title: DNA copy number alterations and PPARG amplification in a patient with multifocal bladder urothelial carcinoma.
abstract: BACKGROUND
  Bladder cancer is the seventh most common cancer worldwide and over 90% are transitional cell carcinoma (TCC). At the first time of diagnosis at least 70% of TCC present as superficial bladder cancer. Because the clinical outcome of superficial bladder tumors is relatively unpredictable, there is a pressing need to identify markers that may predict tumor recurrence and progression and new treatment strategies.
  
  
  METHODS
  We present a unique case of a 67-year old male who underwent total cystectomy after repeated trans-urethral resections of the bladder for multifocal non-muscle invasive bladder cancer. The first and the third tumor were diagnosed as high grade non-infiltrating (HGNI), while the second as carcinoma in situ (CIS). We performed both array comparative genomic hybridization and a targeted chromosomal profile by UroVysion in order to detect copy number variations (CNVs) that may be involved with tumor recurrence and progression. The overall data from this study provide new evidence for the monoclonal origin of urothelial tumor multifocality as several genetic changes were found in different tumors of the same patient. From the analysis of shared CNVs two gained regions emerged at 3p25.2 and 12q23.2, including PPARG and ASCL1 genes, respectively. The copy number level of these genes would seem inversely mutually correlated and highly dependent on histological grade, because the highest level of amplification at 3p25.2 was evidenced in the two HGNI samples, while the highest level of copy number gain at 12q23.2 was reported in the CIS.
  
  
  CONCLUSIONS
  We provide new evidence on the role of PPARG in initiation and maintenance of bladder cancer. For the first time we also suggest a possible explanation for the elevated expression of PPARG in this type of tumor through a focal high level amplification at 3p25.2. Furthermore, a new gene, ASCL1, emerged as a potential candidate to assist PPARG in bladder carcinogenesis.
authors.affiliation: Department of Neuroscience and Biomedical Technologies, University of Milan-Bicocca, Monza, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Conconi
authors.forename: Elena
authors.initials: E
authors.lastname: Panzeri
authors.forename: Serena
authors.initials: S
authors.lastname: Redaelli
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bovo
authors.forename: Marco
authors.initials: M
authors.lastname: Volante
authors.forename: Paolo
authors.initials: P
authors.lastname: Viganò
authors.forename: Guido
authors.initials: G
authors.lastname: Strada
authors.forename: Leda
authors.initials: L
authors.lastname: Dalprà
authors.forename: Angela
authors.initials: A
authors.lastname: Bentivegna
mesh_terms: D000368:Aged; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002278:Carcinoma in Situ / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D015653:Cystectomy; D056915:DNA Copy Number Variations; D018450:Disease Progression; D056426:Genetic Loci; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D047495:PPAR gamma / Q000235:genetics*; D001743:Urinary Bladder / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D019459:Urothelium / Q000378:metabolism / Q000473:pathology / Q000601:surgery
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D047495:PPAR gamma; C065500:ASCL1 protein, human