RESUMEN
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 Pâ¯<â¯.05), with borderline significances achieved in the other two (Pâ¯<â¯.1). The signature also predicted biochemical recurrence in patients receiving post-prostatectomy radiotherapy (nâ¯=â¯130, Pâ¯=â¯.007) or definitive radiotherapy alone (nâ¯=â¯248, Pâ¯=â¯.035). Lastly, the signature predicted metastasis events in a pooled cohort (nâ¯=â¯631, Pâ¯=â¯.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 Pâ¯=â¯.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.
