Top

Published in:

01-09-2017 | Original Article

FGFR3, a marker suggestive of favorable prognosis in urothelial carcinoma

Authors: Sara E. Khalifa, Rasha A. Khairy, Rasha Ramadan

Published in: Comparative Clinical Pathology | Issue 5/2017

Abstract

The detection of fibroblast growth factor receptor 3 (FGFR3) mutations in noninvasive bladder cancer mostly and a finding of FGFR3 overexpression in many invasive bladder cancers (BC) has created hope that targeted therapy against FGFR3 may have a major role in the treatment of BC. We aimed to evaluate immunohistochemically the expression of FGFR3 in urothelial carcinoma of the urinary bladder and correlate the results with various clinicopathologic variables to show the possible prognostic value of this marker. This study included 100 archived paraffin blocks of variable grades and stages of urothelial carcinoma. All cases were immunohistochemically stained with anti-FGFR3 antibody. FGFR3 immunostaining was detected in 88% (88/100) of urothelial carcinoma cases. A significant correlation was detected between FGFR3 expressions with the grade and depth of tumor invasion as 34% of low-grade cases (P = 0.002) and 26% of pTa-stage tumors (P = 0.02) showed high level of FGFR3 expression. Moreover, FGFR3 was significantly highly expressed in 34% of non-muscle-invasive tumors (P = 0.007), 34% of tumors with papillary growth pattern (P = 0.017), and lower-stage tumors (P = 0.00). In conclusion, high expression of FGFR3 in urothelial carcinomas with statistically significant relationships regarding its expression levels with parameters of favorable prognosis like low grade and pTa stage, presence of papillary architecture, and lower-stage urothelial carcinomas raised the probability that FGFR3 expression may have a role in early development of urothelial neoplasia. Further studies are required to investigate the applicability of FGFR3-targeted agents as an additional treatment regimen in patients with FGFR3 overexpression.

Al-Ahmadie HA, Iyer G, Janakiraman M et al (2011) Somatic mutation of fibroblast growth factor receptor-3 (FGFR3) defines a distinct morphological subtype of high-grade urothelial carcinoma. J Pathol 224:270–279CrossRefPubMedPubMedCentral

Bodoor K, Ghabkari A, Jaradat Z, Alkhateeb A, Jaradat S, Al-Ghazo MA, Matalka I, Musleh H, Haddad Y (2010) FGFR3 mutational status and protein expression in patients with bladder cancer in a Jordanian population. Cancer Epidemiol 34:724–732CrossRefPubMed

Burger M, van der Aa MNM, van Oers JMM, Brinkmann A, van der Kwas TH, Steyerberg EC, Stoehr R, Kirkels WJ, Stefan Denzinger S, Wild PJ, Wieland WF, Hofstaedter F, Hartmann A, Zwarthoff EC (2008) Prediction of progression of non–muscle-invasive bladder cancer by WHO 1973 and 2004 grading and by FGFR3 mutation status: a prospective study. Eur Urol 54:835–844CrossRefPubMed

Cheng L, Zhang S, MacLennan GT, Williamson SR, Lopez-Beltran A, Montironi R (2011) Bladder cancer: translating molecular genetic insights into clinical practice. Hum Pathol 42:455–481CrossRefPubMed

Edwards J, Duncan P, Going JJ, Watters AD, Grigor KM, Bartlett JM (2002) Identification of loci associated with putative recurrence genes in transitional cell carcinoma of the urinary bladder. J Pathol 196:380–385CrossRefPubMed

Epstein JI, Eble JN, Sesterhenn IA, Sauter G (2004) Tumors of the urinary system. In: Epstein JI, Eble JN, Sesterhenn I, Sauter G (eds) World Health Organization classification of tumors pathology and genetics: tumors of the urinary system and male genital organs. IARC Press, Lyon, pp 89–157

Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) GLOBOCAN 2008, cancer incidence and mortality worldwide: IARC Cancer Base No. 10 [Internet]. International Agency for Research on Cancer, Lyon Available from: http://globocan.iarc.fr. Accessed October 8, 2016

Helpap B, Kollermann J (2000) Assessment of basal cell status and proliferative patterns in flat and papillary urothelial lesions: a contribution to the new WHO classification of the urothelial tumors of the urinary bladder. Hum Pathol 31:745–750CrossRefPubMed

Hirao S, Hirao T, Marsit CJ, Hirao Y, Schned A, Devi-Ashok T et al (2005) Loss of heterozygosity on chromosome 9q and p53 alterations in human bladder cancer. Cancer 104:1918–1923CrossRefPubMed

Kaufman DS, Shipley WU, Feldman AS (2009) Bladder cancer. Lancet 374:239–249CrossRefPubMed

Khaled H (2005) Systematic management of bladder cancer in Egypt: revisited. J Egypt Natl Canc Inst 17:127–131PubMed

Kimura T, Suzuki H, Ohashi T, Asano K, Kiyota H, Eto Y (2001) The incidence of thanatophoric dysplasia mutations in FGFR3 gene is higher in low-grade or superficial bladder carcinomas. Cancer 92:2555–2561CrossRefPubMed

Knowles MA (2008) Novel therapeutic targets in bladder cancer: mutation and expression of FGF receptors. Future Oncol 4:71–83. doi:10.2217/14796694.4.1.71 CrossRefPubMed

Kompier LC, Lurkin I, der Aa MNM, van Rhijn BWG, van der Kwast TH, Zwarthoff EC (2010) FGFR3, HRAS, KRAS, NRAS and PIK3CA mutations in bladder cancer and their potential as biomarkers for surveillance and therapy. PLoS One 5(11):e13821CrossRefPubMedPubMedCentral

L’Hote CG, Knowles MA (2005) Cell responses to FGFR3 signaling: growth, differentiation and apoptosis. Exp Cell Res 304:417–431CrossRefPubMed

Lamont FR, Tomlinson DC, Cooper PA et al (2011) Small molecule FGF receptor inhibitors block FGFR-dependent urothelial carcinoma growth in vitro and in vivo. Br J Cancer 104:75–82CrossRefPubMed

Martinez-Torrecuadrada J, Cifuentes G, Lopez-Serra P et al (2005) Targeting the extra cellular domain of fibroblast growth factor receptor 3 with human single-chain Fv antibodies inhibits bladder carcinoma cell line proliferation. Clin Cancer Res 11:6280–6290CrossRefPubMed

Matsumoto M, Ohtsuki Y, Ochii K, Seike Y, Iseda N, Sasaki T et al (2004) Fibroblast growth factor receptor 3 protein expression in urothelial carcinoma of the urinary bladder, exhibiting no association with low-grade and/or non-invasive lesions. Oncol Rep 12:967–971PubMed

Mhawech-Fauceglia P, Cheney RT, Fischer G, Beck A, Herrmann FR (2006) FGFR3 and p53 protein expressions in patients with pTa and pT1 urothelial bladder cancer. EJSO 32:231–237CrossRefPubMed

Miyake M, Sugano K, Sugino H, Imai K, Matsumoto E, Maeda K, Fukuzono S, Ichikawa H, Kawashima K, Hirabayashi K, Kodama T, Fujimoto H, Kakizoe T, Kanai Y, Fujimoto K, Hirao Y (2010) 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. Cancer Sci 101:250–258CrossRefPubMed

Moch H, Humphrey PA, Ulbright TM, Reuter VE (2016) The 2016 WHO classification of tumors of the urinary system and male genital organs. International Agency for Research on Cancer (IARC), Lyon, pp 77–133

Ouerhani S, Rouissi K, Kourda N et al (2009) Combined analysis of smoking, TP53, and FGFR3 mutations in Tunisian patients with invasive and superficial high-grade bladder tumors. Cancer Investig 27:998–1007CrossRef

Pich A, Chiusa L, Formiconi A, Galliano D, Bortolin P, Avone R (2001) Biologic differences between noninvasive papillary urothelial neoplasms of low malignant potential and low-grade (grade 1) papillary carcinomas of the bladder. Am J Surg Pathol 25:1528–1533CrossRefPubMed

Ploeg M, Aben KK, Kiemeney LA (2009) The present and future burden of urinary bladder cancer in the world. World J Urol 27:289CrossRefPubMedPubMedCentral

Qing J, Du X, Chen Y et al (2009) Antibody-based targeting of FGFR3 in bladder carcinoma and t(4:14) positive multiple myeloma in mice. J Clin Invest 119:1216–1229CrossRefPubMedPubMedCentral

Ramos D, Navarro S, Villamon R, Gil-Salom M, Llombart-Bosch A (2003) Cytokeratin expression patterns in low-grade papillary urothelial neoplasms of the urinary bladder. Cancer 97:1876–1883CrossRefPubMed

Rebouissou S, Herault A, Letouze E et al (2012) CDKN2A homozygous deletion is associated with muscle invasion in FGFR3-mutated urothelial bladder carcinoma. J Pathol 227:315–324CrossRefPubMed

Sibley K, Cuthbert-Heavens D, Knowles MA (2001) Loss of heterozygosity at 4p16.3 and mutation of FGFR3 in transitional cell carcinoma. Oncogene 20:686–691CrossRefPubMed

Sjodahl G, Lauss M, Gudjonsson S et al (2011) A systematic study of gene mutations in urothelial carcinoma; inactivating mutations in TSC2 and PIK3R1. PLoS One 6:e18583CrossRefPubMedPubMedCentral

Sung J, MuSun J, Jeong BC, Seo SI, Jeon SS, Lee HM, Choi HY, Kangd SY, Choi YL, Kwon GY (2014) FGFR3 over expression is prognostic of adverse outcome for muscle-invasive bladder carcinoma treated with adjuvant chemotherapy. Urol Oncol 32:49.e23–49.e31CrossRef

Theelen WSME, Mittempergher L, Willems SM, Bosma AJ, Peters DGC, van der Noort V, Japenga EJ, Peeters T, Koole K, Šuštić T, Blaauwgeer JL, van Noesel CJ, Bernards R, van den Heuvel M (2016) FGFR1, 2 and 3 protein overexpression and molecular aberrations of FGFR3 in early stage non-small cell lung cancer. J Pathol 2(4):223–233

Tomlinson DC, Baldo O, Harnden P et al (2007) FGFR3 protein expression and its relationship to mutation status and prognostic variables in bladder cancer. J Pathol 213:91–98CrossRefPubMedPubMedCentral

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65:87CrossRefPubMed

Van Oers JM, Adam C, Denzinger S, Stoehr R, Bertz S, Zaak D et al (2006) Chromosome 9 deletions are more frequent than FGFR3 mutations in flat urothelial hyperplasias of the bladder. Int J Cancer 119:1212–1215CrossRefPubMed

Van Oers JMM, Wild PJ, Burger M, Denzinger S, Robert Stoehr R, Rosskopf E, Hofstaedter F, Steyerberg EW, Klinkhammer-Schalke M, Zwarthoff EC, van der Kwast TH, Hartmann A (2007) FGFR3 mutations and a normal CK20 staining pattern define low-grade noninvasive urothelial bladder tumours. Eur Urol 52:760–768CrossRefPubMed

Van Oers JM, Zwarthoff EC, Rehman I et al (2009) FGFR3 mutations indicate better survival in invasive upper urinary tract and bladder tumours. Eur Urol 55:650–657CrossRefPubMed

Van Rhijn BW, Vis AN, Zuiverloon TC, Radvanyi F, van Leenders GJ, Ooms BC, Kirkels WJ, Lockwood GA, Boevé ER, Jöbsis AC, Zwarthoff EC, van der Kwast TH (2003) Molecular grading of urothelial cell carcinoma with fibroblast growth factor receptor 3 and MIB-1 is superior to pathologic grade for the prediction of clinical outcome. J Clin Oncol 21:1912–1921CrossRefPubMed

Van Tilborg AA, de Vries A, de Bont M, Groenfeld LE, van der Kwast TH, Zwarthoff EC (2000) Molecular evolution of multiple recurrent cancers of the bladder. Hum Mol Genet 9:2973–2980CrossRefPubMed

Van Tilborg AA, de Vries A, de Bont M, Groenfeld LE, Zwarthoff EC (2002) The random development of LOH on chromosome 9q in superficial bladder cancers. J Pathol 198:352–358CrossRefPubMed

Title: FGFR3, a marker suggestive of favorable prognosis in urothelial carcinoma
Authors: Sara E. Khalifa
Rasha A. Khairy
Rasha Ramadan
Publication date: 01-09-2017
Publisher: Springer London
Published in: Comparative Clinical Pathology / Issue 5/2017
Print ISSN: 1618-5641
Electronic ISSN: 1618-565X
DOI: https://doi.org/10.1007/s00580-017-2510-7

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

FGFR3, a marker suggestive of favorable prognosis in urothelial carcinoma

Abstract

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 5/2017

Association between oestrogen receptor β immunoexpression and cause of culling, ovarian appearance and the existence of PRRS virus in the porcine ovary

Inhibitory effects of lactic acid bacteria isolated from traditional fermented foods against aflatoxigenic Aspergillus spp.

Modulation of immunity and inflammatory gene expression in buffalo (Bubalus bubalis) with some digestive disorders

Hematological profiles of giant anteaters from different biomes

Hematological and serum biochemical alterations in buffalo with some digestive disorders

The central effect of 3-iodothyronamine on brain neuropeptides in mice