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

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. Hypoxia genes were identified in vitro via RNA-sequencing and combined with in vivo gene co-expression analysis to generate a signatu...

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Published in:EBioMedicine Vol. 31; pp. 182 - 189
Main Authors: Yang, Lingjian, Roberts, Darren, Takhar, Mandeep, Erho, Nicholas, Bibby, Becky A.S., Thiruthaneeswaran, Niluja, Bhandari, Vinayak, Cheng, Wei-Chen, Haider, Syed, McCorry, Amy M.B., McArt, Darragh, Jain, Suneil, Alshalalfa, Mohammed, Ross, Ashley, Schaffer, Edward, Den, Robert B., Jeffrey Karnes, R., Klein, Eric, Hoskin, Peter J., Freedland, Stephen J., Lamb, Alastair D., Neal, David E., Buffa, Francesca M., Bristow, Robert G., Boutros, Paul C., Davicioni, Elai, Choudhury, Ananya, West, Catharine M.L.
Format: Journal Article
Language:English
Published: Netherlands Elsevier B.V 01.05.2018
Elsevier
Subjects:
Advanced Basic Science
Disease-Free Survival
Gene Expression Regulation, Neoplastic
Gene expression signature
Humans
Hypoxia
Internal Medicine
Male
Neoplasm Metastasis
Prognostic biomarker
Prostate cancer
Prostatic Neoplasms - genetics
Prostatic Neoplasms - metabolism
Prostatic Neoplasms - mortality
Prostatic Neoplasms - therapy
Radiotherapy
Research Paper
Survival Rate
Tumor Hypoxia - genetics
Hypoxia
Radiotherapy
Gene expression signature
Prostate cancer
Prognostic biomarker
ISSN:2352-3964, 2352-3964
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Summary: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. 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). 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. A 28-gene hypoxia signature has strong and independent prognostic value for prostate cancer patients. •We identified genes regulated by hypoxia in prostate cancer cell lines.•In a cohort of primary tumours, the hypoxia regulated genes were reduced to a prognostic signature.•The mRNA abundance signature was prognostic of biochemical recurrence/metastatic recurrence in 11 independent cohorts. Hypoxia, i.e. insufficient supply of oxygen, is an important micro-environmental factor in solid tumours, including prostate cancer. In this work, we identified genes whose abundance were affected by induced hypoxia (1% oxygen concentration) from prostate cancer cell lines. The hypoxia-regulated genes were then refined into a signature, i.e. a biomarker consisting of multiple genes, based on their ability to predict patient outcome after radical prostatectomy. The gene signature predicted the risk of developing biochemical and metastatic recurrence in >1000 patients with primary tumours receiving varying treatments. The prognostic value was independent from existing clinic-pathological factors.
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ISSN:2352-3964
2352-3964
DOI:10.1016/j.ebiom.2018.04.019