title: The prognostic impact of a combined carbonic anhydrase IX and Ki67 signature in oral squamous cell carcinoma.
abstract: BACKGROUND
  Tumour hypoxia is associated with impaired apoptosis, resistance to therapy and poor prognosis. We previously reported that high stromal expression of the endogenous marker of hypoxia, carbonic anhydrase IX (CAIX), is associated with significantly reduced survival in oral squamous cell carcinoma (OSCC). In addition to hypoxia, CAIX expression is regulated by proliferation-associated signalling. We hypothesised that incorporating Ki67, a proliferation marker, into our existing CAIX-based stratification of OSCC would identify patients with the least favourable prognosis.
  
  
  METHODS
  Surgically resected tumours from 60 OSCC patients were analysed for CAIX, Ki67 and BAX expression using fluorescence immunohistochemistry and automated quantitative analysis (AQUA).
  
  
  RESULTS
  In patients expressing high stromal CAIX (sCAIX), stratification by tumour Ki67 expression revealed significantly distinct survival outcomes (P=0.005). In our OSCC cohort, below-median Ki67 and top-quartile sCAIX expression (Ki67(lo)sCAIX(hi)) were associated with significantly worse disease-specific survival in univariate (HR 7.2 (2.5-20.4), P=0.001) and multivariate (HR 4.2 (1.4-12.8), P=0.011) analyses. Hypoxia is associated with decreased BAX expression; the Ki67(lo)sCAIX(hi) group was more strongly associated with low BAX expression than high sCAIX alone.
  
  
  CONCLUSIONS
  These data suggest that combined analysis of tumour Ki67 and sCAIX expression may provide a more clinically relevant assessment of tumour hypoxia in OSCC.
authors.affiliation: 1] Department of Oncology, University of Calgary, 1331 - 29 Street NW, Calgary, Alberta, Canada T2N 4N2 [2] Functional Tissue Imaging Unit, Translational Laboratories, Tom Baker Cancer Centre, 1331 - 29 Street NW, Calgary, Alberta, Canada T2N 4N2.
authors.forename: A C
authors.initials: AC
authors.lastname: Klimowicz
authors.forename: P
authors.initials: P
authors.lastname: Bose
authors.forename: S K
authors.initials: SK
authors.lastname: Petrillo
authors.forename: A M
authors.initials: AM
authors.lastname: Magliocco
authors.forename: J C
authors.initials: JC
authors.lastname: Dort
authors.forename: N T
authors.initials: NT
authors.lastname: Brockton
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism*; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000401:mortality; D015687:Cell Hypoxia; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000378:metabolism* / Q000401:mortality; D011379:Prognosis; D013534:Survival; D016896:Treatment Outcome; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D051028:bcl-2-Associated X Protein; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases