FGFR3 protein expression and its relationship to mutation status and prognostic variables in bladder cancer.
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.
Cancer Research UK Clinical Centre, Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds LS9 7TF, UK.
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Tomlinson
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Baldo
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Harnden
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Knowles
D000368:Aged; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D004252:DNA Mutational Analysis; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D042282:Microdissection / Q000379:methods; D018613:Microscopy, Confocal; D009154:Mutation; D009367:Neoplasm Staging; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000032:analysis* / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology
D051498:Receptor, Fibroblast Growth Factor, Type 3