title: Genetic Alterations in the Molecular Subtypes of Bladder Cancer: Illustration in the Cancer Genome Atlas Dataset.
abstract: Recent whole genome mRNA expression profiling studies revealed that bladder cancers can be grouped into molecular subtypes, some of which share clinical properties and gene expression patterns with the intrinsic subtypes of breast cancer and the molecular subtypes found in other solid tumors. The molecular subtypes in other solid tumors are enriched with specific mutations and copy number aberrations that are thought to underlie their distinct progression patterns, and biological and clinical properties.
  
  
  
  The availability of comprehensive genomic data from The Cancer Genome Atlas (TCGA) and other large projects made it possible to correlate the presence of DNA alterations with tumor molecular subtype membership. Our overall goal was to determine whether specific DNA mutations and/or copy number variations are enriched in specific molecular subtypes.
  
  
  
  We used the complete TCGA RNA-seq dataset and three different published classifiers developed by our groups to assign TCGA's bladder cancers to molecular subtypes, and examined the prevalence of the most common DNA alterations within them. We interpreted the results against the background of what was known from the published literature about the prevalence of these alterations in nonmuscle-invasive and muscle-invasive bladder cancers.
  
  
  
  The results confirmed that alterations involving RB1 and NFE2L2 were enriched in basal cancers, whereas alterations involving FGFR3 and KDM6A were enriched in luminal tumors.
  
  
  
  The results further reinforce the conclusion that the molecular subtypes of bladder cancer are distinct disease entities with specific genetic alterations.
  
  
  
  Our observation showed that some of subtype-enriched mutations and copy number aberrations are clinically actionable, which has direct implications for the clinical management of patients with bladder cancer.
authors.affiliation: Department of Urology, U.T. M.D. Anderson Cancer Center, Houston, Texas, USA; Department of Cancer Biology, U.T. M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Woonyoung
authors.initials: W
authors.lastname: Choi
authors.affiliation: Department of Urology, U.T. M.D. Anderson Cancer Center, Houston, Texas, USA; Department of Cancer Biology, U.T. M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ochoa
authors.affiliation: Department of Urology, U.T. M.D. Anderson Cancer Center, Houston, Texas, USA; Department of Cancer Biology, U.T. M.D. Anderson Cancer Center, Houston, Texas, USA. Electronic address: djmcconkey@jhmi.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: McConkey
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Faculty of Medicine, Lund University, Lund, Sweden.
authors.forename: Mattias
authors.initials: M
authors.lastname: Aine
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Faculty of Medicine, Lund University, Lund, Sweden.
authors.forename: Mattias
authors.initials: M
authors.lastname: Höglund
authors.affiliation: University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: William Y
authors.initials: WY
authors.lastname: Kim
authors.affiliation: Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, Madrid, Spain; Departament de Ciències Experimentalsi de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Francisco X
authors.initials: FX
authors.lastname: Real
authors.affiliation: Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Kiltie
authors.affiliation: Institute of Clinical Sciences, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.
authors.forename: Ian
authors.initials: I
authors.lastname: Milsom
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Dyrskjøt
authors.affiliation: TCGA Analysis Working Group, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Seth P
authors.initials: SP
authors.lastname: Lerner
mesh_terms: D001271:Atlases as Topic; D014408:Biomarkers, Tumor / Q000235:genetics*; D056915:DNA Copy Number Variations; D030541:Databases, Genetic; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D056466:Histone Demethylases / Q000235:genetics; D006801:Humans; D009154:Mutation; D051267:NF-E2-Related Factor 2 / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics; D056286:Retinoblastoma Binding Proteins / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009687:Nuclear Proteins; C000606393:RB1 protein, human; D056286:Retinoblastoma Binding Proteins; D056466:Histone Demethylases; C523998:KDM6A protein, human; D044767:Ubiquitin-Protein Ligases; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3
keywords: DNA alterations; Molecular subtypes; Muscle-invasive bladder cancer