Identification of fibroblast growth factor receptor 3 mutations in urine sediment DNA samples complements cytology in bladder tumor detection

Abstract

BACKGROUND Mutations in fibroblast growth factor 3 receptor (FGFR3) are frequent events in low‐grade bladder tumors. To assess the potential utility of the detection of FGFR3 mutations in a screening modality, the authors analyzed urine sediment DNA samples from 192 patients in a retrospective study. METHODS Urine sediment DNA samples from 192 patients were prepared. Seventy‐two patients had undergone transurethral resection (TURBT group) of mainly Ta lesions and 120 patients had undergone cystectomy (cystectomy group). The majority of patients in the cystectomy group had more advanced tumors compared with patients in the TURBT group. DNA preparations were screened for FGFR3 mutations in exons 7, 10, and 15 using single‐strand conformation polymorphism (SSCP) and DNA sequencing. RESULTS Using SSCP, 67% of patients in the TURBT group and 28% in the cystectomy group displayed FGFR3 mutations. Comparative analysis of cytology results and FGFR3 mutational analysis were performed in 122 cases. Within the TURBT group, FGFR3 mutation analysis outperformed cytology. FGFR3 mutation analysis identified change in 68% of urine sediment DNA samples whereas cytology recorded the presence of tumor cells in 32% of the DNA samples. In the cystectomy group, cytology outperformed FGFR3 mutation analysis. Cytology recorded tumor detection in 90% of patients, while SSCP identified mutational change in 24%. CONCLUSIONS Combining FGFR3 mutation results with cytology in both groups correctly identified tumor presence in 105 of 122 (86%) of patients. The greater sensitivity of FGFR3 mutation detection over cytology in identifying the presence of low‐grade, superficial bladder tumors represents a potential new tool to complement standard cytology in screening patients for bladder tumors and recurrent disease. Cancer 2003;98:737–44. © 2003 American Cancer Society. DOI 10.1002/cncr.11536

Clinical significance of fibroblast growth factor receptor-3 mutations in bladder cancer: a systematic review and meta-analysis

“…Of the 63 reports selected for detailed evaluation, 33 were excluded as duplications or because they lacked key data. The final meta-analysis was carried out on the remaining 30 studies (Billerey et al, 2001;Kimura et al, 2001;Bakkar et al, 2003;Rieger-Christ et al, 2003;van Rhijn et al, 2003van Rhijn et al, , 2004Hernández et al, 2005;Jebar et al, 2005;van der Aa et al, 2005;Wallerand et al, 2005;Hernández et al, 2006;Lindgren et al, 2006;Tomlinson et al, 2007;van Oers et al, 2007;Burger et al, 2008;Junker et al, 2008;Eltze et al, 2009;Ouerhani et al, 2009;van Oers et al, 2009;Zieger et al, 2009;Bakkar et al, 2010;Bodoor et al, 2010;Kompier et al, 2010;Miyake et al, 2010;van Rhijn et al, 2010;Al-Ahmadie et al, 2011;Dodurga et al, 2011;Serizawa et al, 2011;Sjödahl et al, 2011;van Rhijn et al, 2012). Twenty-five of the studies (Table 1A) investigated the association between FGFR3 mutations and grade or stage, while the other 13 studies (Table 1B) investigated the prognostic value of FGFR3 mutations for BC.…”

Focal amplifications are associated with high grade and recurrences in stage Ta bladder carcinoma

“…In addition, gene expression analysis disclosed overexpression of FGF3 in a high proportion of the analyzed cases (8 of 12). The oncogenic activation of FGFR3, which activates MAPK pathway, has been reported at much higher frequency (30-70%) in low-grade noninvasive papillary tumors than in high-grade invasive cancer (10-20%) 7,8,33,34 and the presence of FGFR3 mutations to correlate with genetically stable tumors. 35 Novel candidate oncogenes were also discovered, such as MYBL2, a nuclear protein involved in cell cycle progression; YWHAB, an antiapoptotic protein of the 14-3-3-family; and SDC4, an important component of focal adhesions, which represent interesting candidates detected within 2 independent amplicons on chromosome 20, for which DNA amplification was linked to transcript up-regulation.…”

Genetic alterations in urothelial bladder carcinoma

“…74 Mutations of FGFR3 are more frequent in patients with low-stage UC (74% of pTa tumors, 21% of pT1 tumors, 16% of tumors Ͼ pT2, and 0% of carcinomas in situ [CIS]). 75 In addition, and surprisingly, FGFR3 mutations have been associated with a low rate of pTa tumor recurrence. 76 -78 This finding is not understood clearly: Perhaps activation of FGFR3 by mutation induces the inhibition of cell-cycle proliferation and leads to low tumor recurrence.…”