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Prognostic gene expression signature for high-grade serous ovarian cancer

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; Köbel, M; McNeish, I A; Goranova, T; Ennis, D; Macintyre, G; Silva De Silva, D; Ramón Y Cajal, T; García-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; Lubiński, J; Oszurek, O; Tołoczko, 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; García, 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; Ramus, S J
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.
PMID: 32473302
ISSN: 1569-8041
CID: 5377642