title: FGFR3 and Tp53 mutations in T1G3 transitional bladder carcinomas: independent distribution and lack of association with prognosis.
abstract: FGFR3 and Tp53 mutations have been proposed as defining two alternative pathways in the pathogenesis of transitional bladder cancer. FGFR3 mutations are associated with low-grade tumors and a favorable prognosis. Tp53 alterations are associated with advanced tumors and, possibly, with a poor prognosis. We focus here on the subgroup of T1G3 superficial tumors because they are a major clinical challenge. Patients (n = 119) were identified from a prospective study of 1,356 cases. Mutations in FGFR3 (exons 7, 10, and 15) and Tp53 (exons 4-9) were analyzed using PCR and direct sequencing. All cases were followed for recurrence and death. Survival was analyzed using Kaplan-Meier curves and multivariable Cox regression. FGFR3 mutations were detected in 20 (16.8%) tumors; 100 mutations in Tp53 were found in tumors from 78 (65.5%) cases. Multiple alterations in Tp53 were present in 19 tumors (16%). Inactivating mutations were present in 58% of tumors. The combined mutation distribution (FGFR3/Tp53) was: wt/wt (34.5%), mut/wt (7.6%), wt/mut (48.7%), and mut/mut (9.2%), indicating that the presence of either mutation did not depend on the other (P value = 0.767). FGFR3 and Tp53 mutations were not associated with clinicopathologic characteristics of patients and did not predict, alone or in combination, recurrence or survival. Taking the risk of the wt/wt group as reference, the mutation-associated risks of cancer-specific mortality were: mut/wt 1.42 (0.15-13.75), wt/mut 0.67 (0.19-2.31), mut/mut 1.62 (0.27-9.59). These molecular features support the notion that T1G3 tumors are at the crossroads of the two main molecular pathways proposed for bladder cancer development and progression.
authors.affiliation: Universitat Pompeu Fabra, Institut Municipal d'Investigació Mèdica, Hospital del Mar, Barcelona, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Hernández
authors.forename: Elena
authors.initials: E
authors.lastname: López-Knowles
authors.forename: Josep
authors.initials: J
authors.lastname: Lloreta
authors.forename: Manolis
authors.initials: M
authors.lastname: Kogevinas
authors.forename: Roberto
authors.initials: R
authors.lastname: Jaramillo
authors.forename: Alex
authors.initials: A
authors.lastname: Amorós
authors.forename: Adonina
authors.initials: A
authors.lastname: Tardón
authors.forename: Reina
authors.initials: R
authors.lastname: García-Closas
authors.forename: Consol
authors.initials: C
authors.lastname: Serra
authors.forename: Alfredo
authors.initials: A
authors.lastname: Carrato
authors.forename: Núria
authors.initials: N
authors.lastname: Malats
authors.forename: Francisco X
authors.initials: FX
authors.lastname: Real
mesh_terms: D000368:Aged; D002295:Carcinoma, Transitional Cell / Q000175:diagnosis* / Q000235:genetics*; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D018450:Disease Progression; D005091:Exons; D005260:Female; D016158:Genes, p53; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D020125:Mutation, Missense; D016017:Odds Ratio; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics*; D012008:Recurrence; D013997:Time Factors; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis* / Q000235:genetics*
chemical_list: D017931:DNA Primers; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3