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Millstein, J.; Budden, T.; Goode, E. L.; Anglesio, M. S.; Talhouk, A.; Intermaggio, M. P.; Leong, H. S.; Chen, S.; Elatre, W.; Gilks, B.; Nazeran, T.; Volchek, M.; Bentley, R. C.; Wang, C.; Chiu, D. S.; Kommoss, S.; Leung, S. C. Y.; Senz, J.; Lum, A.; Chow, V.; Sudderuddin, H.; Mackenzie, R.; George, J.; Fereday, S.; Hendley, J.; Traficante, N.; Steed, H.; Koziak, J. M.; Kobel, M.; McNeish, I. A.; Goranova, T.; Ennis, D.; Macintyre, G.; De Silva, D. Silva; Ramon y Cajal, T.; Garcia-Donas, J.; Hernando Polo, S.; Rodriguez, G. C.; Cushing-Haugen, K. L.; Harris, H. R.; Greene, C. S.; Zelaya, R. A.; Behrens, S.; Fortner, R. T.; Sinn, P.; Herpel, E.; Lester, J.; Lubinski, J.; Oszurek, O.; Toloczko, A.; Cybulski, C.; Menkiszak, J.; Pearce, C. L.; Pike, M. C.; Tseng, C.; Alsop, J.; Rhenius, V.; Song, H.; Jimenez-Linan, M.; Piskorz, A. M.; Gentry-Maharaj, A.; Karpinskyj, C.; Widschwendter, M.; Singh, N.; Kennedy, C. J.; Sharma, R.; Harnett, P. R.; Gao, B.; Johnatty, S. E.; Sayer, R.; Boros, J.; Winham, S. J.; Keeney, G. L.; Kaufmann, S. H.; Larson, M. C.; Luk, H.; Hernandez, B. Y.; Thompson, P. J.; Wilkens, L. R.; Carney, M. E.; Trabert, B.; Lissowska, J.; Brinton, L.; Sherman, M. E.; Bodelon, C.; Hinsley, S.; Lewsley, L. A.; Glasspool, R.; Banerjee, S. N.; Stronach, E. A.; Haluska, P.; Ray-Coquard, I; Mahner, S.; Winterhoff, B.; Slamon, D.; Levine, D. A.; Kelemen, L. E.; Benitez, J.; Chang-Claude, J.; Gronwald, J.; Wu, A. H.; Menon, U.; Goodman, M. T.; Schildkraut, J. M.; Wentzensen, N.; Brown, R.; Berchuck, A.; Chenevix-Trench, G.; DeFazio, A.; Gayther, S. A.; Garcia, M. J.; Henderson, M. J.; Rossing, M. A.; Beeghly-Fadiel, A.; Fasching, P. A.; Orsulic, S.; Karlan, B. Y.; Konecny, G. E.; Huntsman, D. G.; Bowtell, D. D.; Brenton, J. D.; Doherty, J. A.; Pharoah, P. D. P. and Ramus, S. J. (2020): Prognostic gene expression signature for high-grade serous ovarian cancer. In: Annals of Oncology, Vol. 31, No. 9: pp. 1240-1250

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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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