Document Detail


FGFR3, HRAS, KRAS, NRAS and PIK3CA mutations in bladder cancer and their potential as biomarkers for surveillance and therapy.
MedLine Citation:
PMID:  21072204     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Fifty 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 FINDINGS: To 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/SIGNIFICANCE: The 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.
Authors:
Lucie C Kompier; Irene Lurkin; Madelon N M van der Aa; Bas W G van Rhijn; Theo H van der Kwast; Ellen C Zwarthoff
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-11-03
Journal Detail:
Title:  PloS one     Volume:  5     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2010  
Date Detail:
Created Date:  2010-11-12     Completed Date:  2011-04-27     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e13821     Citation Subset:  IM    
Affiliation:
Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
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MeSH Terms
Descriptor/Qualifier:
Aged
DNA Mutational Analysis
Disease-Free Survival
Female
Gene Frequency
Genetic Predisposition to Disease / genetics
Genotype
Humans
Immunohistochemistry
Male
Mutation*
Neoplasm Recurrence, Local
Phosphatidylinositol 3-Kinases / genetics*
Population Surveillance
Prognosis
Receptor, Fibroblast Growth Factor, Type 3 / genetics*
Tumor Markers, Biological / genetics
Tumor Suppressor Protein p53 / genetics,  metabolism
Urinary Bladder Neoplasms / diagnosis,  genetics*,  therapy
ras Proteins / genetics*
Chemical
Reg. No./Substance:
0/Tumor Markers, Biological; 0/Tumor Suppressor Protein p53; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.1.137/PIK3CA protein, human; EC 2.7.10.1/FGFR3 protein, human; EC 2.7.10.1/Receptor, Fibroblast Growth Factor, Type 3; EC 3.6.5.2/ras Proteins
Comments/Corrections

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