Prognostic gene expression signature for high-grade serous ovarian cancer
Authors: 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, 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, 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
Journal: Annals of Oncology (2020)

•A gene expression signature for high-grade serous ovarian cancer prognostic for 2- and 5-year overall survival (OS).•The 101 gene expression signature performs substantially better than age and stage alone.•Median survival by quintile was 9.5, 5.4, 3.8, 3.2 and 2.3 years.•The top five genes associated with OS were TAP1, ZFHX4, CXCL9, FBN1, and PTGER3 (P < 0.001). BackgroundMedian 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 methodsExpression 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.ResultsExpression 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.ConclusionThe 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. 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. 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. 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. 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.