title: Somatic mutation of fibroblast growth factor receptor-3 (FGFR3) defines a distinct morphological subtype of high-grade urothelial carcinoma.
abstract: FGFR3 mutations are common in low-grade urothelial carcinoma and represent a potential therapeutic target in this disease. Their incidence and functional role in high-grade urothelial carcinoma (HGUC), which displays an increased propensity for recurrence and muscularis propria invasion, is less well defined. We developed a mass spectrometry-based genotyping assay to define the incidence of FGFR3 mutations in a large clinically annotated set of urothelial carcinomas. FGFR3 mutations were found in 17% of HGUC versus 84% of low-grade lesions. Retrospective pathological review of the class of FGFR3 mutant HGUC revealed unique histological features, characterized by a bulky, exophytic component with branching papillary architecture as well as irregular nuclei with a koilocytoid appearance. The predictive value of this histological appearance was confirmed using a prospective set of 49 additional HGUCs. Prospective histological review was able to correctly predict for the presence of an FGFR3 mutation in 13/24 HGUC specimens that exhibited the distinct morphology (54%). All 25 specimens lacking the defined histological features were FGFR3 wild-type for a negative predictive value of 100%. Macrodissection of individual tumours confirmed the presence of the FGFR3 mutant allele in non-invasive and invasive, low and high-grade regions of individual tumours and in the lymph node metastases of patients whose tumours possessed the characteristic morphological signature, suggesting that FGFR3 mutations are not restricted to the more clinically indolent regions of HGUCs. These data suggest that histological screening of HGUCs followed by confirmatory genotyping can be used to enrich for the population of HGUCs most likely to harbour activating mutations in the FGFR-3 receptor tyrosine kinase. Histological review could thus aid in the development of targeted inhibitors of FGFR-3 by facilitating the identification of the subset of patients most likely to harbour activating mutations in the FGFR3 gene.
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, USA.
authors.forename: Hikmat A
authors.initials: HA
authors.lastname: Al-Ahmadie
authors.forename: Gopa
authors.initials: G
authors.lastname: Iyer
authors.forename: Manickam
authors.initials: M
authors.lastname: Janakiraman
authors.forename: Oscar
authors.initials: O
authors.lastname: Lin
authors.forename: Adriana
authors.initials: A
authors.lastname: Heguy
authors.forename: Satish K
authors.initials: SK
authors.lastname: Tickoo
authors.forename: Samson W
authors.initials: SW
authors.lastname: Fine
authors.forename: Anuradha
authors.initials: A
authors.lastname: Gopalan
authors.forename: Ying-bei
authors.initials: YB
authors.lastname: Chen
authors.forename: Arjun
authors.initials: A
authors.lastname: Balar
authors.forename: Jamie
authors.initials: J
authors.lastname: Riches
authors.forename: Bernard
authors.initials: B
authors.lastname: Bochner
authors.forename: Guido
authors.initials: G
authors.lastname: Dalbagni
authors.forename: Dean F
authors.initials: DF
authors.lastname: Bajorin
authors.forename: Victor E
authors.initials: VE
authors.lastname: Reuter
authors.forename: Matthew I
authors.initials: MI
authors.lastname: Milowsky
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics; D011379:Prognosis; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics*; D012189:Retrospective Studies; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods; D016019:Survival Analysis; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery
chemical_list: D009363:Neoplasm Proteins; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3