A prognostic hypoxia gene signature with low heterogeneity within the dominant tumour lesion in prostate cancer patients.

Background: Hypoxia gene signatures measured in a biopsy are promising biomarkers in prostate cancer. We determined the ability of a previously developed signature to correctly classify tumours as more or less hypoxic and investigated how intratumour heterogeneity affected its biomarker performance. Methods: The 32-gene signature was determined from gene expression data of 141 biopsies from the dominant (index) lesion of 94 patients treated with prostatectomy. Hypoxic fraction was measured by pimonidazole immunostaining of whole-mount and biopsy sections and used as reference standard for hypoxia. Results: The signature was correlated with hypoxic fraction in whole-mount sections, and the parameters showed almost the same association with tumour aggressiveness. Gene- and pimonidazole-based classification of patients differed considerably. However, the signature had low intratumour heterogeneity compared to hypoxic fraction in biopsies and showed prognostic significance in three independent cohorts. Conclusion: The biopsy-based 32-gene signature from the index lesion reflects hypoxia-related aggressiveness in prostate cancer. The 32-gene signature was determined from gene expression data of 141 biopsies from the dominant (index) lesion of 94 patients treated with prostatectomy. Hypoxic fraction was measured by pimonidazole immunostaining of whole-mount and biopsy sections and used as reference standard for hypoxia.