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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 ?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.

SUBMITTER: Millstein J

PROVIDER: S-EPMC7484370 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Prognostic gene expression signature for high-grade serous ovarian cancer.

Millstein J J Budden T T Goode E L EL Anglesio M S MS Talhouk A A Intermaggio M P MP Leong H S HS Chen S S Elatre W W Gilks B B Nazeran T T Volchek M M Bentley R C RC Wang C C Chiu D S DS Kommoss S S Leung S C Y SCY Senz J J Lum A A Chow V V Sudderuddin H H Mackenzie R R George J J Fereday S S Hendley J J Traficante N N Steed H H Koziak J M JM Köbel M M McNeish I A IA Goranova T T Ennis D D Macintyre G G Silva De Silva D D Ramón Y Cajal T T García-Donas J J Hernando Polo S S Rodriguez G C GC Cushing-Haugen K L KL Harris H R HR Greene C S CS Zelaya R A RA Behrens S S Fortner R T RT Sinn P P Herpel E E Lester J J Lubiński J J Oszurek O O Tołoczko A A Cybulski C C Menkiszak J J Pearce C L CL Pike M C MC Tseng C C Alsop J J Rhenius V V Song H H Jimenez-Linan M M Piskorz A M AM Gentry-Maharaj A A Karpinskyj C C Widschwendter M M Singh N N Kennedy C J CJ Sharma R R Harnett P R PR Gao B B Johnatty S E SE Sayer R R Boros J J Winham S J SJ Keeney G L GL Kaufmann S H SH Larson M C MC Luk H H Hernandez B Y BY Thompson P J PJ Wilkens L R LR Carney M E ME Trabert B B Lissowska J J Brinton L L Sherman M E ME Bodelon C C Hinsley S S Lewsley L A LA Glasspool R R Banerjee S N SN Stronach E A EA Haluska P P Ray-Coquard I I Mahner S S Winterhoff B B Slamon D D Levine D A DA Kelemen L E LE Benitez J J Chang-Claude J J Gronwald J J Wu A H AH Menon U U Goodman M T MT Schildkraut J M JM Wentzensen N N Brown R R Berchuck A A Chenevix-Trench G G deFazio A A Gayther S A SA García M J MJ Henderson M J MJ Rossing M A MA Beeghly-Fadiel A A Fasching P A PA Orsulic S S Karlan B Y BY Konecny G E GE Huntsman D G DG Bowtell D D DD Brenton J D JD Doherty J A JA Pharoah P D P PDP Ramus S J SJ

Annals of oncology : official journal of the European Society for Medical Oncology 20200528 9

<h4>Background</h4>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.<h4>Patients and methods</h4>Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString tech ...[more]

PMID: 32473302

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Project description:Background: Resistance to platinum-based chemotherapy remains a major impediment in the treatment of serous epithelial ovarian cancer. The objective of this study was to use gene expression profiling to delineate major deregulated pathways and biomarkers associated with the development of intrinsic chemotherapy resistance upon exposure to standard first-line therapy for ovarian cancer. Methods: The study cohort comprised 28 patients divided into two groups based on their varying sensitivity to first-line chemotherapy using progression free survival (PFS) as a surrogate of response. All 28 patients had advanced stage, high-grade serous ovarian cancer, and were treated with the same standard platinum-based chemotherapy. Twelve patient tumors demonstrating relative resistance to platinum chemotherapy corresponding to shorter PFS (< eight months) were compared to sixteen tumors from platinum-sensitive patients (PFS > eighteen months). Whole transcriptome profiling was performed using a Affymetrix high-resolution microarray platform to permit global comparisons of gene expression profiles between tumors from the resistant group and the sensitive group. Results: Microarray data analysis revealed a set of 204 discriminating genes possessing expression levels, which could influence differential chemotherapy response between the two groups. Robust statistical testing was then performed which eliminated a dependence on the normalization algorithm employed, producing a restricted list of differentially regulated genes, and which found IGF1 to be the most strongly differentially expressed gene. Pathway analysis, based on the list of 204 genes, revealed enrichment in genes primarily involved in the IGF1/PI3K/NFκB/ERK gene signalling networks. Conclusions: This study has identified pathway specific prognostic biomarkers possibly underlying a differential chemotherapy response in patients undergoing standard platinum-based treatment of serous epithelial ovarian cancer. Future studies to validate these markers are necessary to apply this knowledge to biomarker-based clinical trials.

Dataset Information

Prognostic gene expression signature for high-grade serous ovarian cancer.

Publications

Prognostic gene expression signature for high-grade serous ovarian cancer.

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