Prognostic gene expression signature for high-grade serous ovarian cancer

• Type of Material: Article
• Authors: J. Millstein, University of Southern California; T. Budden, University of NSW Sydney; E. L. Goode, Mayo Clinic; M. S. Anglesio, University of British Columbia; A. Talhouk, University of British Columbia; M. P. Intermaggio, University of NSW Sydney; H. S. Leong, Peter MacCallum Cancer Center; S. Chen, Cedars Sinai Medical Center; Joellen Schildkraut, Emory University; S. J. Ramus, University of NSW Sydney
• Language: English
• Date: 2020-09-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2020 The Authors. Published by Elsevier Ltd on behalf of European Society for Medical Oncology.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.annonc.2020.05.019
• Title of Journal or Parent Work: Annals of Oncology
• Volume: 31
• Issue: 9
• Start Page: 1240
• End Page: 1250
• Grant/Funding Information: None declared
• Keywords: Cells; gene expression; Oncology; prognosis; Mutation; BRCA2; Survival; Therapy; Science & Technology; Recurrence; CXCL9; high-grade serous ovarian cancer; Women; overall survival; Life Sciences & Biomedicine; formalin-fixed paraffin-embedded
• Research Categories: Health Sciences, Oncology; Health Sciences, Rehabilitation and Therapy; Health Sciences, Immunology; Biology, Genetics

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.