title: S100A9 and EGFR gene signatures predict disease progression in muscle invasive bladder cancer patients after chemotherapy.
abstract: BACKGROUND
  In our previous gene expression profile analysis, IL1B, S100A8, S100A9, and EGFR were shown to be important mediators of muscle invasive bladder cancer (MIBC) progression. The aim of the present study was to investigate the ability of these gene signatures to predict disease progression after chemotherapy in patients with locally recurrent or metastatic MIBC.
  
  
  METHODS
  Patients with locally advanced MIBC who received chemotherapy were enrolled. The expression signatures of four genes were measured and carried out further functional analysis to confirm our findings.
  
  
  RESULTS
  Two of the four genes, S100A9 and EGFR, were determined to significantly influence disease progression (P = 0.023, 0.045, respectively). Based on a receiver operating characteristic curve, a cut-off value for disease progression was determined. Patients with the good-prognostic signature group had a significantly longer time to progression and cancer-specific survival time than those with the poor-prognostic signature group (P < 0.001, 0.042, respectively). In the multivariate Cox regression analysis, gene signature was the only factor that significantly influenced disease progression [hazard ratio: 4.726, confidence interval: 1.623-13.763, P = 0.004]. In immunohistochemical analysis, S100A9 and EGFR positivity were associated with disease progression after chemotherapy. Protein expression of S100A9/EGFR showed modest correlation with gene expression of S100A9/EGFR (r = 0.395, P = 0.014 and r = 0.453, P = 0.004). Our functional analysis provided the evidence demonstrating that expression of S100A9 and EGFR closely associated chemoresistance, and that inhibition of S100A9 and EGFR may sensitize bladder tumor cells to the cisplatin-based chemotherapy.
  
  
  CONCLUSIONS
  The S100A9/EGFR level is a novel prognostic marker to predict the chemoresponsiveness of patients with locally recurrent or metastatic MIBC.
authors.affiliation: Department of Urology, College of Medicine, Chungbuk National University, Cheongju, Republic of Korea.
authors.forename: W T
authors.initials: WT
authors.lastname: Kim
authors.forename: J
authors.initials: J
authors.lastname: Kim
authors.forename: C
authors.initials: C
authors.lastname: Yan
authors.forename: P
authors.initials: P
authors.lastname: Jeong
authors.forename: S Y
authors.initials: SY
authors.lastname: Choi
authors.forename: O J
authors.initials: OJ
authors.lastname: Lee
authors.forename: Y B
authors.initials: YB
authors.lastname: Chae
authors.forename: S J
authors.initials: SJ
authors.lastname: Yun
authors.forename: S C
authors.initials: SC
authors.lastname: Lee
authors.forename: W J
authors.initials: WJ
authors.lastname: Kim
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D040502:Calgranulin B / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D003131:Combined Modality Therapy; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000517:prevention & control; D011379:Prognosis; D016016:Proportional Hazards Models; D017211:Treatment Failure; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D040502:Calgranulin B; C512478:EGFR protein, human; D066246:ErbB Receptors; D002945:Cisplatin
keywords: drug resistance; epidermal growth factor; receptor; urinary bladder; urinary bladder neoplasms