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

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

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