Convergence of prognostic gene signatures suggests underlying mechanisms of human prostate cancer progression

Luca, Bogdan, Moulton, Vincent ORCID: https://orcid.org/0000-0001-9371-6435, Ellis, Christopher, Connell, Shea P., Brewer, Daniel ORCID: https://orcid.org/0000-0003-4753-9794 and Cooper, Colin ORCID: https://orcid.org/0000-0003-2013-8042 (2020) Convergence of prognostic gene signatures suggests underlying mechanisms of human prostate cancer progression. Genes, 11 (7). ISSN 2073-4425

	Microsoft Excel (OpenXML) (Supplementary_Data_2) Download (13kB)
Preview	PDF (2020_Luca et al._Genes) - Published Version Available under License Creative Commons Attribution. Download (2MB) | Preview
	Microsoft Excel (OpenXML) (Supplementary_Data_4) Download (22kB)
	Microsoft Excel (OpenXML) (Supplementary_Data_1) Download (39kB)
	Microsoft Excel (OpenXML) (Supplementary_Data_5) Download (9kB)
	Microsoft Excel (OpenXML) (Supplementary_Data_3) Download (11kB)

Abstract

The highly heterogeneous clinical course of human prostate cancer has prompted the development of multiple RNA biomarkers and diagnostic tools to predict outcome for individual patients. Biomarker discovery is often unstable with, for example, small changes in discovery dataset configuration resulting in large alterations in biomarker composition. Our hypothesis, which forms the basis of this current study, is that highly significant overlaps occurring between gene signatures obtained using entirely different approaches indicate genes fundamental for controlling cancer progression. For prostate cancer, we found two sets of signatures that had significant overlaps suggesting important genes (p < 10 −34 for paired overlaps, hypergeometrical test). These overlapping signatures defined a core set of genes linking hormone signalling (HES6-AR), cell cycle progression (Prolaris) and a molecular subgroup of patients (PCS1) derived by Non Negative Matrix Factorization (NNMF) of control pathways, together designated as SIG-HES6. The second set (designated SIG-DESNT) consisted of the DESNT diagnostic signature and a second NNMF signature PCS3. Stratifications using SIG-HES6 (HES6, PCS1, Prolaris) and SIG-DESNT (DESNT) classifiers frequently detected the same individual high-risk cancers, indicating that the underlying mechanisms associated with SIG-HES6 and SIG-DESNT may act together to promote aggressive cancer development. We show that the use of combinations of a SIG-HES6 signature together with DESNT substantially increases the ability to predict poor outcome, and we propose a model for prostate cancer development involving co-operation between the SIG-HES6 and SIG-DESNT pathways that has implication for therapeutic design.

Item Type:	Article
Uncontrolled Keywords:	aggressive cancer,biomarkers,cancer progression,diagnostic signature,prognostic signature,prostate cancer,genetics,genetics(clinical),sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/1300/1311
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School Faculty of Science > School of Computing Sciences
UEA Research Groups:	Faculty of Science > Research Groups > Computational Biology Faculty of Science > Research Groups > Norwich Epidemiology Centre Faculty of Medicine and Health Sciences > Research Groups > Norwich Epidemiology Centre Faculty of Medicine and Health Sciences > Research Groups > Cancer Studies Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
Related URLs:	http://www.scopus.com/inward/record.url?... https://www.mdpi.com/2073-4425/11/7/802
Depositing User:	LivePure Connector
Date Deposited:	17 Jul 2020 23:46
Last Modified:	19 Oct 2023 02:43
URI:	https://ueaeprints.uea.ac.uk/id/eprint/76164
DOI:	10.3390/genes11070802

Downloads

Actions (login required)

View Item