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 approximately four 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 overall survival in HGSOC patients. PATIENTS AND METHODS: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, were measured using NanoString technology from formalin-fixed, paraffin-embedded (FFPE) tumour tissue from 3,769 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 fifteen 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 (FDR) < 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 (GES) conferred a greater than two-fold increase in risk of death [HR = 2.35 (2.02, 2.71); P < 0.001]. Median survival by GES quintile was 9.5 (8.3, --), 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.