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Prospective Study of FGFR3 Mutations As a Prognostic Factor in Nonmuscle Invasive Urothelial Bladder Carcinomas

Silvia Hernández, Elena López-Knowles, Josep Lloreta, Manolis Kogevinas, Alex Amorós, Adonina Tardón, Alfredo Carrato, Consol Serra, Núria Malats, Francisco X. Real

From the Universitat Pompeu Fabra, Institut Municipal d'Investigació Mèdica, Hospital del Mar, Barcelona; Universidad de Oviedo, Oviedo; Hospital General Universitario, Instituto Biología Molecular y Celular, U. Miguel Hernández, Elche; and the Consorci Hospitalari Parc Tauli, Sabadell, Spain, for the EPICURO Study Investigators

Address reprint requests to Francisco X. Real, MD, PhD, OR Núria Malats, MD, PhD, Institut Municipal d'Investigació Mèdica, Universitat Pompeu Fabra, Carrer del Dr. Aiguader 80, 08003-Barcelona, Spain; e-mail: preal{at}imim.es OR nuria{at}imim.es

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: To determine the frequency and the prognostic value of fibroblast growth factor receptor 3 (FGFR3) mutations in patients with nonmuscle invasive bladder tumors according to tumor stage and grade.

PATIENTS AND METHODS: Seven hundred seventy-two patients with newly diagnosed bladder tumors were recruited. Tumors were reviewed by expert pathologists. Patients were prospectively followed-up (median, 62.6 months for disease-free patients) through review of hospital records and telephone interviews. The sequence of exons 7 and 10 of FGFR3 was analyzed by polymerase chain reaction and direct sequencing. We assessed the association of mutations with stage and grade. The predictive value of mutations for recurrence, progression, and mortality were assessed using Kaplan-Meier and Cox multivariable models.

RESULTS: Mutations were more common among low malignant potential neoplasms (LMPN; 77%) and TaG1/TaG2 tumors (61%/58%) than among TaG3 tumors (34%) and T1G3 tumors (17%). The S249C, Y375C, S248C, and G372C mutations accounted for 91.5% of all sequence changes. The A393E substitution was associated with LMPN (P < .001). The F386L polymorphism was more frequent among patients with low-grade tumors (odds ratio, 6.97; 95%CI, 1.40 to 47.06; P = .009). In the multivariable analysis of all superficial tumors, mutations were associated with increased risk of recurrence. However, in the stratified analyses only patients with TaG1 tumors had a significantly higher risk of recurrence (hazard ratio, 2.12; 95%CI, 1.28 to 3.53; P = .004).

CONCLUSION: The findings of this large study strongly support the notion that FGFR3 mutations characterize a subgroup of bladder cancers with good prognosis; patients with mutant TaG1 tumors have a higher risk of recurrence; and the F386L variant is selectively associated with low-grade tumors.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Urothelial cell carcinomas (UCC) represent more than 90% of bladder tumors, are often papillary, and are classified into nonmuscle invasive (pTa and pT1) and muscle invasive ( pT2). Nonmuscle invasive bladder tumors are a heterogeneous group of cancers with a markedly diverse prognosis. While low grade Ta tumors are characterized by frequent recurrences (approximately 70%) and infrequent progression to muscle-invasive tumors,¹ high-grade Ta and T1 tumors display a high risk of progression. Hence, there is a need to better identify patients who have a low risk of recurrence, in order to avoid over treatment, as well as those who are likely to progress in order to treat them more aggressively. Recent studies have proposed that superficial-low grade/papillary and invasive-high grade tumors progress via different molecular pathways.^2,3 Chromosome 9 losses occur early during urothelial tumorigenesis whereas Tp53 mutations and loss of heterozygosity at chromosome 17 are more frequent in high-grade nonmuscle invasive tumors, flat carcinoma in situ, and invasive tumors.^2-7 The most important recent advance in knowledge on the molecular pathogenesis of bladder cancer has been the identification of activating Fibroblast growth factor receptor 3 (FGFR3) mutations.^8,9 FGFRs regulate cell growth, differentiation, and angiogenesis.^10,11 The FGFR3 mutations identified in bladder cancer are identical to those present in autosomal dominant human skeletal disorders.^12-14 FGFR3 mutations have also been reported in a few other human neoplasms, such as multiple myeloma and cervix cancer, but their overall frequency is much higher in bladder cancer.^8,9,15,16 FGFR3 mutations occur predominantly in superficial/papillary low-grade bladder tumors and have been proposed to be associated with a favorable prognosis.^17,18 Two studies dealing with bladder tumors of a broad range of stages and grades have reported that FGFR3 and Tp53 mutations showed a mutually exclusive distribution, suggesting that the two alterations define different routes of UCC development.^19,20 However, in T1G3 tumors, FGFR3 and Tp53 mutations show an independent distribution, do not display a mutually exclusive pattern, and do not predict patient outcome,²¹ suggesting that the predictive value of FGFR3 mutations may be restricted to specific subtypes of nonmuscle invasive bladder tumors.

A retrospective study showed that FGFR3 mutations are associated with improved survival of patients with Ta and T1 tumors.¹⁸ This study did not assess the role of FGFR3 mutations as a predictor of outcome in specific subgroups of patients because this requires an even larger sample size.

None of the molecular markers thus far studied have had an impact on the management of patients with bladder cancer, including p53.^22,23 Recent publications have dealt with the major pitfalls in study design and execution that are responsible for such difficulties in making progress.²⁴ Two of these pitfalls are the small sample size and retrospective design.

Here, we examine the prevalence and prognostic value of FGFR3 mutations in the largest series of nonmuscle invasive bladder cancers. Our findings provide strong evidence that FGFR3 mutations are associated with low-grade Ta tumors and that they are independent predictors of recurrence in patients with TaG1 tumors.

	PATIENTS AND METHODS

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Patients and Tumor Samples
Patients were drawn from the EPICURO project, comprising 1,356 consecutive, prospectively recruited patients with incident bladder cancer recruited in 18 Spanish hospitals between 1997 and 2001. Clinical and sociodemographic information was retrieved from patient's hospital records. Staging and grading of tumors was carried out according to the criteria of the TNM classification and the WHO-International Society of Urological Pathology²⁵ with the three grade redefinition provided by the WHO.^26,27 Diagnostic slides from all paraffin-embedded blocks were reviewed by a panel of expert pathologists to confirm diagnosis and ensure uniformity of classification criteria. Of 995 Ta and T1 tumors included in the study, 772 yielded a polymerase chain reaction (PCR) product at the first attempt and are the subject of this article; the distribution of cases was: low malignant potential neoplasm (LMPN; n = 43), TaG1 (n = 257), TaG2 (n = 239), TaG3 (n = 88), T1G2 (n = 26), and T1G3 (n = 119). Table 1 summarizes the characteristics of the patients.

Written informed consent was obtained from all patients. The study was approved by the ethics committees of all participating institutions.

FGFR3 Mutation Analysis
Microdissection, DNA extraction, controls, primers, and PCR conditions to amplify exons 7 and 10 of FGFR3 have been reported elsewhere.²¹ Exon 7 was amplified in all cases; exon 10 was amplified in all but nine patients harboring exon 7 mutations (98.8%). Exon 15, in which less than 3% of reported FGFR3 mutations occur,¹⁸ was not analyzed. When a previously undescribed sequence variant was found in tumor DNA (n = 8), it was confirmed using independent PCR reaction products by sequencing both DNA strands. Germline DNA was used to determine the somatic nature of the variant.

As quality control, 25.5% of the PCR products were sequenced in both directions and all mutations were confirmed. For 21.6% of the samples, a completely independent and blind mutational analysis was performed; agreement was higher than 92%.

Statistical Analyses
Mutational status (wild type versus mutated), exon harboring the mutation, specific mutation, and number of mutations—when both exons were analyzed—were considered as variables. Tumors harboring only a synonymous mutation were considered wild type. The association between FGFR3 mutational status and clinical and pathological characteristics of tumors was assessed by applying ², Fisher's exact, Student's, or Mann-Whitney U tests, as appropriate.²⁸ The same tests, plus the trend test, were applied to assess the distribution of demographic, clinical, and pathological characteristics according to tumor stage (T) and nuclear grade (G); for age, ANOVA test was used.

Kaplan-Meier survival curves were computed by mutational status; log-rank and Breslow tests were applied to compare the curves.²⁹ Cox proportional hazard ratios (HR) were estimated to obtain risks of each outcome for cases in each FGFR3 mutational group, after adjusting for established prognostic variables.³⁰ The assumption of proportional hazards was checked for each variable. The final predictive models were fitted after forcing FGFR3 mutation variables at all steps. Since FGFR3 mutations may have a different impact on tumor evolution depending on other molecular/pathological variables associated with T/G, we performed stratified Cox model analyses. Results were considered significant at the two-sided P of .05 level.

	RESULTS

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Median patient age was 68 years (range, 22 years to 80 years). Eighty-seven percent of cases were male. The male:female ratio (6.5:1) is similar to that in the whole EPICURO Study (7:1) and in population cancer registries in Spain (7.4:1). Most patients presented with a single tumor (69.2%). Tumor size, multiplicity, and multifocality significantly increased with TG; solid growth was significantly associated with higher TG. Patients with tumors of higher TG were more frequently treated with endovesical therapies (Table 1).

Prevalence of FGFR3 mutations.
Overall, 397 somatic mutations were detected in 387 (50.1%) of 764 tumors. The most common mutations were: S249C (n = 216; 54.4%), Y375C (n = 96; 24.2%), and R248C (n = 29; 7.3%); these substitutions accounted for 85.9% of all mutations (Table 2). We identified previously undescribed somatic changes in six tumors: I378C (n = 1), A371A (n = 5), and L379L (n = 1). All synonymous mutations were confirmed in independent PCR reactions. The A371A substitution was always found with a pathogenic mutation. Ten tumors (1.3%) harbored two somatic changes: S249C and A393E (n = 3); Y375C and A371A (n = 1), S249C and G382C (n = 1), S249C and Y375C (n = 1), and G372C and A371A (n = 4).

View larger version (20K): [in this window] [in a new window]   Fig 1. Frequency (A) and spectrum (B) of fibroblast growth factor receptor 3 somatic mutations in subgroups of nonmuscle invasive bladder tumors according to T and G. The prevalence of mutations was significantly different among the different tumor subgroups (P < .001).

View larger version (9K): [in this window] [in a new window]   Fig 2. Univariable analysis of (A) recurrence, (B) progression, and (C) disease-specific survival according to fibroblast growth factor receptor 3 (FGFR3) mutational status in the whole group of patients (n = 764) with nonmuscle invasive urothelial cell carcinomas.

View larger version (15K): [in this window] [in a new window]   Fig 3. Univariable analysis of recurrence (A, C, E, G) and progression (B, D, F, H) in patients with fibroblast growth factor receptor 3 (FGFR3) wild type and mutant tumors according to T and G. (A and B) TaG1; (C and D) TaG2; (E and F) TaG3; and (G and H) T1G3.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Several retrospective studies have reported that FGFR3 mutations are associated with low-grade, low-stage bladder cancer and that mutations in FGFR3 and in Tp53 characterize distinct, though partially overlapping, molecular pathways. It has also been proposed that FGFR3 mutations might identify patients with favorable prognosis, though confounding by classical prognostic variables must be taken into account before conclusive evidence can be attained.

We have conducted a large study aimed at analyzing the role of molecular prognostic factors in bladder cancer and have attempted to overcome problems associated with the retrospective analysis of archival tissue. Here, we report the prevalence and distribution of FGFR3 mutations and their association with outcome in 764 patients with nonmuscle invasive tumors.

Our findings confirm that FGFR3 mutations are associated with tumors of low stage and grade and that there is a significant decrease in the prevalence of mutations as depth of invasion and grade increase. Highest prevalence was found in LMPN and lowest was found among T1G3 tumors. TaG1 and TaG2 tumors displayed a similar prevalence of mutations in this study. A comparison with the report of van Rhijn et al¹⁸ shows similar results and a few differences: these authors reported mutations in 88% (81 of 92) of TaG1 tumors whereas we find 61.5% (158 of 257); for the other T and G subgroups the differences between both studies were smaller and did not occur in the same direction (ie, a lower prevalence in our series). Several factors may account for these differences. The study by van Rhijn et al was retrospective, raising the possibility that some selection biases may have contributed. In contrast, our study included all consecutive patients in each participating hospital and had a very high participation rate (84%).³¹ Furthermore, in one of the geographical areas, the study was population-based thus ensuring minimal selection biases. A second difference was that the study by van Rhijn et al included upper urinary tract UCC whereas they were excluded from our study. There are also some differences in the epidemiological profile of UCC: the male:female ratio is higher in Spain than in the Netherlands (7.4 v 4.1).³² In addition, different pathological classifications were used and the techniques used for FGFR3 mutation detection were different: van Rhijn et al used single strand conformation polymorphism analysis of PCR products and sequencing of abnormal bands whereas we performed direct sequencing of PCR products. Both studies had a very high replication of results. It is unlikely that the lower frequency of mutations among TaG1 tumors found in our study is due to a lower sensitivity of the technique: should this be so, we would have expected a lower proportion of mutated tumors across all categories of T and G and this was not the case. Therefore, we conclude that this slight discrepancy is likely to be related, at least in part, to some of the reasons indicated herein.

In the univariable analysis of progression of all cases, both our study and that of van Rhijn et al¹⁸ showed that cases with FGFR3 mutations fared better than those who were wild type. Both studies concur in that using multivariable analysis FGFR3 mutations do not stand as an independent prognostic factor neither for recurrence, nor progression or death. Importantly, the large size of our patient cohort has allowed a stratified analysis of subgroups. These results provide novel evidence that patients with FGFR3 wild type TaG1 tumors have a significantly lower risk of recurrence than those harboring a mutation, after adjusting for other prognostic variables. This effect was statistically significant and robust since it was maintained regardless of the definition of recurrence or progression and of the statistical model used to analyze outcome (ie, linear v compartmental).³³ Among TaG2 tumors, a trend for an increased risk of recurrence was observed but the difference was not statistically significant regardless of the definition and model used. The increased risk was restricted to the appearance of recurrent tumors. In contrast, FGFR3 mutations were not associated with recurrence or progression in patients with TaG3 and T1G3 tumors.²¹ Mutations did not predict progression or bladder cancer-related death although the number of events is still too small to provide a definitive conclusion given the overall good prognosis of nonmuscle invasive tumors. Unlike here, stratified analyses were not performed in the previously published studies because of a lack of statistical power due to the substantially smaller number of patients analyzed.

van Rhijn et al also analyzed FGFR3 mutations combined with other immunohistochemical parameters, such as MIB-1 (Ki67), nuclear p53, and p27 expression.¹⁸ The combination FGFR3/MIB-1 was an independent predictor of progression. It will be important to determine the association of this molecular staging with prognosis after stratification for T and G, as it is possible that the results may differ substantially from those reported earlier. In our complete series of superficial tumors (n = 995), nuclear p53 overexpression was significantly more common among FGFR3 wild type tumors (48.8% v 32.3%; ² < 0.001), but it did not predict outcome in any of the patient subgroups analyzed.³⁴

We find that the A393E mutation is significantly more frequent among LMPN tumors (21%). The other, more common, mutations are equally distributed among subgroups. We also find that the F386L germline polymorphism is strongly associated with tumors of low grade and stage. This finding is important because there is little knowledge about environmental or genetic factors explaining why some patients develop low-grade papillary tumors associated with an indolent clinical course and others develop dysplasia-associated, high-grade, aggressive tumors. This is the first association of the F386L polymorphism with human disease. While the CIs that we find are broad, the HR of 6.97 calls for further analysis through multicenter studies.

Our work provides solid evidence indicating that FGFR3 mutations characterize the papillary low-grade pathway of bladder carcinogenesis and that the mutation frequency decreases steadily among nonmuscle invasive tumors as T and G increase. The data indicate that the prognostic value of FGFR3 mutation detection may be restricted to TaG1 UCC and suggest that other molecular alterations of higher-grade/stage tumors override the association of FGFR3 mutations with prognosis.²¹ Our findings emphasize the need to conduct large studies to evaluate the prognostic value of molecular variables in specific subgroups of patients. FGFR3 mutation detection has a high chance of becoming a useful tool in the standard management of patients with low-grade papillary bladder tumors.

	Appendix

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Annex Members of the Participating Centers
Institut Municipal d'Investigació Mèdica, Universitat Pompeu Fabra (Barcelona) (coordinating center): M. Kogevinas, N. Malats, F.X. Real, M. Sala, G. Castaño, M. Torà, D. Puente, C. Villanueva, C. Murta, J. Fortuny, E. López, S. Hernández, R. Jaramillo. Hospital del Mar, Universitat Autònoma de Barcelona (Barcelona, Spain): J. Lloreta, S. Serrano, L. Ferrer, A. Gelabert, J. Carles, O. Bielsa, K. Villadiego. Hospital Germans Tries i Pujol (Badalona, Spain): L. Cecchini, J.M. Saladié, L. Ibarz. Hospital de Sant Boi (Sant Boi, Spain): M. Céspedes. Centre Hospitalari Parc Taulí (Sabadell, Spain): C. Serra, D. García, J. Pujadas, R. Hernando, A. Cabezuelo, C. Abad, A. Prera, J. Prat. Centre Hospitalari i Cardiològic (Manresa, Spain): M. Domènech, J. Badal, J. Malet. Hospital Universitario (La Laguna, Spain): R. García-Closas, J. Rodríguez de Vera, A.I. Martín. Hospital La Candelaria (Santa Cruz, Spain): J. Taño, F. Cáceres. Hospital General Universitario de Elche, Universidad Miguel Hernández (Elche, Spain): A. Carrato, F. García-López, M. Ull, A. Teruel, E. Andrada, A. Bustos, A. Castillejo, J.L. Soto. Universidad de Oviedo (Oviedo, Spain): A. Tardón. Hospital San Agustín (Avilés, Spain): J.L. Guate, J.M. Lanzas, J. Velasco. Hospital Central Covadonga (Oviedo, Spain): J.M. Fernández, J.J. Rodríguez, A. Herrero. Hospital Central General (Oviedo, Spain): R. Abascal, C. Manzano, T. Miralles. Hospital de Cabueñes (Gijón, Spain): M. Rivas, M. Arguelles. Hospital de Jove (Gijón, Spain): M. Díaz, J. Sánchez, O. González. Hospital de Cruz Roja (Gijón, Spain): A. Mateos, V. Frade. Hospital Alvarez-Buylla (Mieres, Spain): P. Muntañola, C. Pravia. Hospital Jarrio (Coaña, Spain): A.M. Huescar, F. Huergo. Hospital Carmen y Severo Ochoa (Cangas, Spain): J. Mosquera. Centro Nacional de Investigaciones Oncológicas (Madrid, Spain): M. Esteller. Universitat Autònoma de Barcelona (Bellaterra,Spain): R. Miró, R. Marcos. Progenika (Derio, Spain): A. Martínez.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Manolis Kogevinas, Nuria Malats, Francisco X. Real Financial support: Manolis Kogevinas, Nuria Malats, Francisco X. Real Provision of study materials or patients: Adonina Tardón, Alfredo Carrato, Consol Serra Collection and assembly of data: Silvia Hernández, Elena López-Knowles, Josep Lloreta, Manolis Kogevinas, Alex Amorós, Adonina Tardón, Alfredo Carrato, Consol Serra, Nuria Malats, Francisco X. Real Data analysis and interpretation: Silvia Hernández, Elena López-Knowles, Josep Lloreta, Manolis Kogevinas, Alex Amorós, Nuria Malats, Francisco X. Real Manuscript writing: Silvia Hernández, Nuria Malats, Francisco X. Real Final approval of manuscript: Silvia Hernández, Elena López-Knowles, Josep Lloreta, Manolis Kogevinas, Alex Amorós, Adonina Tardón, Alfredo Carrato, Consol Serra, Nuria Malats, Francisco X. Real

 

	ACKNOWLEDGMENTS

 
We thank A. Alfaro, G. Carretero, F. Fernández, T. Lobato, I. López, S. Mancilla, R. García-Closas, and the many clinicians, investigators, nurses, technicians, and patients participating in the study. We also thank Drs Dosemeci, Silverman, Rothman, and García-Closas for their valuable contributions to the study.

	NOTES

 
Supported in part by Grants No. FIS 00/0745, C03/009, C03/010, G03/160, and G03/174 from Instituto de Salud Carlos III, Ministerio de Sanidad. E.L. was supported by a predoctoral fellowship of the Ramón Areces Foundation, Madrid, Spain.

Presented in abstract format at the Annual Meeting of the American Association for Cancer Research, Chicago, IL, September 12-15, 2006.

N.M. and F.X.R. have contributed equally and share senior authorship.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted December 4, 2005; accepted May 18, 2006.

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