title: [Mutation of the FGFR3 oncogene is an independent and favorable prognostic factor for tumor-specific survival in patients with urothelial carcinoma of the upper urinary tract].
abstract: OBJECTIVE
  Urothelial tumors of the upper urinary tract (UUTT) frequently display microsatellite Instability (MSI) and a distinct pathway of tumorigenesis resembling MMR-deficient colorectal cancers has been recognized for MSI-UUTT. For MSS-UUTT however oncogenic mechanisms as in bladder cancer (BC) are debated. Mutation of the oncogene FGFR3 has been linked to lower stage, lower grade and favourable clinical outcome in BC. The aim of this study was to evaluate FGFR3 mutation in MSI and MSS-UUTT.
  
  
  METHODS
  172 unselected UUTT were screened for MSI using the National Cancer Institute Consensus Panel and additional markers; FGFR3 status was studied using mutation analysis. Histopathological and clinical data were reviewed.
  
  
  RESULTS
  Microsatellite status had no impact on histopathological or clinical outcome. 52/99 MSS, 10/22 MSI-low and 25/51 MSI-high UUTT displayed mut. FGFR3 respectively. Overall FGFR3 mutation was associated with favourable stage and grade (p <0.0001 and p <0.002), as 62.1% of mut. vs. 23.5 % of wt. FGFR3 UUTT were stage Ta and T1 and graded G3 in 25.3 % vs. 47.1% respectively. That effect depended on MS-status however, as FGFR3 mutation was related to lower stage (pTa and pT1) in MSS/MSI-L (mut 62.9 % vs. wt 18.7%; p <0.01) only as opposed to MSI-H (mut 60% vs. wt. 50%; p = 0,1) UUTTs and as FGFR3 mut UUTTs tended to display lower grade (G1 and G2) provided stable (mut 74,2 % vs. wt. 44.1%; p <0,01) as opposed to instable microsatellite status (mut 76 % vs. wt. 73 %; p = 0.7). There was no marked relation of MS-status or FGFR3 mutation to sex, age or tobacco-exposure; localization in the renal pelvis (p < 0.01) however was more prevalent in the FGFR3 mut group. As opposed to MSI-status FGFR3 mutation had a favourable impact on survival, as 24.1% vs. 54.2 % cancer related deaths occured in the mutated group (p <0.001); this effect was indendent on stage or MSI-status. Neither MSI- nor FGFR3-status had any influence on subsequent bladder tumors.
  
  
  CONCLUSIONS
  FGFR3 mutation is frequent in UUTT and appears to be independent of MS-status; however it is related to significantly favourable histopathological parameters and clinical outcome in MSS cases. Thus our findings might back the notion, that MSS and MSI-UUTTs stem from different oncogenic pathways and that their differing molecular character might have some relevance. Further research is warranted to study the clinical behavior of these tumors and to evaluate a potential role for MS-status and FGFR3 as prognostic tools.
authors.affiliation: Klinik für Urologie und Institut für Pathologie, Universität Regensburg.
authors.forename: M
authors.initials: M
authors.lastname: Burger
authors.forename: J
authors.initials: J
authors.lastname: Catto
authors.forename: J
authors.initials: J
authors.lastname: van Oers
authors.forename: E
authors.initials: E
authors.lastname: Zwarthoff
authors.forename: F C
authors.initials: FC
authors.lastname: Hamdy
authors.forename: M
authors.initials: M
authors.lastname: Meuth
authors.forename: A R
authors.initials: AR
authors.lastname: Azzouri
authors.forename: O
authors.initials: O
authors.lastname: Cussenot
authors.forename: P J
authors.initials: PJ
authors.lastname: Wild
authors.forename: R
authors.initials: R
authors.lastname: Stoehr
authors.forename: A
authors.initials: A
authors.lastname: Hartmann
mesh_terms: D005260:Female; D005787:Gene Frequency; D042822:Genomic Instability; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D009367:Neoplasm Staging; D009857:Oncogenes; D011379:Prognosis; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics*; D017741:Survivors; D016896:Treatment Outcome; D014571:Urologic Neoplasms / Q000235:genetics* / Q000473:pathology; D019459:Urothelium / Q000473:pathology*
chemical_list: C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3