FGFR3 mutations have different effects on disease course in tumors from the bladder, ureter, and renal pelvis

Abstract

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The urothelial lining of the upper and lower urinary tract is histologically identical and tumors of the upper and lower urinary tract show morphological similarities. Despite these similarities, genetic and epigenetic differences occur: microsatellite instability and promoter hypermethylation are more frequent and more extensively present in upper tract tumors (UTT), when compared to bladder tumors. Methylation is associated with advanced tumor stage and increased tumor progression and mortality rates. On the other hand, fibroblast growth factor receptor 3 (FGFR3) mutations have been found at a high frequency in bladder tumors of low stage and grade with a low risk of progression. We hypothesised that FGFR3 mutations occur at a lower frequency in UTT. We analysed 253 tumor samples, of which 106 were bladder tumors and 154 were UTT (both ureter and renal pelvis). FGFR3 mutations were detected by SNaPshot analysis. Analysis for hypermethylation at 11 CpG islands was performed using methylation sensitive PCR and bisulphite sequencing. FGFR3 mutations occur with the same frequency in bladder (46%, 49/106) and upper tract (49%, 75/154) tumors, and are associated with a milder disease course (less often progression, better survival) in both bladder and ureter tumors (p<0.001). However, in the group of 83 renal pelvis tumors this relation is less significant (p=0.04). This is concordant with the finding that FGFR3 mutation status is not significantly associated with tumor grade (p=0.2) in renal pelvis tumors. In UTT, methylation of the RASSF1A gene is more frequent in tumors without an FGFR3 mutation (p=0.03). The combination of FGFR3 and RASSF1A is related to disease progression and survival in bladder (p<0,001) and ureter (p=0.02) tumors, since patients with an FGFR3 mutant tumor show less often progression when RASSF1A is not methylated. This is not the case for patients with a tumour in the renal pelvis (p=0.2). We conclude that FGFR3 mutations occur at the same frequency in bladder tumors and UTT. In the case of bladder and ureter tumors, the FGFR3 mutation seems to protect the tumor from progressing, and methylation of RASSF1A further distinguishes between mutant tumors that show more (methylated) or less (unmethylated) progression. The FGFR3 mutation does not have the same effect in renal pelvis tumors.