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 languageEnglish
Pages (from-to)182-189
JournalEBioMedicine
Volume31
Early online date23 Apr 2018
DOIs
Publication statusPublished - May 2018

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