This Article Abstract Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bakkar, A. A. Articles by Gil Diez de Medina, S. Search for Related Content PubMed PubMed Citation Articles by Bakkar, A. A. Articles by Gil Diez de Medina, S.

FGFR3 and TP53 Gene Mutations Define Two Distinct Pathways in Urothelial Cell Carcinoma of the Bladder

¹ Equipe mixte Inserm Institut National de la Santé et de la Recherche Médicale, and Service d’Urologie;
² Département de Biochimie et Génétique, Université Paris XII, Assistance Publique Hôpitaux de Paris, Hôpital Henri Mondor; and
³ Unité mixte de Recherche, Centre National de la Recherche Scientifique, Institut Curie, Paris, France

	ABSTRACT

Top ABSTRACT Introduction Materials and Methods Results Discussion REFERENCES

 
FGFR3 and TP53 mutations are frequent in superficial papillary and invasive disease, respectively. We used denaturing high-performance liquid chromatography and sequencing to screen for FGFR3 and TP53 mutations in 81 newly diagnosed urothelial cell carcinomas. Tumors were classified as follows: 31 pTa, 1 carcinoma in situ, 30 pT1, and 19 pT2-T4. Tumor grades were as follows: 10 G1, 29 G2, and 42 G3. FGFR3 mutations were associated with low-stage (P < 0.0001), low-grade (P < 0.008) tumors, whereas TP53 mutations were associated with high-stage (P < 0.003), high-grade (P < 0.02) tumors. Mutations in these two genes were almost mutually exclusive. Our results suggest that FGFR3 and TP53 mutations define separate pathways at initial diagnosis of urothelial cell carcinoma.

	Introduction

Top ABSTRACT Introduction Materials and Methods Results Discussion REFERENCES

 
UCC⁴ of the bladder is a spectrum disease characterized by unpredictability in its biological behavior and response to treatment. UCCs are classified into two broad types: superficial and invasive tumors. Most UCCs present as superficial bladder cancer, confined in 75% of cases to the epithelium (CIS, pTa) or lamina propria (pT1). The remaining (25%) tumors present as muscle invasive disease (pT2), with no history of superficial disease (1) . However, superficial bladder cancer covers many lesions with different biological potentials, and morphologically similar tumors of the same stage may display completely different patterns of behavior (1) . It has been suggested that different genetic changes account for these different forms of UCC and for the observed differences in biological behavior (2) . Losses of chromosome 9 have been described as the most common finding in superficial papillary tumors, but such losses are in fact observed at all stages and grades. Alterations of chromosome 9q occur very early in the disease and seem to be involved in the development of bladder cancer. Regions of interest (at 9p21, 9q12–31, 9q32–33, and 9q34) harboring candidate tumor suppressor genes have been identified on both arms of chromosome 9 (reviewed in Ref. 2 ). However, the prognostic significance of these findings remains unclear. TP53 mutations are frequent in bladder tumors of high stage and grade, and have been associated with invasiveness (3) . It has also been shown that loss of heterozygosity on chromosome 17p, to which TP53 maps, is more frequent in high-grade than in low-grade tumors. The p53 protein functions as a transcription factor, regulating the expression of several downstream genes. Two major functions of p53 are cell cycle arrest and apoptosis (reviewed in Ref. 4 ).

Spruck et al. (5) suggested that UCCs progress via two molecular pathways, with TP53 mutations and loss of heterozygosity on chromosome 17 more frequent in CIS and invasive tumors. In contrast, selective deletions of chromosome 9 are more common in superficial papillary tumors. It was suggested that CIS is the most likely precursor of invasive tumors (5) . However, the role and the position of FGFR3 mutations in current models of bladder carcinogenesis still need to be clarified. FGFR3 receptors belong to a family of highly conserved, structurally related genes, which is classified into four subtypes (FGFR1, 2, 3, and 4) that bind fibroblast growth factors with different affinity (6) . These tyrosine kinase receptors regulate several cellular processes including cell growth, differentiation, migration, wound healing, and angiogenesis, and this depends on the target cell type and the developmental stage (7 , 8) . FGFR3 is located at 4P16.3 and comprises 19 exons spanning 16.5 Kb (9) . FGFR3 activating mutations identified in thanatophoric dysphasia were also found in cervix and bladder cancer (10) . Currently, it is believed that these mutations result in constitutive activation of the receptor (11) . An oncogenic role has been attributed to these mutations in bladder neoplasms, whereas they have an inhibitory role in skeletal diseases (10 , 12) . The coding sequence of FGFR3 spanning exons 2–19 was investigated previously, and somatic mutations in bladder tumors were localized in exons 7, 10, and 15 (10 , 13) . FGFR3 somatic mutations were shown to be the most frequent gene mutation in low-stage bladder tumors, which underlie their importance in bladder cancer (10 , 13) The high frequency of FGFR3 and TP53 mutations in superficial papillary and invasive bladder cancers, respectively, led us to compare these two genetic alteration in 81 bladder cancer tumors of all stages and grades at initial diagnosis, to determine whether they correspond to different disease pathways and could be used for molecular classification of these tumors. In this study, we screened for FGFR3 (exons 7, 10, and 15) and TP53 (exons 2–11) mutations by DHPLC analysis and sequencing in consecutive primary tumors. We found that mutations in FGFR3 and TP53 were almost mutually exclusive, and defined several groups of tumors consistent with the TNM classification in terms of tumor aggressiveness: (a) superficial papillary UCCs with FGFR3 mutations and no TP53 mutations; (b) superficial papillary UCCs with no mutation in either gene; (c) superficial papillary UCCs with TP53 mutations but no FGFR3 mutations; and (d) invasive UCCs with and without TP53 mutations. This observation provides a framework for the molecular classification of bladder cancer.

	Materials and Methods

Top ABSTRACT Introduction Materials and Methods Results Discussion REFERENCES

 
Characteristics of the Patients and Tissue Samples.
All 81 patients of the cohort studied here had newly diagnosed bladder tumors and were admitted for transurethral resection or radical cystectomy. None of the patients had received treatment before the analysis. Median age at time of diagnosis was 64 years (range, 38–86).

We collected matched tumors and blood samples after the patients had given written informed consent. Tumors were graded according to the WHO classification (14) and staged according to the 1997 TNM classification guidelines (15) as follows: 31 pTa, 1 CIS, 30 pT1, and 19 pT2 to pT4 (muscle invasive lesions). Ten of the tumors were classified as G1, 29 as G2, and 42 as G3.

DNA Extraction.
Tumors were snap-frozen in liquid nitrogen and stored at -80°C. Venous blood, used as a source of reference DNA, was collected in EDTA-containing tubes and stored at -20°C until used for DNA extraction. DNA and RNA were extracted simultaneously with the cesium chloride cushion method, as described previously (16) . DNA was extracted from blood with the QIAamp system (Qiagen S.A. France).

PCR.
For TP53, we screened for mutations in exons 2–11 by DHPLC. PCR was performed in a final volume of 50 µl containing 100 ng genomic DNA, 1 x amplification buffer, 1.5 mM MgCl₂, 200 µM of each dNTP, 0.15 µM forward primer, 0.15 µM reverse primer, and 2.5 units of TaqDNA polymerase (HotStarTaq; Qiagen S.A. France).

PCR was carried out as follows: an initial denaturation step (95°C for 15 min) was followed by 40 cycles consisting of denaturation at 94°C for 30 s, primer annealing at 58°C (exons 2 to 11) or 59°C (exon 8) for 30 s, and extension at 72°C for 30 s. The mixture was then heated at 72°C for 10 min as a final extension step. The primers used for TP53 amplification are shown in Table 1 .

DHPLC.
We carried out DHPLC analysis with the Varian (Prostar) Helix system, using the helix analysis column (the helix DNA^R column set). The formation of heteroduplexes and homoduplexes was encouraged by first denaturing PCR products by heating at 95°C for 10 min and then allowing them to reanneal at 62°C (FGFR3) and 58°C (TP53) for 1 h. We applied a 5-µl DNA sample to the column and eluted within a linear acetonitrile gradient as the eluent. The acetonitrile gradient was created by mixing buffer A [100 mM triethylammonium acetate (pH 7.0) and 0.1 mM EDTA] and buffer B [100 mM triethylammonium acetate (pH 7.0), 0.1 mM EDTA, and 25% (v/v) acetonitrile]. The flow rate was 0.45 ml/min, and we increased the proportion of buffer B by 3.3% per min for 4.5–5.5 min. The optimal melting temperature for each amplicon was first roughly determined by the analysis of wild-type sequence using an annealing algorithm at the Stanford DHPLC website (17) .⁵ The melting behavior of the specific DNA was established by repeatedly injecting the sample at temperature steps beginning at 50°C until complete denaturation is reached. A melting curve, retention time versus temperature, is made, and the temperature at which 25–50% denaturation was observed was selected (retention time is 0.75–1 min shorter than that under nondenaturing conditions), using the universal gradient (Varian). The acetonitrile gradient was then adjusted such that the peaks were eluted between 3 and 6.30 min. Whenever possible, mutation detection was checked by analyzing a sample known to harbor a specific sequence variation. DNA fragments were monitored by UV absorbency at 260 nm. Specific values for the gradient ranges and mobile-phase temperatures used are shown in Table 1 .

DNA Sequencing.
PCR products with elution profiles different from that of the corresponding wild-type DNA were sequenced. Sequencing was performed with the Big Dye Terminator kit, following the Applied Biosystems protocol. Samples were sequenced in an ABIPRISM 377 sequencer (Perkin-Elmer Applied Biosystems). If a mutation was identified, matched constitutional DNA samples were also sequenced to confirm the somatic nature of the mutation. Results were confirmed by sequencing on both strands.

Statistical Analysis.
The data are expressed as percentages. We carried out ² analysis, using contingency tables and InStat 2.01 software. We used Fisher’s exact test (two-sided) when appropriate. Values of P 0.05 were considered significant.

	Results

Top ABSTRACT Introduction Materials and Methods Results Discussion REFERENCES

 
The various FGFR3 mutations identified are listed in Table 2 . Overall, these mutations were found in 40% (32 of 81) of the tumors. Six different mutations were detected, five of which (R248C, S249C, G372C, Y375C, and K652E) are identical to those found in thanatophoric dysplasia. The sixth mutation, K652M, has been reported in cases of severe achondroplasia with developmental delay and acanthosis nigricans.

FGFR3 and TP53 mutations identified as a function of stage and grade are shown in Fig. 1, A and B, respectively. These data clearly show opposite patterns for FGFR3 and TP53 mutations, in terms of distribution according to stage and grade, and a significant linear trend was observed for the distribution of mutations according to stage and grade for both genes (Fig. 1, A and B) .

View larger version (22K): [in this window] [in a new window]   Fig. 1. A, FGFR3 and TP53 mutations according to stage. The P was calculated by a 2 test. P < 0.05 was considered significant. FGFR3 mutations were detected in 71% pTa, in 30% pT1, and 5% pT2-pT4 tumors. FGFR3 mutations are associated with low stage (P < 0.0001). TP53 mutations were identified in 6% pTa, in 27% pT1, and in 47% pT2-pT4 tumors. TP53 mutations are associated with high stage (P < 0.003). No mutations in TP53 or FGFR3 were found in the 1 CIS studied here. B, FGFR3 and TP53 mutations according to grade. The P was calculated by 2 test. P < 0.05 was considered significant. FGFR3 mutations were found in 70% G1, 52% G2, and 24% G3 tumors. FGFR3 mutations are associated with low grade (P < 0.008). TP53 mutations were not found in the G1 tumors, and were identified in 14% G2 tumors and in 36% G3 tumors. TP53 mutations are associated with high grade (P < 0.02). C, tumor genotypes according to mutations in both FGFR3 and TP53 at various stages. P was calculated using a two-sided Fisher’s exact test. The frequency of the tumor group containing both mutations (FGFR3mut/TP53mut) at various stages was not significant (P < 0.9).

In pTa tumors, FGFR3 mut/TP53wt was the most prevalent genotype, accounting for 68% of tumors (21 of 31). The next most prevalent genotype was FGFR3wt/TP53wt, found in 9 of 31 tumors (29%). No FGFR3wt/TP53mut genotype was found. The FGFR3mut/TP53mut genotype was found in only 1 of 31 tumors (3%), a pTaG2 tumor (Fig. 1C) .

In pT1 tumors, FGFR3wt/TP53wt was the most frequent genotype, found in 15 of 30 tumors (50%), followed by FGFR3mut/TP53wt, which was found in 8 of 30 tumors (27%), and FGFR3wt/TP53mut, which was found in 6 of 30 tumors (20%). The FGFR3mut/TP53mut genotype was found in only 1 tumor (3%), a (pT1G3; Fig. 1C ).

In pT2-pT4 tumors, the FGFR3wt/TP53wt genotype accounted for 10 of 19 (53%) cases. The next most frequent genotype was FGFR33wt/TP53mut, which was observed in 8 of 19 (42%) tumors. The FGFR3mut/TP53wt genotype was not found. A single FGFR3mut/TP53mut tumor (pT3G3; 5%) was identified (Fig. 1C) .

	Discussion

Top ABSTRACT Introduction Materials and Methods Results Discussion REFERENCES

 
Elucidation of the molecular pathways involved in UCC is essential for our understanding of the etiopathogenesis of the disease, and, hence, for more precise diagnosis, accurate prognosis and better management of patients. To our knowledge, this is the first study investigating mutations in both FGFR3 and TP53 in bladder cancer. This analysis of genotypes in newly diagnosed bladder cancer patients, who had not received treatment previously, provides insight into the molecular basis of bladder cancer. Our results clearly show that FGFR3 and TP53 mutations are almost mutually exclusive at initial diagnosis (Fig. 1C) and more likely define separate pathways in the development of this disease.

Spruck et al. (5) observed that alterations of chromosome 9 were more frequent in superficial papillary tumors, whereas TP53 mutations were more frequent in CIS and invasive tumors. It was suggested that these genetic differences might account for the markedly different clinical behavior and prognosis of superficial papillary noninvasive tumors and CIS. Indeed, they highlighted that UCCs progress via two distinct pathways. Our data concerning the frequency of FGFR3 mutations provide additional evidence that FGFR3 mutations are associated with low-stage, low-grade superficial papillary tumors, as reported previously in retrospective studies (18) . It should also be noted that, in the same study, we found no FGFR3 mutations in the 20 CIS studied (18) . Studies on the prognostic value of FGFR3 mutations have generated promising results, indicating that these mutations are associated with favorable disease characteristics, lower rates of recurrence, and progression (19) . These mutations may correspond to the so-called "primary abnormalities" (20) involved in the production of low-grade/well-differentiated neoplasms. Such abnormalities alter cellular proliferation, but have little effect on cellular differentiation. FGFR3 mutations might give a growth advantage for cancer cells, but, on the other hand, cell cycle and/or apoptosis mechanisms or genomic stability may still be maintained. Most of the FGFR3 mutations we identified were in tumors that did not harbor TP53 mutations (Fig. 1C) . Therefore, genomic stability may have been maintained, because it has been suggested that TP53 mutations destabilize the genome (21) . Our results on TP53 mutations, which were most frequent in high-stage, high-grade tumors, are consistent with those of previous investigators (3 , 5) .

We analyzed the mutations in the two genes in individual tumors and found that FGFR3mut/TP53wt was the most prevalent genotype in pTa (68%) tumors. Thus, FGFR3 mutations are probably key genetic alterations in these lesions and may occur early in their development. FGFR3 mutations occur with high frequency (75%) in urothelial papilloma (22) , and it is still to be determined whether some pTa tumors might have been evolved from these lesions. In pT1 tumors, this genotype accounts for 27% of cases and was not observed in muscle invasive cancer. The presence of this genotype in both pTa and pT1 tumors indicates that a subgroup of pT1 is, from a molecular point of view, related to pTa. However, the clearly higher frequency of this genotype in pTa than in pT1 tumors (P < 0.01) and the presence of other genotypes in pT1 tumors that are not found in pTa tumors (FGFR3wt/TP53mut; 20%) are consistent with previous data suggesting that these two lesions harbor different genetic changes (23) and that their grouping together as superficial bladder cancer is imprecise and misleading.

The FGFR3wt/TP53wt genotype accounted for a considerable proportion of tumors, and was found in 29% of pTa, 50% of pT1, and 53% of pT2 tumors. The search for key genetic and/or epigenetic alterations should focus on these lesions, as other pathways may also be at work. Other alterations described in bladder cancer should perhaps also be studied in light of FGFR3 and TP53 mutations.

The FGFR3wt/TP53mut genotype was not observed in pTa tumors, but was found in 20% of pT1 and 42% of pT2 tumors. The increasing frequency of this genotype from pT1 to pT2-pT4 suggests that this genotype may be associated with more chromosomal alterations. This possibility is consistent with data showing a higher level of allelic imbalances in pT2-pT4 than in pT1 tumors and that tumors in which both TP53 alleles are inactivated have many imbalances (24) . Because TP53 is involved in checkpoint control after DNA damage, changes in this gatekeeper gene may lead to the accumulation of additional genetic changes (25) .

Our data suggest that pT1 tumors may be seen as an intermediate group, resembling both pTa and pT2-pT4 tumors, as they included the three main genotypes: FGFR3mut/TP53wt (27%), FGFR3wt/TP53wt (50%), and FGFR3wt/TP53mut (20%). These findings reaffirm the heterogeneity of this group of tumors. Given the clear variability in the biological potential of these lesions, grouping them according to common molecular changes may improve predictions of prognosis. Tumors with TP53 mutations may not be grouped with those harboring FGFR3 mutations.

The FGFR3mut /Tp53mut genotype was found in only a few tumors: a pTaG2(3%), a pT1G3 (3%), and a pT2G3 (5%) tumor. Mutations in both genes may result from different oncogenic mechanisms occurring in the same tumor, which is not the general rule, at least with respect to these two gene mutations. It is possible that these mutations define distinctive, separate pathways that are occasionally interrelated. The identification of this genotype in pTa, pT1, and pT3 tumors suggests that there is an intricate interplay between the effects of the two mutations, according to the surrounding molecular microenvironment, which would finally determine tumor phenotype.

The data presented herein suggest that mutations in the FGFR3 and TP53 genes at initial diagnosis probably define separate molecular pathways in UCCs, possibly leading to two different major clinical phenotypes. Moreover, molecular classification according to FGFR3 and TP53 mutational status might parallel that of TNM and grading classification, constituting an initial step toward a simple practical molecular classification of tumors facilitating the identification of patients with low and high risks of progression. FGFR3 mutations might prove to be a powerful diagnostic tool and an important therapeutic target in UCC. Furthermore, tumor classification according to both gene mutations might serve as landmarks for future searches for other genetic or epigenetic alterations in bladder cancer.

	ACKNOWLEDGMENTS

 
We thank Dr. Brigitte Bressac-de Paillerets (Institute Gustav Roussy) for kindly providing us with TP53 primers and useful discussions on DHPLC conditions.

	FOOTNOTES

 
Grant support: This research was funded by: INSERM, Université Paris 12-BQR, Association de la recherche contre le Cancer (ARC), Délégation à la recherche Clinique, Assistance Publique Hôpitaux de Paris (AP-HP; PHRC AOA 94015), L’association Claude Bernard, le ministère du Travail, UMR 144-Laboratoire Associé, Ligue Nationale Contre Le Cancer, Comité de Paris.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Requests for reprints: Dominique K. Chopin, EMI Institut National de la Santé et de la Recherche Médicale, 03–37, Faculté de Médecine, Centre de Recherches Chirurgicales, 8 rue du Général Sarrail, 94000, Créteil, Cedex, France. Phone: 33-1-498-13551; Fax: 33-1-498-13552; E-mail: chopin{at}univ-paris12.fr

⁴ The abbreviations used are: UCC, urothelial cell carcinoma; CIS, carcinoma in situ; FGFR3, fibroblast growth factor receptor 3; DHPLC, denaturing high-performance liquid chromatography; TNM, Tumor-Node-Metastasis; mut, mutated; wt, wild type.

⁵ Internet address: http://insertion.stanford.edu/melt.html.

Received 7/18/03. Revised 9/18/03. Accepted 10/16/03.

	REFERENCES

Top ABSTRACT Introduction Materials and Methods Results Discussion REFERENCES

 

1. Lee R., Droller M. J. The natural history of bladder cancer. Implications for therapy. Urol. Clin. N. Am., 27: 1-13, vii. 2000.[Medline]
2. Knowles M. A. The genetics of transitional cell carcinoma: progress and potential clinical application. BJU Int., 84: 412-427, 1999.[Medline]
3. Fujimoto K., Yamada Y., Okajima E., Kakizoe T., Sasaki H., Sugimura T., Terada M. Frequent association of p53 gene mutation in invasive bladder cancer. Cancer Res., 52: 1393-1398, 1992.[Abstract/Free Full Text]
4. Olumi A. F. A critical analysis of the use of p53 as a marker for management of bladder cancer. Urol. Clin. N. Am., 27: 75-82, ix 2000.[Medline]
5. Spruck C. H., 3rd, Ohneseit P. F., Gonzalez-Zulueta M., Esrig D., Miyao N., Tsai Y. C., Lerner S. P., Schmutte C., Yang A. S., Cote R., Dubeau L., Nicolas P. W., Hermann G. G., Steven K., Horn T., Skinner D. G., Jones P. Two molecular pathways to transitional cell carcinoma of the bladder. Cancer Res., 54: 784-788, 1994.[Abstract/Free Full Text]
6. Johnson D. E., Williams L. T. Structural and functional diversity in the FGF receptor multigene family. Adv. Cancer Res., 60: 1-41, 1993.[Medline]
7. Basilico C., Moscatelli D. The FGF family of growth factors and oncogenes. Adv. Cancer Res., 59: 115-165, 1992.[Medline]
8. Mason I. J. The ins and outs of fibroblast growth factors. Cell, 78: 547-552, 1994.[Medline]
9. Perez-Castro A. V., Wilson J., Altherr M. R. Genomic organization of the human fibroblast growth factor receptor 3 (FGFR3) gene and comparative sequence analysis with the mouse Fgfr3 gene. Genomics, 41: 10-16, 1997.[Medline]
10. Cappellen D., De Oliveira C., Ricol D., de Medina S., Bourdin J., Sastre-Garau X., Chopin D., Thiery J. P., Radvanyi F. Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Nat. Genet., 23: 18-20, 1999.[Medline]
11. Webster M. K., Donoghue D. J. Enhanced signaling and morphological transformation by a membrane- localized derivative of the fibroblast growth factor receptor 3 kinase domain. Mol. Cell. Biol., 17: 5739-5747, 1997.[Abstract]
12. Li C., Chen L., Iwata T., Kitagawa M., Fu X. Y., Deng C. X. A Lys644Glu substitution in fibroblast growth factor receptor 3 (FGFR3) causes dwarfism in mice by activation of STATs and ink4 cell cycle inhibitors. Hum. Mol. Genet., 8: 35-44, 1999.[Abstract/Free Full Text]
13. Sibley K., Cuthbert-Heavens D., Knowles M. A. Loss of heterozygosity at 4p16.3 and mutation of FGFR3 in transitional cell carcinoma. Oncogene, 20: 686-691, 2001.[Medline]
14. Mostofi F. K. Sobin L. H. Torloni H. eds. . International Histological Classification of Tumors, No 10: Histological Typing of Urinary Bladder Tumors, WHO Geneva 1973.
15. Sobin L. H., Fleming I. D. TNM Classification of Malignant Tumors, Ed. 5 (1997). Union Internationale Contre le Cancer and the American Joint Committee on Cancer. Cancer (Phila.), 80: 1803-1804, 1997.
16. Cappellen D., Gil Diez de Medina S., Chopin D., Thiery J. P., Radvanyi F. Frequent loss of heterozygosity on chromosome 10q in muscle-invasive transitional cell carcinomas of the bladder. Oncogene, 14: 3059-3066, 1997.[Medline]
17. Jones A. C., Austin J., Hansen N., Hoogendoorn B., Oefner P. J., Cheadle J. P., O’Donovan M. C. Optimal temperature selection for mutation detection by Denaturing HPLC and comparison to single-stranded conformation polymorphism and heteroduplex analysis. Clin. Chem., 45: 1133-1140, 1999.[Abstract/Free Full Text]
18. Billerey C., Chopin D., Aubriot-Lorton M. H., Ricol D., Gil Diez de Medina S., Van Rhijn B., Bralet M. P., Lefrere-Belda M. A., Lahaye J. B., Abbou C. C., Bonaventure J., Zafrani E. S., van der Kwast T., Thiery J. P., Radvanyi F. Frequent FGFR3 mutations in papillary non-invasive bladder (pTa) tumors. Am. J. Pathol., 158: 1955-1959, 2001.[Abstract/Free Full Text]
19. van Rhijn B. W., Lurkin I., Radvanyi F., Kirkels W. J., van der Kwast T. H., Zwarthoff E. C. The fibroblast growth factor receptor 3 (FGFR3) mutation is a strong indicator of superficial bladder cancer with low recurrence rate. Cancer Res., 61: 1265-1268, 2001.[Abstract/Free Full Text]
20. Cordon-Cardo C., Cote R. J., Sauter G. Genetic and molecular markers of urothelial premalignancy and malignancy. Scand J. Urol. Nephrol., 205(Suppl.): 82-93, 2000.
21. Hainaut P., Hollstein M. p53 and human cancer: the first ten thousand mutations. Adv. Cancer Res., 77: 81-137, 2000.[Medline]
22. Van Rhijn B. W., Montironi R., Zwarthoff E. C., Jobsis A. C., Van Der Kwast T. H. Frequent FGFR3 mutations in urothelial papilloma. J. Pathol., 198: 245-251, 2002.[Medline]
23. Richter J., Jiang F., Gorog J. P., Sartorius G., Egenter C., Gasser T. C., Moch H., Mihatsch M. J., Sauter G. Marked genetic differences between stage pTa and stage pT1 papillary bladder cancer detected by comparative genomic hybridization. Cancer Res., 57: 2860-2864, 1997.[Abstract/Free Full Text]
24. Primdahl H., Wikman F. P., von der Maase H., Zhou X. G., Wolf H., Orntoft T. F. Allelic imbalances in human bladder cancer: genome-wide detection with high-density single-nucleotide polymorphism arrays. J. Natl. Cancer Inst., 94: 216-223, 2002.[Abstract/Free Full Text]
25. Moll U. M., Schramm L. M. p53–an acrobat in tumorigenesis. Crit. Rev. Oral. Biol. Med., 9: 23-37, 1998.[Abstract]

This article has been cited by other articles:

				L. Knoops, R. Haas, S. de Kemp, D. Majoor, A. Broeks, E. Eldering, J. P. de Boer, M. Verheij, C. van Ostrom, A. de Vries, et al. In vivo p53 response and immune reaction underlie highly effective low-dose radiotherapy in follicular lymphoma Blood, August 15, 2007; 110(4): 1116 - 1122. [Abstract] [Full Text] [PDF]

				A. P. Mitra, R. H. Datar, and R. J. Cote Molecular Pathways in Invasive Bladder Cancer: New Insights Into Mechanisms, Progression, and Target Identification J. Clin. Oncol., December 10, 2006; 24(35): 5552 - 5564. [Abstract] [Full Text] [PDF]

				J. A. Landolfi and K. A. Terio Transitional Cell Carcinoma in Fishing Cats (Prionailurus viverrinus): Pathology and Expression of Cyclooxygenase-1, -2, and p53. Vet. Pathol., September 1, 2006; 43(5): 674 - 681. [Abstract] [Full Text] [PDF]

				S. Hernandez, E. Lopez-Knowles, J. Lloreta, M. Kogevinas, A. Amoros, A. Tardon, A. Carrato, C. Serra, N. Malats, and F. X. Real Prospective Study of FGFR3 Mutations As a Prognostic Factor in Nonmuscle Invasive Urothelial Bladder Carcinomas J. Clin. Oncol., August 1, 2006; 24(22): 3664 - 3671. [Abstract] [Full Text] [PDF]

				E. Gormally, P. Vineis, G. Matullo, F. Veglia, E. Caboux, E. Le Roux, M. Peluso, S. Garte, S. Guarrera, A. Munnia, et al. TP53 and KRAS2 Mutations in Plasma DNA of Healthy Subjects and Subsequent Cancer Occurrence: A Prospective Study. Cancer Res., July 1, 2006; 66(13): 6871 - 6876. [Abstract] [Full Text] [PDF]

				I.-J. Kim, H. C. Kang, S.-G. Jang, K. Kim, S.-A Ahn, H.-J. Yoon, S. N. Yoon, and J.-G. Park Oligonucleotide microarray analysis of distinct gene expression patterns in colorectal cancer tissues harboring BRAF and K-ras mutations Carcinogenesis, March 1, 2006; 27(3): 392 - 404. [Abstract] [Full Text] [PDF]

				R.A. Crallan, N.T. Georgopoulos, and J. Southgate Experimental models of human bladder carcinogenesis Carcinogenesis, March 1, 2006; 27(3): 374 - 381. [Abstract] [Full Text] [PDF]

				M. A. Knowles Molecular subtypes of bladder cancer: Jekyll and Hyde or chalk and cheese? Carcinogenesis, March 1, 2006; 27(3): 361 - 373. [Abstract] [Full Text] [PDF]

				K. Zieger, L. Dyrskjot, C. Wiuf, J. L. Jensen, C. L. Andersen, K. M.-E. Jensen, and T. F. Orntoft Role of Activating Fibroblast Growth Factor Receptor 3 Mutations in the Development of Bladder Tumors Clin. Cancer Res., November 1, 2005; 11(21): 7709 - 7719. [Abstract] [Full Text] [PDF]

				V. Loyant, A. Jaffre, J. Breton, I. Baldi, A. Vital, F. Chapon, S. Dutoit, Y. Lecluse, H. Loiseau, P. Lebailly, et al. Screening of TP53 mutations by DHPLC and sequencing in brain tumours from patients with an occupational exposure to pesticides or organic solvents Mutagenesis, September 1, 2005; 20(5): 365 - 373. [Abstract] [Full Text] [PDF]

				S. Hernandez, E. Lopez-Knowles, J. Lloreta, M. Kogevinas, R. Jaramillo, A. Amoros, A. Tardon, R. Garcia-Closas, C. Serra, A. Carrato, et al. FGFR3 and Tp53 Mutations in T1G3 Transitional Bladder Carcinomas: Independent Distribution and Lack of Association with Prognosis Clin. Cancer Res., August 1, 2005; 11(15): 5444 - 5450. [Abstract] [Full Text] [PDF]

				H. Wallerand, A. A. Bakkar, S. G. D. de Medina, J.-C. Pairon, Y.-C. Yang, D. Vordos, H. Bittard, S. Fauconnet, J.-C. Kouyoumdjian, M.-C. Jaurand, et al. Mutations in TP53, but not FGFR3, in urothelial cell carcinoma of the bladder are influenced by smoking: contribution of exogenous versus endogenous carcinogens Carcinogenesis, January 1, 2005; 26(1): 177 - 184. [Abstract] [Full Text] [PDF]

				B. W. G. van Rhijn, T. H. van der Kwast, A. N. Vis, W. J. Kirkels, E. R. Boeve, A. C. Jobsis, and E. C. Zwarthoff FGFR3 and P53 Characterize Alternative Genetic Pathways in the Pathogenesis of Urothelial Cell Carcinoma Cancer Res., March 15, 2004; 64(6): 1911 - 1914. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bakkar, A. A. Articles by Gil Diez de Medina, S. Search for Related Content PubMed PubMed Citation Articles by Bakkar, A. A. Articles by Gil Diez de Medina, S.