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

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

Journal: EBioMedicine 2018;31():182-189

PMID: 29729848

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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.

Address: Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, Manchester M20 4BX, UK.; GenomeDx Biosciences, Vancouver, BC, Canada.; Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, Manchester M20 4BX, UK; Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.; Informatics & Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada; Sydney Medical School, University of Sydney, Sydney, Australia.; Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.; Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK; Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.; Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast BT9 7BL, Northern Ireland, UK.; James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA.; Northwestern Feinberg School of Medicine, Chicago, IL, USA.; Department of Radiation Oncology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States.; Department of Urology, Mayo Clinic Rochester, MN, USA.; Glickman Urological Institute, Cleveland Clinic, Cleveland, OH, USA.; Mount Vernon Cancer Centre, Rickmansworth Road, Northwood, Middlesex HA6 2RN, UK.; Department of Surgery, Division of Urology, Center for Integrated Research on Cancer and Lifestyle, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK; Nuffield Department of Surgical Sciences, University of Oxford, Old Road Campus Research Building, Headington, Oxford OX3 7DQ, UK.; Nuffield Department of Surgical Sciences, University of Oxford, Old Road Campus Research Building, Headington, Oxford OX3 7DQ, UK.; Princess Margaret Cancer Centre, University Health Network, Toronto, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.; Informatics & Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.; Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, Manchester M20 4BX, UK; NIHR Manchester Biomedical Research Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, UK. Electronic address: [email protected].

DOI: 10.1016/j.ebiom.2018.04.019

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MeSH Terms: Disease-Free Survival, Gene Expression Regulation, Neoplastic, Humans, Male, Neoplasm Metastasis, Prostatic Neoplasms, Survival Rate, Tumor Hypoxia