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ARID1A alterations are associated with FGFR3-wild type, poor-prognosis, urothelial bladder tumors.
- Source :
-
PloS one [PLoS One] 2013 May 01; Vol. 8 (5), pp. e62483. Date of Electronic Publication: 2013 May 01 (Print Publication: 2013). - Publication Year :
- 2013
-
Abstract
- Urothelial bladder cancer (UBC) is heterogeneous at the clinical, pathological, genetic, and epigenetic levels. Exome sequencing has identified ARID1A as a novel tumor suppressor gene coding for a chromatin remodeling protein that is mutated in UBC. Here, we assess ARID1A alterations in two series of patients with UBC. In the first tumor series, we analyze exons 2-20 in 52 primary UBC and find that all mutant tumors belong to the aggressive UBC phenotype (high grade non-muscle invasive and muscle invasive tumors) (P = 0.05). In a second series (n = 84), we assess ARID1A expression using immunohistochemistry, a surrogate for mutation analysis, and find that loss of expression increases with higher stage/grade, it is inversely associated with FGFR3 overexpression (P = 0.03) but it is not correlated with p53 overexpression (P = 0.30). We also analyzed the expression of cytokeratins in the same set of tumor and find, using unsupervised clustering, that tumors with ARID1A loss of expression are generally KRT5/6-low. In this patient series, loss of ARID1A expression is also associated with worse prognosis, likely reflecting the higher prevalence of losses found in tumors of higher stage and grade. The independent findings in these two sets of patients strongly support the notion that ARID1A inactivation is a key player in bladder carcinogenesis occurring predominantly in FGFR3 wild type tumors.
- Subjects :
- Aged
Aged, 80 and over
Base Sequence
Carcinoma, Transitional Cell mortality
Carcinoma, Transitional Cell pathology
Cell Line, Tumor
DNA Mutational Analysis
DNA-Binding Proteins
Female
HEK293 Cells
Humans
Kaplan-Meier Estimate
Male
Middle Aged
Mutation, Missense
Nuclear Proteins metabolism
Prognosis
Receptor, Fibroblast Growth Factor, Type 3 metabolism
Transcription Factors metabolism
Tumor Suppressor Protein p53 genetics
Tumor Suppressor Protein p53 metabolism
Urinary Bladder Neoplasms mortality
Urinary Bladder Neoplasms pathology
Urothelium pathology
Carcinoma, Transitional Cell genetics
Nuclear Proteins genetics
Receptor, Fibroblast Growth Factor, Type 3 genetics
Transcription Factors genetics
Urinary Bladder Neoplasms genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 8
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 23650517
- Full Text :
- https://doi.org/10.1371/journal.pone.0062483