Journal
ANNALS OF ONCOLOGY
Volume 31, Issue 9, Pages 1240-1250Publisher
ELSEVIER
DOI: 10.1016/j.annonc.2020.05.019
Keywords
formalin-fixed paraffin-embedded; gene expression; high-grade serous ovarian cancer; overall survival; prognosis
Categories
Funding
- National Institutes of Health/National Cancer Institute (NCI) [P50 CA136393, R01CA172404, R01CA168758]
- Canadian Institutes for Health Research (Proof-of-Principle I program)
- United States Department of Defense Ovarian Cancer Research Program [OC110433]
- National Institutes of Health/National Cancer Institute [P50 CA136393, K22 CA193860, P30CA014089, P01CA196569, P30CA034196]
- Janet D. Cottrelle Foundation Scholar's program
- Career Enhancement Awardee of the Mayo Clinic SPORE in Ovarian Cancer [P50 CA136393]
- Cancer Australia [1067110]
- Dr Chew Wei Memorial Professorship in Gynecologic Oncology
- Janet D. Cottrelle Foundation
- Canada Research Chairs program (Research Chair in Molecular and Genomic Pathology)
- European Union's Horizon 2020 European Research Council Programme [742432]
- charity The Eve Appeal
- National Institute for Health Research (NIHR)
- University College London Hospitals (UCLH) Biomedical Research Centre
- Miriam and Sheldon Adelson Medical Research Foundation
- American Cancer Society Early Detection Professorship [SIOP-06-258-01-COUN]
- National Center for Advancing Translational Sciences (NCATS) [UL1TR000124]
- BC Cancer Foundation
- VGH+UBC Hospital Foundation
- Canadian Institutes of Health Research [MOP-86727]
- National Health and Medical Research Council Enabling [310670, 628903]
- Cancer Institute NSW [12/RIG/1-17, 15/RIG/1-16]
- U.S. Army Medical Research and Materiel Command [DAMD17-01-1-0729]
- Cancer Council Victoria
- Queensland Cancer Fund
- Cancer Council New South Wales
- Cancer Council South Australia
- Cancer Council Tasmania
- Cancer Foundation of Western Australia [191, 211, 182]
- National Health and Medical Research Council of Australia [ID199600, ID400413, ID400281]
- Ovarian Cancer Action [006]
- Cancer Research UK [A15973, A15601, A18072, A17197, A19274, A19694, A16561]
- National Institute for Health Research Cambridge and Imperial Biomedical Research Centres
- Department of Defense Award [W81XWH-17-1-0144]
- The Eve Appeal (The Oak Foundation)
- National Institute for Health Research University College London Hospitals Biomedical Research Centre [MR_UU_12023]
- MRC [MR_UU_12023]
- NATIONAL CANCER INSTITUTE [ZIACP010126] Funding Source: NIH RePORTER
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Background: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is similar to 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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