FGFR3 and Tp53 mutations in T1G3 transitional bladder carcinomas: independent distribution and lack of association with prognosis.
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.
Hernández
Silvia
S
Universitat Pompeu Fabra, Institut Municipal d'Investigació Mèdica, Hospital del Mar, Barcelona, Spain.
López-Knowles
Elena
E
Lloreta
Josep
J
Kogevinas
Manolis
M
Jaramillo
Roberto
R
Amorós
Alex
A
Tardón
Adonina
A
García-Closas
Reina
R
Serra
Consol
C
Carrato
Alfredo
A
Malats
Núria
N
Real
Francisco X
FX
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*
D017931:DNA Primers; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3