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. FreedlandAlastair D. Lamb, David E. Neal, Francesca M. Buffa, Robert G. Bristow, Paul C. Boutros, Elai Davicioni, Ananya Choudhury, Catharine M.L. West

Research output: Contribution to journalArticle

23 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)182-189
Number of pages8
JournalEBioMedicine
Volume31
DOIs
StatePublished - May 2018

Keywords

  • Gene expression signature
  • Hypoxia
  • Prognostic biomarker
  • Prostate cancer
  • Radiotherapy

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Yang, L., Roberts, D., Takhar, M., Erho, N., Bibby, B. A. S., Thiruthaneeswaran, N., Bhandari, V., Cheng, W. C., Haider, S., McCorry, A. M. B., McArt, D., Jain, S., Alshalalfa, M., Ross, A., Schaffer, E., Den, R. B., Jeffrey Karnes, R., Klein, E., Hoskin, P. J., ... West, C. M. L. (2018). Development and Validation of a 28-gene Hypoxia-related Prognostic Signature for Localized Prostate Cancer. EBioMedicine, 31, 182-189. https://doi.org/10.1016/j.ebiom.2018.04.019