Clinical Trial

. 2018 May:31:182-189.

doi: 10.1016/j.ebiom.2018.04.019. Epub 2018 Apr 23.

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

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.

PMID: 29729848
PMCID: PMC6014579
DOI: 10.1016/j.ebiom.2018.04.019

Clinical Trial

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

Lingjian Yang et al. EBioMedicine. 2018 May.

. 2018 May:31:182-189.

doi: 10.1016/j.ebiom.2018.04.019. Epub 2018 Apr 23.

Authors

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.

PMID: 29729848
PMCID: PMC6014579
DOI: 10.1016/j.ebiom.2018.04.019

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.

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Figures

**Fig. 1**
Kaplan-Meier or receiver operating characteristic plots for independent validation of the 28-gene hypoxia signature in prostatectomy-treated cohorts.

**Fig. 2**
Kaplan-Meier plots for independent validation of the 28-gene hypoxia signature in A) post-prostatectomy radiotherapy cohort; B) radiotherapy-treated cohort.

See this image and copyright information in PMC

Comment in

Hypoxia-related gene panel is prognostic.
Stone L. Stone L. Nat Rev Urol. 2018 Jul;15(7):398. doi: 10.1038/s41585-018-0025-x. Nat Rev Urol. 2018. PMID: 29777192 No abstract available.

References

1. Hill R.P., Bristow R.G., Fyles A., Koritzinsky M., Milosevic M., Wouters B.G. Hypoxia and predicting radiation response. Semin Radiat Oncol. 2015;25:260–272. - PubMed
1. Parker C., Milosevic M., Toi A., Sweet J., Panzarella T., Bristow R. Polarographic electrode study of tumor oxygenation in clinically localized prostate cancer. Int J Radiat Oncol Biol Phys. 2004;58:750–757. - PubMed
1. Lalonde E., Ishkanian A.S., Sykes J., Fraser M., Ross-Adams H., Erho N. Tumour genomic and microenvironmental heterogeneity for integrated prediction of 5-year biochemical recurrence of prostate cancer: a retrospective cohort study. Lancet Oncol. 2014;15:1521–1532. - PubMed
1. Milosevic M., Warde P., Ménard C., Chung P., Toi A., Ishkanian A. Tumor hypoxia predicts biochemical failure following radiotherapy for clinically localized prostate cancer. Clin Cancer Res. 2012;18:2108–2114. - PubMed
1. Turaka A., Buyyounouski M.K., Hanlon A.L., Horwitz E.M., Greenberg R.E., Movsas B. Hypoxic prostate/Muscle P<span class="small">o</span><sub>2</sub> ratio predicts for outcome in patients with localized prostate cancer: long-term results. Int J Radiat Oncol Biol Phys. 2012;82:e433–e439. - PubMed

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

Affiliations

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

Authors

Affiliations

Abstract

Figures

Comment in

References

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MeSH terms

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LinkOut - more resources

Full Text Sources

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Medical