title: Identification of nine genomic regions of amplification in urothelial carcinoma, correlation with stage, and potential prognostic and therapeutic value.
abstract: We performed a genome wide analysis of 164 urothelial carcinoma samples and 27 bladder cancer cell lines to identify copy number changes associated with disease characteristics, and examined the association of amplification events with stage and grade of disease. Multiplex inversion probe (MIP) analysis, a recently developed genomic technique, was used to study 80 urothelial carcinomas to identify mutations and copy number changes. Selected amplification events were then analyzed in a validation cohort of 84 bladder cancers by multiplex ligation-dependent probe assay (MLPA). In the MIP analysis, 44 regions of significant copy number change were identified using GISTIC. Nine gene-containing regions of amplification were selected for validation in the second cohort by MLPA. Amplification events at these 9 genomic regions were found to correlate strongly with stage, being seen in only 2 of 23 (9%) Ta grade 1 or 1-2 cancers, in contrast to 31 of 61 (51%) Ta grade 3 and T2 grade 2 cancers, p<0.001. These observations suggest that analysis of genomic amplification of these 9 regions might help distinguish non-invasive from invasive urothelial carcinoma, although further study is required. Both MIP and MLPA methods perform well on formalin-fixed paraffin-embedded DNA, enhancing their potential clinical use. Furthermore several of the amplified genes identified here (ERBB2, MDM2, CCND1) are potential therapeutic targets.
authors.affiliation: Division of Translational Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Chekaluk
authors.forename: Chin-Lee
authors.initials: CL
authors.lastname: Wu
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rosenberg
authors.forename: Markus
authors.initials: M
authors.lastname: Riester
authors.forename: Qishan
authors.initials: Q
authors.lastname: Dai
authors.forename: Sharron
authors.initials: S
authors.lastname: Lin
authors.forename: Yanan
authors.initials: Y
authors.lastname: Guo
authors.forename: W Scott
authors.initials: WS
authors.lastname: McDougal
authors.forename: David J
authors.initials: DJ
authors.lastname: Kwiatkowski
mesh_terms: D002277:Carcinoma / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D056915:DNA Copy Number Variations; D005784:Gene Amplification; D006801:Humans; D009154:Mutation; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D015203:Reproducibility of Results; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000473:pathology; D014571:Urologic Neoplasms / Q000235:genetics* / Q000473:pathology*