title: Novel tumor subgroups of urothelial carcinoma of the bladder defined by integrated genomic analysis.
abstract: OBJECTIVE
  There is a need for improved subclassification of urothelial carcinoma (UC) at diagnosis. A major aim of this study was to search for novel genomic subgroups.
  
  
  METHODS
  We assessed 160 tumors for genome-wide copy number alterations and mutation in genes implicated in UC. These comprised all tumor grades and stages and included 49 high-grade stage T1 (T1G3) tumors.
  
  
  RESULTS
  Our findings point to the existence of genomic subclasses of the "gold-standard" grade/stage groups. The T1G3 tumors separated into 3 major subgroups that differed with respect to the type and number of copy number events and to FGFR3 and TP53 mutation status. We also identified novel regions of copy number alteration, uncovered relationships between molecular events, and elucidated relationships between molecular events and clinico-pathologic features. FGFR3 mutant tumors were more chromosomally stable than their wild-type counterparts and a mutually exclusive relationship between FGFR3 mutation and overrepresentation of 8q was observed in non-muscle-invasive tumors. In muscle-invasive (MI) tumors, metastasis was positively associated with losses of regions on 10q (including PTEN), 16q and 22q, and gains on 10p, 11q, 12p, 19p, and 19q. Concomitant copy number alterations positively associated with TP53 mutation in MI tumors were losses on 16p, 2q, 4q, 11p, 10q, 13q, 14q, 16q, and 19p, and gains on 1p, 8q, 10q, and 12q. Significant complexity was revealed in events affecting chromosome 9.
  
  
  CONCLUSIONS
  These findings may lead to improved biologic understanding and the development of prognostic biomarkers. Novel regions of copy number alteration may reveal potential therapeutic targets.
authors.affiliation: Cancer Research UK Centre, Leeds Institute of Molecular Medicine, St James's University Hospital, Beckett Street, Leeds, United Kingdom.
authors.forename: Carolyn D
authors.initials: CD
authors.lastname: Hurst
authors.affiliation: Cancer Research UK Centre, Leeds Institute of Molecular Medicine, St James's University Hospital, Beckett Street, Leeds, United Kingdom.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Platt
authors.affiliation: Cancer Research UK Centre, Leeds Institute of Molecular Medicine, St James's University Hospital, Beckett Street, Leeds, United Kingdom.
authors.forename: Claire F
authors.initials: CF
authors.lastname: Taylor
authors.affiliation: Cancer Research UK Centre, Leeds Institute of Molecular Medicine, St James's University Hospital, Beckett Street, Leeds, United Kingdom.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Knowles
mesh_terms: D002277:Carcinoma / Q000145:classification* / Q000235:genetics* / Q000473:pathology; D002899:Chromosomes, Human, Pair 9; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D005784:Gene Amplification; D042822:Genomic Instability; D023281:Genomics; D006801:Humans; D009154:Mutation; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D001749:Urinary Bladder Neoplasms / Q000145:classification* / Q000235:genetics* / Q000473:pathology