title: The tumour hypoxia marker pimonidazole reflects a transcriptional programme associated with aggressive prostate cancer.
abstract: BACKGROUND
  The hypoxia marker pimonidazole is a candidate biomarker of cancer aggressiveness. We investigated the transcriptional programme associated with pimonidazole staining in prostate cancer.
  
  
  METHODS
  Index tumour biopsies were taken by image guidance from an investigation cohort of 52 patients, where 43 patients received pimonidazole before prostatectomy. Biopsy location within the index tumour was verified for 46 (88%) patients, who were included for gene expression profiling and immunohistochemistry. Two independent cohorts of 59 and 281 patients were used for validation.
  
  
  RESULTS
  Expression of genes in proliferation, DNA repair and hypoxia response was a major part of the transcriptional programme associated with pimonidazole staining. A signature of 32 essential genes was constructed and showed positive correlation to Ki67 staining, confirming the increased proliferation in hypoxic tumours as suggested from the gene data. Positive correlations were also found to tumour stage and lymph node status, but not to blood prostate-specific antigen level, consistent with the findings for pimonidazole staining. The association with aggressiveness was confirmed in validation cohorts, where the signature correlated with Gleason score and had independent prognostic impact, respectively.
  
  
  CONCLUSIONS
  Pimonidazole staining reflects an aggressive hypoxic phenotype of prostate cancer characterised by upregulation of proliferation, DNA repair and hypoxia response genes.
authors.affiliation: Department of Radiation Biology, Norwegian Radium Hospital, Oslo University Hospital, Pb 4950, Nydalen, Oslo 0424, Norway.
authors.forename: H B
authors.initials: HB
authors.lastname: Ragnum
authors.affiliation: Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
authors.forename: L
authors.initials: L
authors.lastname: Vlatkovic
authors.affiliation: Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
authors.forename: A K
authors.initials: AK
authors.lastname: Lie
authors.affiliation: Department of Urology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
authors.forename: K
authors.initials: K
authors.lastname: Axcrona
authors.affiliation: Department of Radiation Biology, Norwegian Radium Hospital, Oslo University Hospital, Pb 4950, Nydalen, Oslo 0424, Norway.
authors.forename: C H
authors.initials: CH
authors.lastname: Julin
authors.affiliation: Department of Radiation Biology, Norwegian Radium Hospital, Oslo University Hospital, Pb 4950, Nydalen, Oslo 0424, Norway.
authors.forename: K M
authors.initials: KM
authors.lastname: Frikstad
authors.affiliation: Department of Radiology and Nuclear Medicine, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
authors.forename: K H
authors.initials: KH
authors.lastname: Hole
authors.affiliation: Department of Radiology and Nuclear Medicine, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
authors.forename: T
authors.initials: T
authors.lastname: Seierstad
authors.affiliation: Department of Radiation Biology, Norwegian Radium Hospital, Oslo University Hospital, Pb 4950, Nydalen, Oslo 0424, Norway.
authors.forename: H
authors.initials: H
authors.lastname: Lyng
mesh_terms: D015687:Cell Hypoxia; D006801:Humans; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D009593:Nitroimidazoles / Q000493:pharmacokinetics; D016016:Proportional Hazards Models; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D013194:Staining and Labeling; D014018:Tissue Distribution; D059467:Transcriptome
chemical_list: D009593:Nitroimidazoles; C033815:pimonidazole