prevention and Translational Genomics, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, USA.
⁹ Department of Pathology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, USA.
¹⁰ British Columbia's Ovarian Cancer Research (OVCARE) Program, BC Cancer, Vancouver General Hospital, and University of British Columbia, Vancouver, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
¹¹ British Columbia's Ovarian Cancer Research (OVCARE) Program, BC Cancer, Vancouver General Hospital, and University of British Columbia, Vancouver, Canada.
¹² Anatomical Pathology, Royal Women's Hospital, Parkville, Australia.
¹³ Department of Pathology, Duke University Hospital, Durham, USA.
¹⁴ Department of Health Science Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, USA.
¹⁵ Department of Women's Health, Tuebingen University Hospital, Tuebingen, Germany.
¹⁶ The Jackson Laboratory for Genomic Medicine, Farmington, USA.
¹⁷ Peter MacCallum Cancer Center, Melbourne, Australia; Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, Australia.
¹⁸ Peter MacCallum Cancer Center, Melbourne, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia.
¹⁹ Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Royal Alexandra Hospital, Edmonton, Canada.
²⁰ Alberta Health Services-Cancer Care, Calgary, Canada.
²¹ Department of Pathology and Laboratory Medicine, University of Calgary, Foothills Medical Center, Calgary, Canada.
²² Division of Cancer and Ovarian Cancer Action Research Centre, Department Surgery & Cancer, Imperial College London, London, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
²³ Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
²⁴ Medical Oncology Service, Hospital Sant Pau, Barcelona, Spain.
²⁵ HM Hospitales D Centro Integral Oncológico HM Clara Campal, Madrid, Spain.
²⁶ Medical Oncology Service, Hospital Universitario Funcacion Alcorcon, Alcorcón, Spain.
²⁷ Division of Gynecologic Oncology, NorthShore University HealthSystem, University of Chicago, Evanston, USA.
²⁸ Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, USA.
²⁹ Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, USA; Department of Epidemiology, University of Washington, Seattle, USA.
³⁰ Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
³¹ Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, USA.
³² Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³³ Department of Pathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
³⁴ Department of Pathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; National Center for Tumor Diseases, University Hospital and German Cancer Research Center, Heidelberg, Germany.
³⁵ David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, USA; Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, USA.
³⁶ Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
³⁷ Department of Gynecological Surgery and Gynecological Oncology of Adults and Adolescents, Pomeranian Medical University, Szczecin, Poland.
³⁸ Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, USA; Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, USA.
³⁹ Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, USA; Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, USA.
⁴⁰ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, USA.
⁴¹ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
⁴² Department of Pathology, Addenbrooke's Hospital NHS Trust, Cambridge, UK.
⁴³ MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, University College London, London, UK.
⁴⁴ Department of Women's Cancer, Institute for Women's Health, University College London, London, UK.
⁴⁵ Department of Pathology, Barts Health National Health Service Trust, London, UK.
⁴⁶ Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, Australia; Department of Gynaecological Oncology, Westmead Hospital, Sydney, Australia.
⁴⁷ Pathology West ICPMR Westmead, Westmead Hospital, The University of Sydney, Sydney, Australia; University of Western Sydney at Westmead Hospital, Sydney, Australia.
⁴⁸ Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, Australia; The Crown Princess Mary Cancer Centre Westmead, Sydney-West Cancer Network, Westmead Hospital, Sydney, Australia.
⁴⁹ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁵⁰ Department of Gynaecological Oncology, Westmead Hospital, Sydney, Australia.
⁵¹ Department of Laboratory Medicine and Pathology, Division of Anatomic Pathology, Mayo Clinic, Rochester, USA.
⁵² Department of Oncology, Mayo Clinic, Rochester, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, USA.
⁵³ Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, USA.
⁵⁴ Samuel Oschin Comprehensive Cancer Institute, Cancer Prevention and Genetics Program, Cedars-Sinai Medical Center, Los Angeles, USA.
⁵⁵ John A. Burns School of Medicine, Department of Obstetrics and Gynecology, University of Hawaii, Honolulu, USA.
⁵⁶ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, USA.
⁵⁷ Department of Cancer Epidemiology and Prevention, M Sklodowska Curie National Research Institute of Oncology, Warsaw, Poland.
⁵⁸ Department of Health Sciences Research, Mayo Clinic College of Medicine, Jacksonville, USA.
⁵⁹ Cancer Research UK Clinical Trials Unit, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
⁶⁰ Department of Medical Oncology, Beatson West of Scotland Cancer Centre and University of Glasgow, Glasgow, UK.
⁶¹ The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London, UK.
⁶² Division of Cancer and Ovarian Cancer Action Research Centre, Department Surgery & Cancer, Imperial College London, London, UK.
⁶³ Department of Oncology, Mayo Clinic, Rochester, USA.
⁶⁴ Centre Leon Berard and University Claude Bernard Lyon 1, Lyon, France.
⁶⁵ Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Munich, Germany.
⁶⁶ Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, USA.
⁶⁷ David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, USA.
⁶⁸ Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA; Gynecologic Oncology, Laura and Isaac Pearlmutter Cancer Center, NYU Langone Medical Center, New York, USA.
⁶⁹ Hollings Cancer Center and Department of Public Health Sciences, Medical University of South Carolina, Charleston, USA.
⁷⁰ Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, Spain; Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
⁷¹ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁷² Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, USA.
⁷³ Division of Cancer and Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, UK.
⁷⁴ Department of Gynecologic Oncology, Duke University Hospital, Durham, USA.
⁷⁵ Center for Bioinformatics and Functional Genomics and the Cedars Sinai Genomics Core, Cedars-Sinai Medical Center, Los Angeles, USA.
⁷⁶ Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain.
⁷⁷ Children's Cancer Institute, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, Australia.
⁷⁸ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, USA.
⁷⁹ David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, USA; Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
⁸⁰ British Columbia's Ovarian Cancer Research (OVCARE) Program, BC Cancer, Vancouver General Hospital, and University of British Columbia, Vancouver, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada; Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, Canada; Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, Canada.
⁸¹ Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, USA.
⁸² Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁸³ School of Women's and Children's Health, Faculty of Medicine, University of NSW Sydney, Sydney, Australia; Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, Australia. Electronic address: s.ramus@unsw.edu.au.

Abstract

Background: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC.

Patients and methods: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies.

Results: Expression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02-2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to -), 5.4 (4.6-7.0), 3.8 (3.3-4.6), 3.2 (2.9-3.7) and 2.3 (2.1-2.6) years.

Conclusion: The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.

Keywords: formalin-fixed paraffin-embedded; gene expression; high-grade serous ovarian cancer; overall survival; prognosis.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Cystadenocarcinoma, Serous* / genetics
Female
Humans
Ovarian Neoplasms* / genetics
Prognosis
Proportional Hazards Models
Survival Analysis
Transcriptome

Abstract

Publication types

MeSH terms

Grants and funding