FGFR3, HRAS, KRAS, NRAS and PIK3CA mutations in bladder cancer and their potential as biomarkers for surveillance and therapy.

Lucie C Kompier,Theo H Van Der Kwast,Irene Lurkin,Ellen C Zwarthoff,Madelon N M Van Der Aa,Bas W G Van Rhijn,Venugopalan Cheriyath

doi:10.1371/journal.pone.0013821

Lucie C Kompier, Theo H Van Der Kwast + Show 5 more

Open Access

https://doi.org/10.1371/journal.pone.0013821

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Abstract

BackgroundFifty percent of patients with muscle–invasive bladder cancer (MI-BC) die from their disease and current chemotherapy treatment only marginally increases survival. Novel therapies targeting receptor tyrosine kinases or activated oncogenes may improve outcome. Hence, it is necessary to stratify patients based on mutations in relevant oncogenes. Patients with non-muscle-invasive bladder cancer (NMI-BC) have excellent survival, however two-thirds develop recurrences. Tumor specific mutations can be used to detect recurrences in urine assays, presenting a more patient-friendly diagnostic procedure than cystoscopy.Methodology/Principal FindingsTo address these issues, we developed a mutation assay for the simultaneous detection of 19 possible mutations in the HRAS, KRAS, and NRAS genes. With this assay and mutation assays for the FGFR3 and PIK3CA oncogenes, we screened primary bladder tumors of 257 patients and 184 recurrences from 54 patients. Additionally, in primary tumors p53 expression was obtained by immunohistochemistry. Of primary tumors 64% were mutant for FGFR3, 11% for RAS, 24% for PIK3CA, and 26% for p53. FGFR3 mutations were mutually exclusive with RAS mutations (p = 0.001) and co-occurred with PIK3CA mutations (p = 0.016). P53 overexpression was mutually exclusive with PIK3CA and FGFR3 mutations (p≤0.029). Mutations in the RAS and PIK3CA genes were not predictors for recurrence-free, progression-free and disease-specific survival. In patients presenting with NMI-BC grade 3 and MI-BC, 33 and 36% of the primary tumors were mutant. In patients with low-grade NMI-BC, 88% of the primary tumors carried a mutation and 88% of the recurrences were mutant.Conclusions/SignificanceThe mutation assays present a companion diagnostic to define patients for targeted therapies. In addition, the assays are a potential biomarker to detect recurrences during surveillance. We showed that 88% of patients presenting with low-grade NMI-BC are eligible for such a follow-up. This may contribute to a reduction in the number of cystoscopical examinations.

Highlights

Bladder cancer is the fifth most common cancer in the Western World [1]
Agents inhibiting targets downstream in these pathways are in clinical trials. This suggests that screening bladder tumors for mutations in genes such as FGFR3, RAS and PIK3CA can be of importance for future therapy decisions
We subsequently investigated the mutation spectrum of FGFR3, HRAS, KRAS, NRAS and PIK3CA in a large series of primary tumors of 257 patients with non-muscle-invasive bladder cancer (NMI-BC) and muscle–invasive bladder cancer (MI-BC)

Summary

Introduction

Bladder cancer is the fifth most common cancer in the Western World [1]. Of the bladder tumors 15–20% presents as muscleinvasive disease (MI-BC), the remaining group as non-muscleinvasive tumors (NMI-BC). We have recently shown that with FGFR3 mutation analysis on urine samples from bladder cancer patients it was possible to detect recurrent tumors [53,54].

Results

Conclusion