Virchows Arch DOI 10.1007/s00428-014-1596-4
ORIGINAL ARTICLE
FGFR3 mutations, but not FGFR3 expression and FGFR3 copy-number variations, are associated with favourable non-muscle invasive bladder cancer Yann Neuzillet & Bas W. G. van Rhijn & Nadia L. Prigoda & Bharati Bapat & Liyang Liu & Peter J. Bostrom & Neil E. Fleshner & Brenda L. Gallie & Alexandre R. Zlotta & Michael A. S. Jewett & Theo H. van der Kwast
Received: 10 April 2014 / Revised: 26 April 2014 / Accepted: 22 May 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract The fibroblast growth factor receptor 3 (FGFR3) is a tyrosine kinase receptor frequently activated by point mutations in bladder cancer (BC). These mutations are associated with genetically stable, Ta and low-grade BC, representing the favourable BC pathway. Conversely, FGFR3 over-expression was recently found in 40 % of muscle invasive BC. We examined FGFR3 mutation status and protein expression in patients originally diagnosed as T1. We also investigated copynumber variations in FGFR3 as a possible alternative mechanism to activate FGFR3. We included 84 patients with T1 BC as their initial diagnosis. A uropathologist reviewed the slides for grade and (sub)stage. The FGFR3 mutation status was examined by PCRSNaPshot and FGFR3 protein expression by standard
immuno-histochemistry (FGFR3-B9). Copy-number status was determined in 69/84 cases with nine probes covering nine exons of the FGFR3 gene (MLPA). Of 27 BC with FGFR3 mutations, 26 (96 %) showed FGFR3 over-expression. Of the 57 wild-type BC, 27 (47 %) BC showed over-expression. Pathological parameters significantly differed (p G base substitution in codon 249
was significantly associated with favourable BC disease characteristics. In addition to almost all FGFR3 mutant BC, 47 % of wild-type BC displayed FGFR3 overexpression, suggesting an alternative mechanism to activate FGFR3. Increased FGFR3 copy number was a rare event and did not account for this mechanism. Nevertheless, FGFR3 wild-type tumours with overexpression of the protein may still represent a subset that might potentially benefit from FGFR3-targeted therapy. Keywords Bladder cancer . FGFR3 . Amplification . Mutation . Immunochemistry . Copy number
Introduction Bladder cancer (BC) is the fifth most common malignancy in developed countries [1]. BC is conceptualised according to a dichotomy: Non-muscle invasive bladder cancer (NMIBC), which represents 75 % of the primary diagnoses, and muscle invasive bladder cancer (MIBC) [2, 3]. Prognosis of NMIBC is generally good with a 5year disease-specific survival rate above 85 %. On the other hand, MIBC has a poor prognosis with a 3-year disease-specific survival around 50 %. In case of organ metastasis, systemic treatment is considered palliative. The natural history of NMIBC is characterised by two main events, namely, recurrence (15–61 %) and progression (0.2–17 %) [2]. The most important variables to predict recurrence are multiplicity, prior recurrence rate and size and to predict progression are presence of CIS,
the tumour grade and stage [2]. Molecular markers hold considerable promise to predict the biological behaviour of NMIBC and are usually related to progression rather than to recurrence [3]. Fibroblast growth factor receptor 3 (FGFR3) is commonly mutated in NMIBC, and its mutation has been linked to favourable (low-grade/stage) bladder cancers [4]. These mutations are rare in MIBC. The majority of FGFR3 mutations are located in hot spots, namely, the codons 249 (≈61 %), 375 (≈19 %), 248 (≈8 %) and 372 (≈6 %), with the rest occurring at very low frequencies (
ORIGINAL ARTICLE
FGFR3 mutations, but not FGFR3 expression and FGFR3 copy-number variations, are associated with favourable non-muscle invasive bladder cancer Yann Neuzillet & Bas W. G. van Rhijn & Nadia L. Prigoda & Bharati Bapat & Liyang Liu & Peter J. Bostrom & Neil E. Fleshner & Brenda L. Gallie & Alexandre R. Zlotta & Michael A. S. Jewett & Theo H. van der Kwast
Received: 10 April 2014 / Revised: 26 April 2014 / Accepted: 22 May 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract The fibroblast growth factor receptor 3 (FGFR3) is a tyrosine kinase receptor frequently activated by point mutations in bladder cancer (BC). These mutations are associated with genetically stable, Ta and low-grade BC, representing the favourable BC pathway. Conversely, FGFR3 over-expression was recently found in 40 % of muscle invasive BC. We examined FGFR3 mutation status and protein expression in patients originally diagnosed as T1. We also investigated copynumber variations in FGFR3 as a possible alternative mechanism to activate FGFR3. We included 84 patients with T1 BC as their initial diagnosis. A uropathologist reviewed the slides for grade and (sub)stage. The FGFR3 mutation status was examined by PCRSNaPshot and FGFR3 protein expression by standard
immuno-histochemistry (FGFR3-B9). Copy-number status was determined in 69/84 cases with nine probes covering nine exons of the FGFR3 gene (MLPA). Of 27 BC with FGFR3 mutations, 26 (96 %) showed FGFR3 over-expression. Of the 57 wild-type BC, 27 (47 %) BC showed over-expression. Pathological parameters significantly differed (p G base substitution in codon 249
was significantly associated with favourable BC disease characteristics. In addition to almost all FGFR3 mutant BC, 47 % of wild-type BC displayed FGFR3 overexpression, suggesting an alternative mechanism to activate FGFR3. Increased FGFR3 copy number was a rare event and did not account for this mechanism. Nevertheless, FGFR3 wild-type tumours with overexpression of the protein may still represent a subset that might potentially benefit from FGFR3-targeted therapy. Keywords Bladder cancer . FGFR3 . Amplification . Mutation . Immunochemistry . Copy number
Introduction Bladder cancer (BC) is the fifth most common malignancy in developed countries [1]. BC is conceptualised according to a dichotomy: Non-muscle invasive bladder cancer (NMIBC), which represents 75 % of the primary diagnoses, and muscle invasive bladder cancer (MIBC) [2, 3]. Prognosis of NMIBC is generally good with a 5year disease-specific survival rate above 85 %. On the other hand, MIBC has a poor prognosis with a 3-year disease-specific survival around 50 %. In case of organ metastasis, systemic treatment is considered palliative. The natural history of NMIBC is characterised by two main events, namely, recurrence (15–61 %) and progression (0.2–17 %) [2]. The most important variables to predict recurrence are multiplicity, prior recurrence rate and size and to predict progression are presence of CIS,
the tumour grade and stage [2]. Molecular markers hold considerable promise to predict the biological behaviour of NMIBC and are usually related to progression rather than to recurrence [3]. Fibroblast growth factor receptor 3 (FGFR3) is commonly mutated in NMIBC, and its mutation has been linked to favourable (low-grade/stage) bladder cancers [4]. These mutations are rare in MIBC. The majority of FGFR3 mutations are located in hot spots, namely, the codons 249 (≈61 %), 375 (≈19 %), 248 (≈8 %) and 372 (≈6 %), with the rest occurring at very low frequencies (
