title: Genetic and Immunohistochemical Expression of Integrins ITGAV, ITGA6, and ITGA3 As Prognostic Factor for Colorectal Cancer: Models for Global and Disease-Free Survival.
abstract: OBJECTIVE
  To evaluate the relationship between the expression profiles of 84 extracellular matrix (ECM) genes and the prognosis of patients with colorectal cancer (CRC).
  
  
  METHODS
  This retrospective study included 114 patients with stage I-IV CRC who underwent primary tumour resection. Quantitative real-time PCR and immunohistochemistry assays were conducted using primary tumour samples. Kaplan-Meier survival curves were also generated to identify differences in global survival (GS) and disease-free survival (DFS) for the hypo- or hyperexpression status of each marker. The log-rank test was used to verify whether the differences were significant. Stepwise Cox regression models were also used to identify the risk factors associated with GS and DFS in a multivariate mode, and then were used to score the risk of death associated with each marker, either independently or in association.
  
  
  RESULTS
  In the univariate analyses, significant differences in GS in relation to the expression profiles of ITGAV (p = 0.001), ITGA3 (p = 0.002), ITGA6 (p = 0.001), SPARC (p = 0.036), MMP9 (p = 0.034), and MMP16 (p = 0.038) were observed. For DFS, significant differences were observed in associated with ITGAV (p = 0.004) and ITGA3 (p = 0.001). However, only the ITGAV and ITGA6 gene markers for GS (hazard ratio (HR) = 3.209, 95% confidence interval (CI) = 1.412-7.293, p = 0.005 and HR = 3.105, 95% CI = 1.367-7.055, p = 0.007, respectively), and ITGA3 for DFS (HR = 3.806, 95% CI = 1.573-9.209, p = 0.003), remained in the final Cox regression models. A scoring system was developed to evaluate the risk of patient death based on the number of markers for the components of the final GS model. Scores of 0, 1, or 2 were associated with the following mean survival rates [CI]: 47.162 [44.613-49.711], 39.717 [35.471-43.964], 30.197 [24.030-36.327], respectively.
  
  
  CONCLUSIONS
  Multivariate mathematical models demonstrated an association between hyperexpression of the ITGAV and ITGA6 integrins and GS, and also between the ITGA3 integrin and DFS, in patients with colorectal tumours. A risk scoring system based on detected hyperexpression of 0, 1, or 2 markers (e.g., ITGAV and/or ITGA6) was also found to accurately correlate with the GS curves generated for the present cohort.
authors.affiliation: Postgraduate Program in Interdisciplinary Surgery Science, Federal University of São Paulo UNIFESP-Escola Paulista de Medicina, São Paulo, Brazil.
authors.forename: Marcelo Moura
authors.initials: MM
authors.lastname: Linhares
authors.affiliation: Postgraduate Program in Interdisciplinary Surgery Science, Federal University of São Paulo UNIFESP-Escola Paulista de Medicina, São Paulo, Brazil.|Hospital de Cancer de Barretos-Fundação Pio XII, Barretos, Brazil.
authors.forename: Renato José
authors.initials: RJ
authors.lastname: Affonso
authors.affiliation: Postgraduate Program in Interdisciplinary Surgery Science, Federal University of São Paulo UNIFESP-Escola Paulista de Medicina, São Paulo, Brazil.|Hospital de Cancer de Barretos-Fundação Pio XII, Barretos, Brazil.
authors.forename: Luciano de Souza
authors.initials: Lde S
authors.lastname: Viana
authors.affiliation: Postgraduate Program in Interdisciplinary Surgery Science, Federal University of São Paulo UNIFESP-Escola Paulista de Medicina, São Paulo, Brazil.|Hospital de Cancer de Barretos-Fundação Pio XII, Barretos, Brazil.
authors.forename: Sandra Regina Morini
authors.initials: SR
authors.lastname: Silva
authors.affiliation: Postgraduate Program in Interdisciplinary Surgery Science, Federal University of São Paulo UNIFESP-Escola Paulista de Medicina, São Paulo, Brazil.|Hospital de Cancer de Barretos-Fundação Pio XII, Barretos, Brazil.
authors.forename: Marcos Vinicius Araujo
authors.initials: MV
authors.lastname: Denadai
authors.affiliation: Molecular Biology Laboratory, Federal University of São Paulo UNIFESP - EPM / GRAACC, São Paulo, Brazil.
authors.forename: Silvia Regina Caminada
authors.initials: SR
authors.lastname: de Toledo
authors.affiliation: Postgraduate Program in Interdisciplinary Surgery Science, Federal University of São Paulo UNIFESP-Escola Paulista de Medicina, São Paulo, Brazil.
authors.forename: Delcio
authors.initials: D
authors.lastname: Matos
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039422:Integrin alpha3 / Q000235:genetics*; D039503:Integrin alpha6 / Q000235:genetics* / Q000378:metabolism; D039564:Integrin alphaV / Q000235:genetics* / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D016016:Proportional Hazards Models
chemical_list: D014408:Biomarkers, Tumor; D016326:Extracellular Matrix Proteins; D039422:Integrin alpha3; D039503:Integrin alpha6; D039564:Integrin alphaV