FGFR3 Protein Expression and Its Relationship to Mutation Status and Prognostic Variables in Bladder Cancer

J Pathol. 2007 Sep;213(1):91-8. doi: 10.1002/path.2207.

Abstract

FGFR3 is frequently activated by mutation in urothelial carcinoma (UC) and represents a potential target for therapy. In multiple myeloma, both over-expression and mutation of FGFR3 contribute to tumour development. To define the population of UC patients who may benefit from FGFR-targeted therapy, we assessed both mutation and receptor over-expression in primary UCs from a population of new patients. Manual or laser capture microdissection was used to isolate pure tumour cell populations. Where present, non-invasive and invasive components in the same section were microdissected. A screen of the region of the highest tumour stage in each sample yielded a mutation frequency of 42%. Mutations comprised 61 single and five double mutations, all in hotspot codons previously identified in UC. There was a significant association of mutation with low tumour grade and stage. Subsequently, non-invasive areas from the 43 tumours with both non-invasive and invasive components were analysed separately; 18 of these had mutation in at least one region, including nine with mutation in all regions examined, eight with mutation in only the non-invasive component and one with different mutations in different regions. Of the eight with mutation in only the non-invasive component, six were predicted to represent a single tumour and two showed morphological dissimilarity of fragments within the block, indicating the possible presence of distinct tumour clones. Immunohistochemistry showed over-expression of FGFR3 protein in many tumours compared to normal bladder and ureteric controls. Increased expression was associated with mutation (85% of mutant tumours showed high-level expression). Overall, 42% of tumours with no detectable mutation showed over-expression, including many muscle-invasive tumours. This may represent a non-mutant subset of tumours in which FGFR3 signalling contributes to the transformed phenotype and which may benefit from FGFR-targeted therapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Carcinoma / metabolism*
  • Carcinoma / pathology
  • DNA Mutational Analysis
  • Female
  • Gene Expression
  • Gene Frequency
  • Humans
  • Immunohistochemistry
  • Male
  • Microdissection / methods
  • Microscopy, Confocal
  • Mutation
  • Neoplasm Staging
  • Receptor, Fibroblast Growth Factor, Type 3 / analysis*
  • Receptor, Fibroblast Growth Factor, Type 3 / genetics
  • Urinary Bladder Neoplasms / metabolism*
  • Urinary Bladder Neoplasms / pathology

Substances

  • Receptor, Fibroblast Growth Factor, Type 3