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

EBioMedicine. 2018 May:31:182-189. doi: 10.1016/j.ebiom.2018.04.019. Epub 2018 Apr 23.

Authors

Lingjian Yang¹, Darren Roberts¹, Mandeep Takhar², Nicholas Erho², Becky A S Bibby¹, Niluja Thiruthaneeswaran³, Vinayak Bhandari⁴, Wei-Chen Cheng⁵, Syed Haider⁶, Amy M B McCorry⁷, Darragh McArt⁷, Suneil Jain⁷, Mohammed Alshalalfa², Ashley Ross⁸, Edward Schaffer⁹, Robert B Den¹⁰, R Jeffrey Karnes¹¹, Eric Klein¹², Peter J Hoskin¹³, Stephen J Freedland¹⁴, Alastair D Lamb¹⁵, David E Neal¹⁶, Francesca M Buffa⁶, Robert G Bristow¹⁷, Paul C Boutros¹⁸, Elai Davicioni², Ananya Choudhury¹, Catharine M L West¹⁹

Affiliations

¹ Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, Manchester M20 4BX, UK.
² GenomeDx Biosciences, Vancouver, BC, Canada.
³ 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.
⁴ Informatics & Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada; Sydney Medical School, University of Sydney, Sydney, Australia.
⁵ Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
⁶ Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK; Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
⁷ Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast BT9 7BL, Northern Ireland, UK.
⁸ James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
⁹ Northwestern Feinberg School of Medicine, Chicago, IL, USA.
¹⁰ Department of Radiation Oncology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States.
¹¹ Department of Urology, Mayo Clinic Rochester, MN, USA.
¹² Glickman Urological Institute, Cleveland Clinic, Cleveland, OH, USA.
¹³ Mount Vernon Cancer Centre, Rickmansworth Road, Northwood, Middlesex HA6 2RN, UK.
¹⁴ 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.
¹⁵ 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.
¹⁶ Nuffield Department of Surgical Sciences, University of Oxford, Old Road Campus Research Building, Headington, Oxford OX3 7DQ, UK.
¹⁷ Princess Margaret Cancer Centre, University Health Network, Toronto, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
¹⁸ Informatics & Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
¹⁹ 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: catharine.west@manchester.ac.uk.

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.

Keywords: Gene expression signature; Hypoxia; Prognostic biomarker; Prostate cancer; Radiotherapy.

Publication types

Clinical Trial, Phase III
Randomized Controlled Trial
Validation Study

MeSH terms

Disease-Free Survival
Gene Expression Regulation, Neoplastic*
Humans
Male
Neoplasm Metastasis
Prostatic Neoplasms* / genetics
Prostatic Neoplasms* / metabolism
Prostatic Neoplasms* / mortality
Prostatic Neoplasms* / therapy
Survival Rate
Tumor Hypoxia / genetics*

Abstract

Publication types

MeSH terms

Grants and funding