title: ARID1A alterations are associated with FGFR3-wild type, poor-prognosis, urothelial bladder tumors.
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.
authors: Epithelial Carcinogenesis Group, Molecular Pathology Programme, Spanish National Cancer Research Centre, Madrid, Spain.
authors: Cristina
authors: C
authors: Balbás-Martínez
authors: María
authors: M
authors: Rodríguez-Pinilla
authors: Ariel
authors: A
authors: Casanova
authors: Orlando
authors: O
authors: Domínguez
authors: David G
authors: DG
authors: Pisano
authors: Gonzalo
authors: G
authors: Gómez
authors: Josep
authors: J
authors: Lloreta
authors: José A
authors: JA
authors: Lorente
authors: Núria
authors: N
authors: Malats
authors: Francisco X
authors: FX
authors: Real
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D019459:Urothelium / Q000473:pathology
chemical_list: C112476:ARID1A protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3
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