Prognostic gene expression signature for high-grade serous ovarian cancer
Joshua Millstein(University of Southern California), Timothy Budden(Children's Medical Research Institute), Ellen L. Goode(Mayo Clinic in Florida), Michael S. Anglesio(BC Cancer Agency), Aline Talhouk(BC Cancer Agency), Maria P. Intermaggio(UNSW Sydney), Huei San Leong(Peter MacCallum Cancer Centre), Shuang Chen(Cedars-Sinai Medical Center), Wafaa Elatre(University of Southern California), C. Blake Gilks(BC Cancer Agency), Tayyebeh M. Nazeran(University of British Columbia), Mila Volchek(Royal Women's Hospital), Rex C. Bentley(Duke University Hospital), C. Wang(Mayo Clinic in Florida), Derek S. Chiu(University of British Columbia), Stefan Kommoss, Samuel Leung(University of British Columbia), Janine Senz(BC Cancer Agency), Amy Lum(University of British Columbia), Vickie Chow(University of British Columbia), Hanwei Sudderuddin(University of British Columbia), Robertson Mackenzie(University of British Columbia), Joshy George(Jackson Laboratory), David D.L. Bowtell(The University of Melbourne), Georgia Chenevix‐Trench(The University of Melbourne), A. Green(The University of Melbourne), Penelope M. Webb(Royal Alexandra Hospital), Anna DeFazio(Alberta Health Services), Dorota M. Gertig(University of Calgary), Nadia Traficante(Peter MacCallum Cancer Centre), Sián Fereday(University of Cambridge), Sue Moore(Ovarian Cancer Action), Jillian A. Hung(University of Cambridge), K.R. Harrap(University of Cambridge), T. Sadkowsky(Hospital de Sant Pau), Nirmala Pandeya(HM Hospitales), M. Malt(Hospital Universitario Fundación Alcorcón), Anne Mellon(NorthShore University HealthSystem), R. Paul Robertson(Fred Hutch Cancer Center), T. Vanden Bergh(University of Washington), Marsha Jones(Translational Therapeutics (United States)), P. Mackenzie(Dartmouth College), J. Maidens(German Cancer Research Center), K. Nattress(German Cancer Research Center), Yoke-Eng Chiew(Heidelberg University), Annie Stenlake(German Cancer Research Center), Harold C. Sullivan(Cedars-Sinai Medical Center), B. Alexander(Pomeranian Medical University), P. Ashover(Pomeranian Medical University), Scott D. Brown(Pomeranian Medical University), T. Corrish(Pomeranian Medical University), L. Green(Pomeranian Medical University), L. M. Jackman(University of Southern California), Kaltin Ferguson(University of Southern California), Karla Martin(University of Southern California), A. Martyn(University of Cambridge), B. Ranieri(University of Cambridge), Jeff White(University of Cambridge), V. Jayde(Addenbrooke's Hospital), Pamela Mamers(University of Cambridge), Leanne Bowes(MRC Clinical Trials Unit at UCL), Laura Galletta(MRC Clinical Trials Unit at UCL), Daniel A. Giles(University College London), Joy Hendley(National Health Service), Kathryn Alsop(The University of Sydney), Tannin A. Schmidt(The University of Sydney), H. Shirley(The University of Sydney), Colleen T. Ball(The University of Sydney), Christian D. Young(QIMR Berghofer Medical Research Institute), S. Viduka(Westmead Hospital), Hoa Tran(The University of Sydney), Sanela Bilic(Mayo Clinic in Florida), Lydia Glavinas(Mayo Clinic), Julia Brooks(Mayo Clinic), R. Stuart‐Harris(Mayo Clinic in Florida), Fred Kirsten(University of Hawaiʻi at Mānoa), J Rutovitz(University of Hawaiʻi at Mānoa), P. Clingan(Cedars-Sinai Medical Center), Akisha Glasgow(University of Hawaiʻi at Mānoa), Anthony Proietto(University of Hawaiʻi at Mānoa), Stephen Braye(National Cancer Institute), Geoffrey Otton(The Maria Sklodowska-Curie National Research Institute of Oncology), Jenny Shannon(National Cancer Institute), Tony Bonaventura(Jacksonville College), Jocelyn M. Stewart(National Cancer Institute), Stephen Begbie(Cancer Research UK), Michael Friedländer(Cancer Research UK), Dany Bell(Beatson West of Scotland Cancer Centre), Sally Baron‐Hay(Royal Marsden NHS Foundation Trust), A. Ferrier(Ovarian Cancer Action), G. Gard(Mayo Clinic), David Nevell(Université Claude Bernard Lyon 1), Nick Pavlakis(LMU Klinikum), Susan Valmadre(University of Minnesota), B. Young(University of California, Los Angeles), C. Camaris(Memorial Sloan Kettering Cancer Center), R. Crouch(Medical University of South Carolina), L. Edwards(Spanish National Cancer Research Centre), Neville F. Hacker(Universität Hamburg), Donald E. Marsden(Pomeranian Medical University), Greg Robertson(University of Southern California), Philip Beale(MRC Clinical Trials Unit at UCL), Jane Beith(Cedars-Sinai Medical Center), J. Carter(Emory University), C. Dalrymple(National Cancer Institute), R. Houghton(Ovarian Cancer Action), Peter Russell(Duke University Hospital), Matthew Links(QIMR Berghofer Medical Research Institute), John J. Grygiel(The University of Sydney), Jane Hill(Cedars-Sinai Medical Center), Alison H. Brand(Spanish National Cancer Research Centre), Karen Byth(Cancer Institute of New South Wales), Richard Jaworski(University of Washington), Paul R. Harnett(Vanderbilt University), Raghwa Sharma(University of California, Los Angeles), Gerard Wain(Cedars-Sinai Medical Center), B Ward(Cedars-Sinai Medical Center), D. Papadimos(University of California, Los Angeles), A. Crandon(University of British Columbia), Michael P. Cummings(The University of Melbourne), K. Horwood(University of Cambridge), Andreas Obermair(University of Utah), Lewis Perrin(University of Cambridge), David Wyld(Cancer Institute of New South Wales), James Nicklin(The University of Melbourne), Martin Davy(QIMR Berghofer Medical Research Institute), Martin K. Oehler(Translational Therapeutics (United States)), Christopher L. Hall(University of Cambridge), Tom Dodd(The University of Sydney), Timothy M. Healy(University of Cambridge), Keir Pittman(The University of Melbourne), Doug Henderson(The University of Melbourne), J. Miller(Cancer Institute of New South Wales), J. Pierdes(Cancer Institute of New South Wales), Penny Blomfield(University of California, Los Angeles), D. Challis(University of Utah), Rachel McIntosh(University of Cambridge), Alyssa Parker(Cancer Institute of New South Wales), Robert Brown, Robert Rome(Cancer Institute of New South Wales), Deborah Allen(University of Utah), Peter Grant(Cancer Institute of New South Wales), Simon Hyde(University of British Columbia), R. Laurie(Cancer Institute of New South Wales), Melissa Robbie(University of California, Los Angeles), David Healy(Westmead Hospital), Thomas W. Jobling, T. Manolitsas(University of Cambridge), J. McNealage(University of Cambridge), Peter A. W. Rogers(University of Cambridge), B. Susil(Ovarian Cancer Action), E. Sumithran(University of Utah), Ian Simpson(Translational Therapeutics (United States)), Kelly‐Anne Phillips(The University of Melbourne), Danny Rischin(University of California, Los Angeles), Stephen B. Fox(University of California, Los Angeles), Daryl Johnson, Stephen Lade(University of Cambridge), Maurice B. Loughrey(Cancer Institute of New South Wales), N. O’Callaghan(QIMR Berghofer Medical Research Institute), William K. Murray(University of Cambridge), Paul Waring(The University of Melbourne), Virginia Billson(The University of Melbourne), Jan Pyman(University of Cambridge), Deborah Neesham(The University of Melbourne), Michael Quinn(University of Cambridge), Craig Underhill(University of Utah), Rachel Bell(University of Cambridge), L. F. Ng(University of California, Los Angeles), Robert Blum(University of California, Los Angeles), Vinod Ganju(Cancer Institute of New South Wales), Ian Hammond, Yee Leung, Anthony J. McCartney, Marion G. Buck, I. Haviv(Cancer Institute of New South Wales), D. Purdie(University of California, Los Angeles), David C. Whiteman(Cancer Institute of New South Wales), Nikolajs Zeps(University of Cambridge), Sián Fereday(Peter MacCallum Cancer Centre), Joy Hendley(Peter MacCallum Cancer Centre), Nadia Traficante(Peter MacCallum Cancer Centre), Helen Steed(University of British Columbia), Jennifer M. Koziak(Alberta Health Services), Martin Köbel(University of Calgary), Iain A. McNeish(Cancer Institute of New South Wales), Teodora Goranova(University of Cambridge), D. Ennis(Cancer Institute of New South Wales), Geoff Macintyre(University of Cambridge), D. Silva De Silva(University of Cambridge), Teresa Ramón y Cajal(Hospital de Sant Pau), Jesús García-Donás(University of British Columbia), Susanna Hernando Polo(University of Cambridge), Gus Rodriguez(NorthShore University HealthSystem), Kara L. Cushing‐Haugen(Cancer Institute of New South Wales), Holly R. Harris(University of Cambridge), Casey S. Greene(University of California, Los Angeles), René A. Zelaya(Dartmouth College), Sabine Behrens(The University of Melbourne), Renée T. Fortner(German Cancer Research Center), Hans‐Peter Sinn(Heidelberg University), Esther Herpel(University of British Columbia), Jenny Lester(Cedars-Sinai Medical Center), Jan Lubiński(Cancer Institute of New South Wales), Oleg Oszurek(Cancer Institute of New South Wales), Aleksandra Tołoczko(University of California, Los Angeles), Cezary Cybulski(Cancer Institute of New South Wales), Janusz Menkiszak(University of Cambridge), Celeste Leigh Pearce(University of Southern California), Malcolm C. Pike(University of Southern California), Chiu-Chen Tseng(University of Southern California), Jennifer Alsop(University of Cambridge), Valerie Rhenius(University of California, Los Angeles), Honglin Song(University of Cambridge), Mercedes Jimenez‐Liñan(The University of Sydney), Anna Piskorz(The University of Sydney), A. Gentry-Maharaj(University of British Columbia), Chloe Karpinskyj(University of Cambridge), Martin Widschwendter(University of Cambridge), Naveena Singh(National Health Service), Catherine J. Kennedy(Cancer Institute of New South Wales), Raghwa Sharma(University of California, Los Angeles), Paul R. Harnett(Westmead Hospital), Bo Gao(The University of Melbourne), Sharon E. Johnatty(QIMR Berghofer Medical Research Institute), R. Drew Sayer(Cancer Institute of New South Wales), Jessica Boros(Cancer Institute of New South Wales), Stacey J. Winham(University of Calgary), Gary L. Keeney(Mayo Clinic), Scott H. Kaufmann(Mayo Clinic), Melissa C. Larson(University of Utah), Hui‐Ying Luk(University of Hawaiʻi at Mānoa), Brenda Y. Hernandez(University of Hawaiʻi at Mānoa), Pamela J. Thompson(Cedars-Sinai Medical Center), Lynne R. Wilkens(University of Hawaiʻi at Mānoa), Michael E. Carney(University of Hawaiʻi at Mānoa), Britton Trabert(University of Cambridge), Jolanta Lissowska(Cancer Institute of New South Wales), Louise A. Brinton(National Cancer Institute), Mark E. Sherman(Jacksonville College), Clara Bodelón(Cancer Institute of New South Wales), Samantha Hinsley(University of Cambridge), Liz-Anne Lewsley(University of Cambridge), Rosalind Glasspool(Beatson West of Scotland Cancer Centre), Susana Banerjee(Royal Marsden NHS Foundation Trust), Euan A. Stronach(Cancer Institute of New South Wales), Paul Haluska(Mayo Clinic), Isabelle Ray‐Coquard(Université Claude Bernard Lyon 1), Sven� Mahner(University of Utah), Boris Winterhoff(University of Minnesota), Dennis J. Slamon(University of California, Los Angeles), Douglas A. Levine(Memorial Sloan Kettering Cancer Center), Linda E. Kelemen(Medical University of South Carolina), Javier Benı́tez(Cedars-Sinai Medical Center), Jenny Chang‐Claude(Universität Hamburg), J. Gronwald(University of Cambridge), Anna H. Wu(University of Southern California), Usha Menon(University of Cambridge), Marc T. Goodman(Cedars-Sinai Medical Center), Joellen M. Schildkraut(Emory University), Nicholas Wentzensen(University of Cambridge), Robert Brown(The University of Melbourne), Andrew Berchuck(University of Cambridge), Georgia Chenevix‐Trench(QIMR Berghofer Medical Research Institute), Anna DeFazio(Cancer Institute of New South Wales), Simon A. Gayther(Cedars-Sinai Medical Center), María J. García(Cancer Institute of New South Wales), Michelle J. Henderson(University of California, Los Angeles), Mary Anne Rossing(Cancer Institute of New South Wales), Alicia Beeghly‐Fadiel(University of California, Los Angeles), Peter A. Fasching(Cancer Institute of New South Wales), Sandra Oršulić(Cedars-Sinai Medical Center), Beth Y. Karlan(Cedars-Sinai Medical Center), Gottfried E. Konecny(University of British Columbia), David G. Huntsman(BC Cancer Agency), David D.L. Bowtell(Peter MacCallum Cancer Centre), James D. Brenton(Cedars-Sinai Medical Center), J.A. Doherty(University of Utah), Paul D.P. Pharoah(University of Cambridge), Susan J. Ramus(University of Cambridge)
Cited by 172Open Access
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.
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