Prognostic gene expression signature for high-grade serous ovarian cancer

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Millstein, J
Budden, T
Goode, EL
Anglesio, MS
Talhouk, A
Intermaggio, MP
Leong, HS
Chen, S
Elatre, W
Gilks, B
Nazeran, T
Volchek, M
Bentley, RC
Hung, J
et al.
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2020
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http://creativecommons.org/licenses/by-nc-nd/4.0/
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.

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Annals of Oncology
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© 2020 The Authors. Published by Elsevier Ltd on behalf of European Society for Medical Oncology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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Oncology and carcinogenesis
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Millstein, J; Budden, T; Goode, EL; Anglesio, MS; Talhouk, A; Intermaggio, MP; Leong, HS; Chen, S; Elatre, W; Gilks, B; Nazeran, T; Volchek, M; Bentley, RC; Hung, J: et al., Prognostic gene expression signature for high-grade serous ovarian cancer, Annals of Oncology, 2020, 31 (9), pp. 1240-1250
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