Prognostic gene expression signature for high-grade serous ovarian cancer.

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.

Authors:

J Millstein, T Budden, EL Goode, MS Anglesio, A Talhouk, MP Intermaggio, HS Leong, S Chen, W Elatre, B Gilks, T Nazeran, M Volchek, RC Bentley, C Wang, DS Chiu, S Kommoss, SCY Leung, J Senz, A Lum, V Chow, H Sudderuddin, R Mackenzie, J George, AOCS Group, S Fereday, J Hendley, N Traficante, H Steed, JM Koziak, M Köbel, IA McNeish, T Goranova, D Ennis, G Macintyre, D Silva De Silva, T Ramón Y Cajal, J García-Donas, S Hernando Polo, GC Rodriguez, KL Cushing-Haugen, HR Harris, CS Greene, RA Zelaya, S Behrens, RT Fortner, P Sinn, E Herpel, J Lester, J Lubiński, O Oszurek, A Tołoczko, C Cybulski, J Menkiszak, CL Pearce, MC Pike, C Tseng, J Alsop, V Rhenius, H Song, M Jimenez-Linan, AM Piskorz, A Gentry-Maharaj, C Karpinskyj, M Widschwendter, N Singh, CJ Kennedy, R Sharma, PR Harnett, B Gao, SE Johnatty, R Sayer, J Boros, SJ Winham, GL Keeney, SH Kaufmann, MC Larson, H Luk, BY Hernandez, PJ Thompson, LR Wilkens, ME Carney, B Trabert, J Lissowska, L Brinton, ME Sherman, C Bodelon, S Hinsley, LA Lewsley, R Glasspool, SN Banerjee, EA Stronach, P Haluska, I Ray-Coquard, S Mahner, B Winterhoff, D Slamon, DA Levine, LE Kelemen, J Benitez, J Chang-Claude, J Gronwald, AH Wu, U Menon, MT Goodman, JM Schildkraut, N Wentzensen, R Brown, A Berchuck, G Chenevix-Trench, A deFazio, SA Gayther, MJ García, MJ Henderson, MA Rossing, A Beeghly-Fadiel, PA Fasching, S Orsulic, BY Karlan, GE Konecny, DG Huntsman, DD Bowtell, JD Brenton, JA Doherty, PDP Pharoah, SJ Ramus

Journal:

Ann Oncol

Citation info:

31(9):1240-1250

Publication date:

1st Sep 2020

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