Abstract
TP53 and FGFR3 mutations are the most common mutations in bladder cancers. FGFR3 mutations are most frequent in low-grade low-stage tumours, whereas TP53 mutations are most frequent in high-grade high-stage tumours. Several studies have reported FGFR3 and TP53 mutations to be mutually exclusive events, whereas others have reported them to be independent. We carried out a meta-analysis of published findings for FGFR3 and TP53 mutations in bladder cancer (535 tumours, 6 publications) and additional unpublished data for 382 tumours. TP53 and FGFR3 mutations were not independent events for all tumours considered together (OR = 0.25 [0.18–0.37], p = 0.0001) or for pT1 tumours alone (OR = 0.47 [0.28–0.79], p = 0.0009). However, if the analysis was restricted to pTa tumours or to muscle-invasive tumours alone, FGFR3 and TP53 mutations were independent events (OR = 0.56 [0.23–1.36] (p = 0.12) and OR = 0.99 [0.37–2.7] (p = 0.35), respectively). After stratification of the tumours by stage and grade, no dependence was detected in the five tumour groups considered (pTaG1 and pTaG2 together, pTaG3, pT1G2, pT1G3, pT2-4). These differences in findings can be attributed to the putative existence of two different pathways of tumour progression in bladder cancer: the CIS pathway, in which FGFR3 mutations are rare, and the Ta pathway, in which FGFR3 mutations are frequent. TP53 mutations occur at the earliest stage of the CIS pathway, whereas they occur would much later in the Ta pathway, at the T1G3 or muscle-invasive stage.
Highlights
Bladder cancer is one of the most common cancers worldwide
Similar results were obtained despite the continuity correction required to correct for too small sample sizes in some defined by the combination of stage/grade. Due to their inverse distributions as a function of stage and grade and the small number of double-mutated tumours (FGFR3 mutated, TP53 mutated) observed in small series, FGFR3 and TP53 mutations had been reported to be mutually exclusive events, with FGFR3 mutation strongly associated with the Ta pathway and TP53 mutation strongly associated with the Carcinoma in situ (CIS) pathway [10,11]
The group of Real showed for the first time, in a study of a large series of tumours, that FGFR3 and TP53 mutations were independent events in pT1G3 tumours (n = 119) [12]
Summary
Bladder cancer is one of the most common cancers worldwide. It is the fourth most prevalent cancer in men and the 11th most prevalent cancer in women in the United States [1]. More than 90% of bladder cancers are carcinomas, which may present at different stages. Generally low-grade tumours, which do not invade beyond the basement membrane. Carcinoma in situ (CIS) is a flat tumour that does not invade the basement membrane but is always of high grade. T1 tumours invade the subepithelial connective tissue but do not infiltrate the underlying muscularis propria. T2, T3 and T4 tumours invade the muscularis propria, perivesical tissue and adjacent organs, respectively [2]
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