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Article

Convergence of Prognostic Gene Signatures Suggests Underlying Mechanisms of Human Prostate Cancer Progression

1
School of Computing Sciences, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK
2
Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK
3
The Earlham Institute, Norwich Research Park, Norwich NR4 7UZ, UK
*
Author to whom correspondence should be addressed.
These authors jointly supervised this work.
Genes 2020, 11(7), 802; https://doi.org/10.3390/genes11070802
Received: 8 June 2020 / Revised: 27 June 2020 / Accepted: 10 July 2020 / Published: 16 July 2020
(This article belongs to the Special Issue Genetic Complexity of Hormone Sensitive Cancers)
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. View Full-Text
Keywords: prostate cancer; prognostic signature; diagnostic signature; biomarkers; cancer progression; aggressive cancer prostate cancer; prognostic signature; diagnostic signature; biomarkers; cancer progression; aggressive cancer
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MDPI and ACS Style

Luca, B.-A.; Moulton, V.; Ellis, C.; Connell, S.P.; Brewer, D.S.; Cooper, C.S. Convergence of Prognostic Gene Signatures Suggests Underlying Mechanisms of Human Prostate Cancer Progression. Genes 2020, 11, 802. https://doi.org/10.3390/genes11070802

AMA Style

Luca B-A, Moulton V, Ellis C, Connell SP, Brewer DS, Cooper CS. Convergence of Prognostic Gene Signatures Suggests Underlying Mechanisms of Human Prostate Cancer Progression. Genes. 2020; 11(7):802. https://doi.org/10.3390/genes11070802

Chicago/Turabian Style

Luca, Bogdan-Alexandru, Vincent Moulton, Christopher Ellis, Shea P. Connell, Daniel S. Brewer, and Colin S. Cooper 2020. "Convergence of Prognostic Gene Signatures Suggests Underlying Mechanisms of Human Prostate Cancer Progression" Genes 11, no. 7: 802. https://doi.org/10.3390/genes11070802

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