title: Gene Expression Profile of the Clinically Aggressive Micropapillary Variant of Bladder Cancer.
abstract: Progression of conventional urothelial carcinoma of the bladder to a tumor with unique microscopic features referred to as micropapillary carcinoma is coupled with aggressive clinical behavior signified by a high propensity for metastasis to regional lymph nodes and distant organs resulting in shorter survival.
  
  
  
  To analyze the expression profile of micropapillary cancer and define its molecular features relevant to clinical behavior.
  
  
  
  We retrospectively identified 43 patients with micropapillary bladder cancers and a reference set of 89 patients with conventional urothelial carcinomas and performed whole-genome expression messenger RNA profiling.
  
  
  
  The tumors were segregated into distinct groups according to hierarchical clustering analyses. They were also classified according to luminal, p53-like, and basal categories using a previously described algorithm. We applied Ingenuity Pathway Analysis software (Qiagen, Redwood City, CA, USA) and gene set enrichment analysis for pathway analyses. Cox proportional hazards models and Kaplan-Meier methods were used to assess the relationship between survival and molecular subtypes. The expression profile of micropapillary cancer was validated for selected markers by immunohistochemistry on parallel tissue microarrays.
  
  
  
  We show that the striking features of micropapillary cancer are downregulation of miR-296 and activation of chromatin-remodeling complex RUVBL1. In contrast to conventional urothelial carcinomas that based on their expression can be equally divided into luminal and basal subtypes, micropapillary cancer is almost exclusively luminal, displaying enrichment of active peroxisome proliferator-activated receptor γ and suppression of p63 target genes. As with conventional luminal urothelial carcinomas, a subset of micropapillary cancers exhibit activation of wild-type p53 downstream genes and represent the most aggressive molecular subtype of the disease with the shortest survival. The involvement of miR-296 and RUVBL1 in the development of micropapillary bladder cancer was identified by the analyses of correlative associations of genome expression profiles and requires mechanistic validation.
  
  
  
  Micropapillary cancer evolves through the luminal pathway and is characterized by the activation of miR-296 and RUVBL1 target genes.
  
  
  
  Our observations have important implications for prognosis and for possible future development of more effective therapies for micropapillary bladder cancer.
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Charles Chuanhai
authors.initials: CC
authors.lastname: Guo
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Vipulkumar
authors.initials: V
authors.lastname: Dadhania
authors.affiliation: Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Majewski
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Bondaruk
authors.affiliation: Institute of Informatics, University of Warsaw, Warsaw, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Sykulski
authors.affiliation: Faculty of Biology, University of Warsaw, Warsaw, Poland.
authors.forename: Weronika
authors.initials: W
authors.lastname: Wronowska
authors.affiliation: Institute of Informatics, University of Warsaw, Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Gambin
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Shizhen
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Enrique
authors.initials: E
authors.lastname: Fuentes-Mattei
authors.affiliation: Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ashish Madhav
authors.initials: AM
authors.lastname: Kamat
authors.affiliation: Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Colin
authors.initials: C
authors.lastname: Dinney
authors.affiliation: Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Arlene
authors.initials: A
authors.lastname: Siefker-Radtke
authors.affiliation: Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Woonyoung
authors.initials: W
authors.lastname: Choi
authors.affiliation: Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Baggerly
authors.affiliation: Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: David
authors.initials: D
authors.lastname: McConkey
authors.affiliation: Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: John N
authors.initials: JN
authors.lastname: Weinstein
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: bczernia@mdanderson.org.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Czerniak
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities / Q000235:genetics; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics; D015536:Down-Regulation; D050990:GATA3 Transcription Factor / Q000235:genetics; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D053547:Keratin-14 / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics; D047495:PPAR gamma / Q000235:genetics; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000032:analysis*; D012189:Retrospective Studies; D015996:Survival Rate; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000235:genetics; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D060170:Uroplakin II / Q000235:genetics; D000073336:Whole Genome Sequencing
chemical_list: C497483:CD44 protein, human; D002352:Carrier Proteins; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D018960:Hyaluronan Receptors; C507540:KRT14 protein, human; D053547:Keratin-14; C549871:MIRN296 microRNA, human; D035683:MicroRNAs; D047495:PPAR gamma; D012333:RNA, Messenger; C115051:TP63 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C554658:UPK2 protein, human; D060170:Uroplakin II; D000074183:ATPases Associated with Diverse Cellular Activities; D004265:DNA Helicases; C486549:RUVBL1 protein, human
keywords: Expression profile; Micropapillary bladder cancer; Molecular signature; Prognosis