Journal Article

ARID1A Alterations Are Associated with FGFR3-Wild Type, Poor-Prognosis, Urothelial Bladder Tumors

Casanova, Ariel, Lorente, José A., Gómez, Gonzalo, Domínguez, Orlando, Real, Francisco X., Lloreta, Josep, Balbás-Martínez, Cristina, Pisano, David G., Rodríguez-Pinilla, María, Malats, Núria

2013

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Aged / Aged, 80 and over / Alterations / Base Sequence / Bioinformatics / Biology / Bladder / Bladder cancer / Cancer / Carcinogenesis / Carcinogens / Carcinoma, Transitional Cell - genetics / Carcinoma, Transitional Cell - mortality / Carcinoma, Transitional Cell - pathology / Care and treatment / Cell Line, Tumor / Chromatin remodeling / Clustering / Càncer / Deactivation / Deoxyribonucleic acid / Development and progression / DNA / DNA Mutational Analysis / Epigenetics / Exons / Female / Fetge / Fibroblast growth factor receptors / Gene expression / Gene mutation / Gene sequencing / Genes / Genetic aspects / Genomes / Health aspects / HEK293 Cells / Humans / Immunohistochemistry / Inactivation / Invasiveness / Kaplan-Meier Estimate / Lymphoma / Lymphomas / Male / Medical prognosis / Medical research / Medicine / Middle Aged / Muscles / Mutation / Mutation, Missense / Nuclear Proteins - genetics / Nuclear Proteins - metabolism / p53 Protein / Pathology / Patients / Prognosis / Protein expression / Proteins / Proteïnes / Receptor, Fibroblast Growth Factor, Type 3 - genetics / Receptor, Fibroblast Growth Factor, Type 3 - metabolism / Survival analysis / Transcription factors / Transcription Factors - genetics / Transcription Factors - metabolism / Tumor suppressor genes / Tumor Suppressor Protein p53 - genetics / Tumor Suppressor Protein p53 - metabolism / Tumors / Urinary bladder / Urinary Bladder Neoplasms - genetics / Urinary Bladder Neoplasms - mortality / Urinary Bladder Neoplasms - pathology / Urothelial cancer / Urothelium - pathology