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
Affiliations
Lingjian Yang
Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, Manchester M20 4BX, UK
Darren Roberts
Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, Manchester M20 4BX, UK
Mandeep Takhar
GenomeDx Biosciences, Vancouver, BC, Canada
Nicholas Erho
GenomeDx Biosciences, Vancouver, BC, Canada
Becky A.S. Bibby
Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, Manchester M20 4BX, UK
Niluja Thiruthaneeswaran
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
Vinayak Bhandari
Informatics & Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada; Sydney Medical School, University of Sydney, Sydney, Australia
Wei-Chen Cheng
Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK
Syed Haider
Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK; Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK
Amy M.B. McCorry
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast BT9 7BL, Northern Ireland, UK
Darragh McArt
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast BT9 7BL, Northern Ireland, UK
Suneil Jain
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast BT9 7BL, Northern Ireland, UK
Mohammed Alshalalfa
GenomeDx Biosciences, Vancouver, BC, Canada
Ashley Ross
James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA
Edward Schaffer
Northwestern Feinberg School of Medicine, Chicago, IL, USA
Robert B. Den
Department of Radiation Oncology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States
R. Jeffrey Karnes
Department of Urology, Mayo Clinic Rochester, MN, USA
Eric Klein
Glickman Urological Institute, Cleveland Clinic, Cleveland, OH, USA
Peter J. Hoskin
Mount Vernon Cancer Centre, Rickmansworth Road, Northwood, Middlesex HA6 2RN, UK
Stephen J. Freedland
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
Alastair D. Lamb
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
David E. Neal
Nuffield Department of Surgical Sciences, University of Oxford, Old Road Campus Research Building, Headington, Oxford OX3 7DQ, UK
Francesca M. Buffa
Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK; Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK
Robert G. Bristow
Princess Margaret Cancer Centre, University Health Network, Toronto, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
Paul C. Boutros
Informatics & Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
Elai Davicioni
GenomeDx Biosciences, Vancouver, BC, Canada
Ananya Choudhury
Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, Manchester M20 4BX, UK
Catharine M.L. West
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; Corresponding author at: Translational Radiobiology Group, University of Manchester, Manchester Academic Health Centre, Christie Hospital, Wilmslow Road, Manchester M20 4BX, UK.
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. Keywords: Gene expression signature, Hypoxia, Prognostic biomarker, Prostate cancer, Radiotherapy
