title: FGFR3 overexpression is prognostic of adverse outcome for muscle-invasive bladder carcinoma treated with adjuvant chemotherapy.
abstract: BACKGROUND
  Alterations in fibroblast growth factor receptor 3 (FGFR3) have been implicated in the pathogenesis of urothelial carcinoma. However, its clinicopathological significance has not been clearly established, especially in muscle-invasive bladder cancer (MIBC).
  
  
  OBJECTIVE
  The aim of our study was to investigate the mutation and overexpression of FGFR3 in MIBC cases from radical cystectomy and to analyze the prognostic and predictive significance in the groups with or without adjuvant chemotherapy.
  
  
  METHODS
  Study cohorts included 72 cases of MIBC including 42 patients who were treated with adjuvant chemotherapy. The mutation status of FGFR3 exons 7, 10, and 15 was investigated and protein expression was evaluated. The findings were analyzed for the association with relevant clinicopathological findings.
  
  
  RESULTS
  FGFR3 mutations were found in 7 patients (9.7%) and were correlated with a pattern of papillary growth, moderate histologic grade (G2 vs. G3), and moderately advanced TNM stage (II-III vs. IV). FGFR3 protein overexpression was detected in 33 cases (45.8%) but was not associated with the relevant clinicopathological parameters. In patients treated with adjuvant chemotherapy, FGFR3 overexpression was correlated with shorter disease-free survival (P = 0.067, 95% confidence interval: 14.8-29.6, marginal significance) and overall survival (P = 0.035), remaining as a significant independent prognostic factor for disease-free survival and overall survival in multivariate analysis using Cox proportional hazards model. In patients without adjuvant chemotherapy, FGFR3 mutation or overexpression did not have prognostic significance in multivariate analysis.
  
  
  CONCLUSIONS
  We report the FGFR3 alterations in MIBCs, and discuss their biological implication in subsets of patients. FGFR3 overexpression was predictive of adverse outcome in patients with adjuvant cisplatin-based chemotherapy after radical cystectomy. The utility of FGFR3 as a therapeutic target is suggested.
authors.affiliation: Department of Pathology, Kyung Hee University Medical Center, Kyung Hee University School of Medicine, Seoul, Republic of Korea.
authors.forename: Ji-Youn
authors.initials: JY
authors.lastname: Sung
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Jong-Mu
authors.initials: JM
authors.lastname: Sun
authors.affiliation: Department of Urology, Samsung Medical center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Byong
authors.initials: B
authors.lastname: Chang Jeong
authors.affiliation: Department of Urology, Samsung Medical center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Seong
authors.initials: S
authors.lastname: Il Seo
authors.affiliation: Department of Urology, Samsung Medical center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Seong
authors.initials: S
authors.lastname: Soo Jeon
authors.affiliation: Department of Urology, Samsung Medical center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Hyun
authors.initials: H
authors.lastname: Moo Lee
authors.affiliation: Department of Urology, Samsung Medical center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Han
authors.initials: H
authors.lastname: Yong Choi
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: So
authors.initials: S
authors.lastname: Young Kang
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Electronic address: geeo@skku.edu.
authors.forename: Yoon-La
authors.initials: YL
authors.lastname: Choi
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Electronic address: ylachoi@skku.edu.
authors.forename: Ghee
authors.initials: G
authors.lastname: Young Kwon
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000008:administration & dosage; D015653:Cystectomy / Q000379:methods; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009132:Muscles / Q000473:pathology; D009154:Mutation; D009361:Neoplasm Invasiveness; D017063:Outcome Assessment, Health Care / Q000379:methods / Q000706:statistics & numerical data; D011379:Prognosis; D016016:Proportional Hazards Models; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000096:biosynthesis / Q000235:genetics*; D012189:Retrospective Studies; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000601:surgery
chemical_list: C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3; D002945:Cisplatin
keywords: Adjuvant; Carcinoma; Chemotherapy; Cisplatin; Mutation; Receptor fibroblast growth factor, type 3; Transitional cell; Urinary bladder