Fibroblast growth factor receptor 3 mutation in voided urine is a useful diagnostic marker and significant indicator of tumor recurrence in non‐muscle invasive bladder cancer

Abstract

The fibroblast growth factor receptor (FGFR)-3 gene encodes a receptor tyrosine kinase that is frequently mutated in non-muscle invasive bladder cancer (NMIBC). A sensitive and quantitative assay using peptide nucleic acid-mediated real-time PCR was developed for detecting FGFR3 mutations in the urine samples and evaluated as a molecular marker for detecting intravesical recurrence of NMIBC in patients undergoing transurethral resection of bladder tumor. FGFR3 mutation was examined in tumor tissues and serially taken pre-and postoperative urine sediments in 45 NMIBC patients with a median follow up of 32 months. FGFR3 mutations were detected in 53.3% (24/45) of primary tumor tissues, among which intravesical recurrence developed in 37.5% (9/24) of cases. FGFR3 mutation in the primary tumor was not a significant prognostic indicator for recurrence, while the proportion of FGFR3 mutation (i.e. tumor cellularity was ‡11%) in the preoperative urine sediments was a significant indicator for recurrence in patients with FGFR3 mutations in the primary tumors. FGFR3 mutations were detected in 78% (7/9) of postoperative urine samples from recurrent cases with FGFR3 mutations in the tumor, while no mutations were detected in the urine of 15 non-recurrent cases. Urine cytology was negative in all cases with FGFR3 mutations in the primary tumors, while the sensitivity of cytological examination was as high as 56% (5/9) in cases showing wild-type FGFR3 in the primary tumors. Urine FGFR3 mutation assay and cytological examination may be available in the future as complementary diagnostic modalities in postoperative management of NMIBC. (Cancer Sci 2010; 101: 250-258) U rothelial carcinoma (UC) is a histological subtype accounting for more than 90% of all bladder cancers, and there are 357 000 new cases every year worldwide.(1) Bladder UCs are generally divided into two groups for clinical management, depending on the pathological stage. Most of the newly diagnosed UCs are non-muscle invasive bladder cancer (NMIBC; i.e., pTa or pT1), and the initial treatment is transurethral resection of bladder tumor (TURBT). After the initial TURBT, the patients undergo intensive surveillance by cystoscopic examination at regular intervals; usually every 3 months, because up to 70% of these patients will experience intravesical recurrence, and 10-30% of the lesions will progress to lifethreatening muscle-invasive disease ( ‡pT2).(2) Cystoscopy is an inconvenient, invasive, and expensive diagnostic modality, but currently it is the gold standard for detecting intravesical recurrence in the postoperative follow up. Although urine bound diagnostic tests including urinary cytology, nuclear matrix protein (NMP)22, and bladder tumour antigen (BTA) tests are used in the management after TURBT or bladder cancer screening, their usefullness is limited due to their poor sensitivity or specificity.(3) In previous reports, various molecular markers detectable in urine have been considered as a useful and non-invasive clinical assay improving the sens...

FGFR3 Is Overexpressed Waldenström Macroglobulinemia and Its Inhibition by Dovitinib Induces Apoptosis and Overcomes Stroma-Induced Proliferation

“…We found that it was overexpressed compared to normal CD19þ cells. Unlike multiple myeloma, WM neoplastic cells lack immunoglobulin heavy chain locus translocations (4,14,19). These findings are in agreement with previous reports showing that overexpression of wildtype FGFR3 in B lymphoid cells was oncogenic and cooperated with MYC to accelerate development of Bcell lineage neoplasms (20).…”

“…The extracellular portion of FGFR3 interacts with FGF3, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation (2). FGFR3 was shown to play a major role in several types in cancer; it was shown to mediate growth and neoplasia in colorectal (3), bladder (4), and oral (5) cancers.…”

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.…”

“…FGFR3 mutations have also been detected in >70% of non-muscle-invasive bladder tumors, but they have only been detected in 10-20% of tumors that invade the bladder muscle. Although a number of studies have reported that FGFR3 mutations are significantly associated with low tumor grade and early cancer stages, other studies have shown that they are not (Bodoor et al, 2010;Miyake et al, 2010). Therefore, the prognostic value of FGFR3 remains controversial (Cheng et al, 2011;Mukhtar and Perry, 2011).…”

Roles of Fibroblast Growth Factor Receptors in Carcinogenesis

“…The high recurrence rate (60-80%) of noninvasive tumors requires long-term, expensive patient monitoring. Recent data suggest that detection of FGFR3 mutations in urine from patients with FGFR3 mutations in the primary tumor indicates recurrence (101,102). Thus, identification of FGFR3 mutations is not only a potential biomarker for bladder cancer diagnosis and prognosis but could also indicate tumor recurrence.…”