1. Prognostic gene expression signature for high-grade serous ovarian cancer
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A. Green, Robertson Mackenzie, J. Hung, J. Boros, Linda E. Kelemen, S. Hernando Polo, Karen Byth, M. Links, J. Maidens, Amy Lum, R. Blum, C. Tseng, E. Sumithran, Oleg Oszurek, K. Nattress, Jolanta Lissowska, Gustavo C. Rodriguez, Ian Hammond, Mercedes Jimenez-Linan, K. Harrap, Andrew Berchuck, Naveena Singh, K. Ferguson, Raghwa Sharma, Paul R. Harnett, Simon A. Gayther, Brenda Y. Hernandez, S. Chen, R. Sayer, Hoa Tran, Susana Banerjee, Tony Bonaventura, Lewis Perrin, Britton Trabert, M. Malt, Kathryn Alsop, Peter Grant, Scott W. Brown, M. T. Goodman, J. Stewart, S.C.Y. Leung, Pamela J. Thompson, Boris Winterhoff, Peter Sinn, Iain A. McNeish, Anna M. Piskorz, Timothy Budden, Tom Jobling, T. Manolitsas, Clara Bodelon, Danny Rischin, R. Stuart-Harris, T. Sadkowsky, Janusz Menkiszak, L. Galletta, M. Cummings, M. C. Pike, Rene A. Zelaya, D. Nevell, Martin Widschwendter, Andreas Obermair, Melissa C. Larson, Penny Blomfield, D. Marsden, Keith Horwood, L.F. Ng, P. Clingan, Jenny Lester, Aline Talhouk, Bo Gao, D. Wyld, J. McNealage, Blake Gilks, Robert M. Rome, Geoff Macintyre, V. Billson, Izhak Haviv, C. Camaris, María Josefa Mosteiro García, Jacek Gronwald, L R Wilkens, Holly R. Harris, Margaret Davy, M. Robbie, Beatrice Susil, V. Jayde, Jennifer A. Doherty, G. Wain, N. Wentzensen, V. Chow, Hanwei Sudderuddin, T. Vanden Bergh, R. Houghton, Gottfried E. Konecny, D. Challis, M. Loughrey, Michael E. Carney, L. Edwards, Paul D.P. Pharoah, Alan L. Parker, Beth Y. Karlan, Catherine J. Kennedy, J. White, A.H. Wu, Stephen Lade, J. Hill, Peter Rogers, Y.E. Chiew, Chad A. Hall, Alicia Beeghly-Fadiel, T. Corrish, Rex C. Bentley, T. Dodd, J. Nicklin, S. Valmadre, R. Crouch, Stephen B. Fox, D.D. Bowtell, M. Jones, Sabine Behrens, G. Gard, Robert S. Brown, David H. Giles, C. Ball, Celeste Leigh Pearce, F. Kirsten, H. Shirley, Paul Waring, Cezary Cybulski, H. Song, J. Shannon, Darren Ennis, Y. Leung, A. Proietto, R. Jaworski, I.L. Ray-Coquard, Stacey J. Winham, E. Herpel, P. Beale, Jan Lubinski, P. Webb, Joy Hendley, Michael C. J. Quinn, L. Jackman, Valerie Rhenius, Amy E. Glasgow, S. Braye, A. Stenlake, Ellen L. Goode, Javier Benítez, T. Ramón y Cajal, H. Luk, Mark E. Sherman, R. McIntosh, Joellen M. Schildkraut, M. Friedlander, Sian Fereday, S. Moore, Anna deFazio, Joshua Millstein, Janine Senz, Vinod Ganju, A. Martyn, P. Ashover, Geoffrey Otton, L A Brinton, Jane Beith, Jennifer Alsop, Sanela Bilic, D. Gertig, a A. Ferrier, Simon Hyde, Deborah Neesham, Gary L. Keeney, Anthony McCartney, B. Young, L. Bowes, Susan J. Ramus, D.S. Chiu, Stefan Kommoss, D. Papadimos, Martin K. Oehler, A. Mellon, Nadia Traficante, R. Laurie, J. Carter, Sharon E. Johnatty, Tayyebeh M. Nazeran, D. Bell, Mila Volchek, A. Brand, Kara L. Cushing-Haugen, Daniel Johnson, Nick Pavlakis, A. Crandon, N. Pandeya, S. Viduka, R.M. Glasspool, Chloe Karpinskyj, Jenny Chang-Claude, A. Toloczko, David G. Huntsman, Euan A. Stronach, Georgia Chenevix-Trench, Jan Pyman, Nikolajs Zeps, Sandra Orsulic, G. Robertson, K. Martin, Liz-Anne Lewsley, A Gentry-Maharaj, Teodora Goranova, C. Young, Julia Brooks, N. O’Callaghan, S. Begbie, J. Rutovitz, Judy Miller, Jesús García-Donas, T. Healy, Samantha Hinsley, David D.L. Bowtell, James D. Brenton, Usha Menon, Wafaa Elatre, Scott H. Kaufmann, P. Mamers, Bruce M. Brown, David C. Whiteman, Mary Anne Rossing, C. Dalrymple, Kelly-Anne Phillips, Douglas A. Levine, Helen Steed, P. Russell, Peter A. Fasching, Michael D. Buck, Michelle J. Henderson, David W. Allen, DJ Slamon, R. Bell, Neville F. Hacker, J. Grygiel, B. Ranieri, Joshy George, Casey S. Greene, Tiffany M. Schmidt, Lawrence W. Green, Jennifer M Koziak, P.R. Harnett, B. Ward, H. Sullivan, Renée T. Fortner, David L. Healy, S. Baron-Hay, David M. Purdie, B. Alexander, I. Simpson, P. Mackenzie, Michael S. Anglesio, K. Pittman, J. Pierdes, Martin Köbel, H.S. Leong, Chen Wang, Lydia Glavinas, Paul Haluska, C. Underhill, D. Henderson, Maria P. Intermaggio, William K. Murray, R. Robertson, D. Silva De Silva, Sven Mahner, Imperial College Healthcare NHS Trust- BRC Funding, Cancer Research UK, Ovarian Cancer Action, Rhenius, Valerie [0000-0003-4215-3235], Brenton, James [0000-0002-5738-6683], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
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0301 basic medicine ,Oncology ,False discovery rate ,medicine.medical_specialty ,overall survival ,Article ,Transcriptome ,03 medical and health sciences ,Ovarian tumor ,0302 clinical medicine ,Internal medicine ,high-grade serous ovarian cancer ,Medicine ,Humans ,1112 Oncology and Carcinogenesis ,Oncology & Carcinogenesis ,Cystadenocarcinoma ,Survival analysis ,Proportional Hazards Models ,Ovarian Neoplasms ,business.industry ,Proportional hazards model ,AOCS Group ,Hematology ,formalin-fixed paraffin-embedded ,medicine.disease ,Prognosis ,Survival Analysis ,3. Good health ,Cystadenocarcinoma, Serous ,Clinical trial ,Serous fluid ,030104 developmental biology ,030220 oncology & carcinogenesis ,gene expression ,Female ,prognosis ,business - Abstract
Background: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is similar to 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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