Development and Validation of a 28-gene Hypoxia-related Prognostic Signature for Localized Prostate Cancer

Lingjian Yang; Darren Roberts; Mandeep Takhar; Nicholas Erho; Becky A S Bibby; Niluja Thiruthaneeswaran; Vinayak Bhandari; Wei-Chen Cheng; Syed Haider; Amy M B McCorry; Darragh McArt; Suneil Jain; Mohammed Alshalalfa; Ashley Ross; Edward Schaffer; Robert B Den; R Jeffrey Karnes; Eric Klein; Peter J Hoskin; Stephen J Freedland; Alastair D Lamb; David E Neal; Francesca M Buffa; Robert G Bristow; Paul C Boutros; Elai Davicioni; Ananya Choudhury; Catharine M L West

doi:10.1016/j.ebiom.2018.04.019

Development and Validation of a 28-gene Hypoxia-related Prognostic Signature for Localized Prostate Cancer

Lingjian Yang, Darren Roberts, Mandeep Takhar, Nicholas Erho, Becky A S Bibby, Niluja Thiruthaneeswaran, Vinayak Bhandari, Wei-Chen Cheng, Syed Haider, Amy M B McCorry, Darragh McArt, Suneil Jain, Mohammed Alshalalfa, Ashley Ross, Edward Schaffer, Robert B Den, R Jeffrey Karnes, Eric Klein, Peter J Hoskin, Stephen J FreedlandAlastair D Lamb, David E Neal, Francesca M Buffa, Robert G Bristow, Paul C Boutros, Elai Davicioni, Ananya Choudhury, Catharine M L West

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Abstract

BACKGROUND: Hypoxia is associated with a poor prognosis in prostate cancer. This work aimed to derive and validate a hypoxia-related mRNA signature for localized prostate cancer.

METHOD: Hypoxia genes were identified in vitro via RNA-sequencing and combined with in vivo gene co-expression analysis to generate a signature. The signature was independently validated in eleven prostate cancer cohorts and a bladder cancer phase III randomized trial of radiotherapy alone or with carbogen and nicotinamide (CON).

RESULTS: A 28-gene signature was derived. Patients with high signature scores had poorer biochemical recurrence free survivals in six of eight independent cohorts of prostatectomy-treated patients (Log rank test P < .05), with borderline significances achieved in the other two (P < .1). The signature also predicted biochemical recurrence in patients receiving post-prostatectomy radiotherapy (n = 130, P = .007) or definitive radiotherapy alone (n = 248, P = .035). Lastly, the signature predicted metastasis events in a pooled cohort (n = 631, P = .002). Prognostic significance remained after adjusting for clinic-pathological factors and commercially available prognostic signatures. The signature predicted benefit from hypoxia-modifying therapy in bladder cancer patients (intervention-by-signature interaction test P = .0026), where carbogen and nicotinamide was associated with improved survival only in hypoxic tumours.

CONCLUSION: A 28-gene hypoxia signature has strong and independent prognostic value for prostate cancer patients.

Original language	English
Pages (from-to)	182-189
Journal	EBioMedicine
Volume	31
Early online date	23 Apr 2018
DOIs	https://doi.org/10.1016/j.ebiom.2018.04.019
Publication status	Published - May 2018

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Development and Validation of a 28-gene Hypoxia-related Prognostic Signature for Localized Prostate Cancer
Copyright 2018 the authors. This is an open access article published under a Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits distribution and reproduction for non-commercial purposes, provided the author and source are cited.
Final published version, 936 KBLicence: CC BY-NC-ND

Defining the clinical importance of epithelial-stroma-immune signalling in colorectal cancer using a molecular pathology approach
McCorry, A. (Author), Lawler, M. (Supervisor), Dunne, P. (Supervisor) & Salto-Tellez, M. (Supervisor), Jul 2021
Student thesis: Doctoral Thesis › Doctor of Philosophy

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Yang, L., Roberts, D., Takhar, M., Erho, N., Bibby, B. A. S., Thiruthaneeswaran, N., Bhandari, V., Cheng, W.-C., Haider, S., McCorry, A. M. B., McArt, D., Jain, S., Alshalalfa, M., Ross, A., Schaffer, E., Den, R. B., Jeffrey Karnes, R., Klein, E., Hoskin, P. J., ... West, C. M. L. (2018). Development and Validation of a 28-gene Hypoxia-related Prognostic Signature for Localized Prostate Cancer. EBioMedicine, 31, 182-189. https://doi.org/10.1016/j.ebiom.2018.04.019

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title = "Development and Validation of a 28-gene Hypoxia-related Prognostic Signature for Localized Prostate Cancer",

abstract = "BACKGROUND: Hypoxia is associated with a poor prognosis in prostate cancer. This work aimed to derive and validate a hypoxia-related mRNA signature for localized prostate cancer.METHOD: Hypoxia genes were identified in vitro via RNA-sequencing and combined with in vivo gene co-expression analysis to generate a signature. The signature was independently validated in eleven prostate cancer cohorts and a bladder cancer phase III randomized trial of radiotherapy alone or with carbogen and nicotinamide (CON).RESULTS: A 28-gene signature was derived. Patients with high signature scores had poorer biochemical recurrence free survivals in six of eight independent cohorts of prostatectomy-treated patients (Log rank test P < .05), with borderline significances achieved in the other two (P < .1). The signature also predicted biochemical recurrence in patients receiving post-prostatectomy radiotherapy (n = 130, P = .007) or definitive radiotherapy alone (n = 248, P = .035). Lastly, the signature predicted metastasis events in a pooled cohort (n = 631, P = .002). Prognostic significance remained after adjusting for clinic-pathological factors and commercially available prognostic signatures. The signature predicted benefit from hypoxia-modifying therapy in bladder cancer patients (intervention-by-signature interaction test P = .0026), where carbogen and nicotinamide was associated with improved survival only in hypoxic tumours.CONCLUSION: A 28-gene hypoxia signature has strong and independent prognostic value for prostate cancer patients.",

author = "Lingjian Yang and Darren Roberts and Mandeep Takhar and Nicholas Erho and Bibby, {Becky A S} and Niluja Thiruthaneeswaran and Vinayak Bhandari and Wei-Chen Cheng and Syed Haider and McCorry, {Amy M B} and Darragh McArt and Suneil Jain and Mohammed Alshalalfa and Ashley Ross and Edward Schaffer and Den, {Robert B} and {Jeffrey Karnes}, R and Eric Klein and Hoskin, {Peter J} and Freedland, {Stephen J} and Lamb, {Alastair D} and Neal, {David E} and Buffa, {Francesca M} and Bristow, {Robert G} and Boutros, {Paul C} and Elai Davicioni and Ananya Choudhury and West, {Catharine M L}",

note = "Copyright {\textcopyright} 2018. Published by Elsevier B.V.",

year = "2018",

month = may,

doi = "10.1016/j.ebiom.2018.04.019",

language = "English",

volume = "31",

pages = "182--189",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier B.V.",

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Yang, L, Roberts, D, Takhar, M, Erho, N, Bibby, BAS, Thiruthaneeswaran, N, Bhandari, V, Cheng, W-C, Haider, S, McCorry, AMB, McArt, D, Jain, S, Alshalalfa, M, Ross, A, Schaffer, E, Den, RB, Jeffrey Karnes, R, Klein, E, Hoskin, PJ, Freedland, SJ, Lamb, AD, Neal, DE, Buffa, FM, Bristow, RG, Boutros, PC, Davicioni, E, Choudhury, A & West, CML 2018, 'Development and Validation of a 28-gene Hypoxia-related Prognostic Signature for Localized Prostate Cancer', EBioMedicine, vol. 31, pp. 182-189. https://doi.org/10.1016/j.ebiom.2018.04.019

TY - JOUR

T1 - Development and Validation of a 28-gene Hypoxia-related Prognostic Signature for Localized Prostate Cancer

AU - Yang, Lingjian

AU - Roberts, Darren

AU - Takhar, Mandeep

AU - Erho, Nicholas

AU - Bibby, Becky A S

AU - Thiruthaneeswaran, Niluja

AU - Bhandari, Vinayak

AU - Cheng, Wei-Chen

AU - Haider, Syed

AU - McCorry, Amy M B

AU - McArt, Darragh

AU - Jain, Suneil

AU - Alshalalfa, Mohammed

AU - Ross, Ashley

AU - Schaffer, Edward

AU - Den, Robert B

AU - Jeffrey Karnes, R

AU - Klein, Eric

AU - Hoskin, Peter J

AU - Freedland, Stephen J

AU - Lamb, Alastair D

AU - Neal, David E

AU - Buffa, Francesca M

AU - Bristow, Robert G

AU - Boutros, Paul C

AU - Davicioni, Elai

AU - Choudhury, Ananya

AU - West, Catharine M L

PY - 2018/5

Y1 - 2018/5

N2 - BACKGROUND: Hypoxia is associated with a poor prognosis in prostate cancer. This work aimed to derive and validate a hypoxia-related mRNA signature for localized prostate cancer.METHOD: Hypoxia genes were identified in vitro via RNA-sequencing and combined with in vivo gene co-expression analysis to generate a signature. The signature was independently validated in eleven prostate cancer cohorts and a bladder cancer phase III randomized trial of radiotherapy alone or with carbogen and nicotinamide (CON).RESULTS: A 28-gene signature was derived. Patients with high signature scores had poorer biochemical recurrence free survivals in six of eight independent cohorts of prostatectomy-treated patients (Log rank test P < .05), with borderline significances achieved in the other two (P < .1). The signature also predicted biochemical recurrence in patients receiving post-prostatectomy radiotherapy (n = 130, P = .007) or definitive radiotherapy alone (n = 248, P = .035). Lastly, the signature predicted metastasis events in a pooled cohort (n = 631, P = .002). Prognostic significance remained after adjusting for clinic-pathological factors and commercially available prognostic signatures. The signature predicted benefit from hypoxia-modifying therapy in bladder cancer patients (intervention-by-signature interaction test P = .0026), where carbogen and nicotinamide was associated with improved survival only in hypoxic tumours.CONCLUSION: A 28-gene hypoxia signature has strong and independent prognostic value for prostate cancer patients.

AB - BACKGROUND: Hypoxia is associated with a poor prognosis in prostate cancer. This work aimed to derive and validate a hypoxia-related mRNA signature for localized prostate cancer.METHOD: Hypoxia genes were identified in vitro via RNA-sequencing and combined with in vivo gene co-expression analysis to generate a signature. The signature was independently validated in eleven prostate cancer cohorts and a bladder cancer phase III randomized trial of radiotherapy alone or with carbogen and nicotinamide (CON).RESULTS: A 28-gene signature was derived. Patients with high signature scores had poorer biochemical recurrence free survivals in six of eight independent cohorts of prostatectomy-treated patients (Log rank test P < .05), with borderline significances achieved in the other two (P < .1). The signature also predicted biochemical recurrence in patients receiving post-prostatectomy radiotherapy (n = 130, P = .007) or definitive radiotherapy alone (n = 248, P = .035). Lastly, the signature predicted metastasis events in a pooled cohort (n = 631, P = .002). Prognostic significance remained after adjusting for clinic-pathological factors and commercially available prognostic signatures. The signature predicted benefit from hypoxia-modifying therapy in bladder cancer patients (intervention-by-signature interaction test P = .0026), where carbogen and nicotinamide was associated with improved survival only in hypoxic tumours.CONCLUSION: A 28-gene hypoxia signature has strong and independent prognostic value for prostate cancer patients.

U2 - 10.1016/j.ebiom.2018.04.019

DO - 10.1016/j.ebiom.2018.04.019

M3 - Article

C2 - 29729848

SN - 2352-3964

VL - 31

SP - 182

EP - 189

JO - EBioMedicine

JF - EBioMedicine

ER -

Development and Validation of a 28-gene Hypoxia-related Prognostic Signature for Localized Prostate Cancer

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Defining the clinical importance of epithelial-stroma-immune signalling in colorectal cancer using a molecular pathology approach

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