Fibroblast Growth Factor Receptor 3 Mutations in Bladder Tumors Correlate with Low Frequency of Chromosome Alterations

Abstract

The aim of this study was to analyze the distribution of FGFR3 mutations in bladder tumors of different grade and stage and determine the relation of mutations to chromosomal alterations detected by comparative genomic hybridization (CGH). One hundred bladder cancer samples served as templates for manual microdissection. DNA was isolated from dissected samples containing at least 80% tumor cells. Mutations in FGFR3 were analyzed by SNaPshot analysis. CGH was carried out according to standard protocols. FGFR3 mutations were detected in 45 of 92 samples (48.9%). Concerning T-category, the following mutation frequencies occurred: pTa, 69%; pT1, 38%; and pT2-3, 0%. The mutation frequency was significantly associated with tumor grade: G1, 72%; G2, 56%; and G3, 4%. In pTaG1 tumors, mutations were found in 74%. A significantly lower number of genetic alterations per tumor detected by CGH was associated with FGFR3 mutations (2 vs 8). This association was also seen in pTaG1 tumors: 2.5 (with mutation) vs 7.5 (without mutation). FGFR3 mutations characterize noninvasive low-risk tumors of low malignancy. The low malignant potential of these tumors is underlined by a low number of genetic alterations per tumor. Therefore, FGFR3 represents a valuable prognostic marker of tumors with low malignant potential and can be used as surrogate marker for the detection of genetically stable bladder tumors.

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

“…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.…”

Clinical and pathological implications of miRNA in bladder cancer

“…32,33 Some studies presented the relationship with outcome possibly because of different its related miRNA target such as miR-145, miR-101, miR-100, and miR-99a being characteristic for low-grade, non-muscle-invasive bladder cancer. 23 The miR-183-96-182 cluster was shown to be upregulated in many human cancers, such as breast, lung, and prostate, but also in bladder malignant tumors.…”

“…Urinary biomarkers, including miRNAs, may be related to multiple urologic pathologies (such as prostate or renal cancer), not only bladder cancer, and hence it is important to develop specific ways to accurately differentiate among them. 32 Some of these miRNAs have the potential of becoming biomarkers for bladder cancer diagnosis and prognosis, as well as for predicting treatment targets. 47 For instance, miR-143, miR-222, and miR-452 detected in urine specimens were clinically useful for noninvasive bladder cancer diagnostics, 6 and miR-9, miR-182, and miR-200b were found to be related to bladder tumor aggressiveness and survival.…”