title: Multifocal urothelial cancers with the mutator phenotype are of monoclonal origin and require panurothelial treatment for tumor clearance.
abstract: OBJECTIVE
  UC is a disease of the entire urothelium, characterized by multiplicity and multifocality. The clonal relationship among multiple UCs has implications regarding adjuvant chemotherapy. It has been investigated in studies of chromosomal alteration and single gene mutation. However, these genetic changes can occur in unrelated tumors under similar carcinogenic selection pressures. Tumors with high MSI have numerous DNA mutations, of which many provide no selection benefit. While these tumors represent an ideal model for studying UC clonality, their low frequency has prevented their previous investigation.
  
  
  METHODS
  We investigated 32 upper and lower urinary tract UCs with high MSI and 4 nonUC primary cancers in 9 patients. We used the high frequency and specificity of individual DNA mutations in these tumors (MSI at 17 loci) and the early timing of epigenetic events (methylation of 7 gene promoters) to investigate tumor clonality.
  
  
  RESULTS
  Molecular alterations varied among tumors from different primary organs but they appeared related in the UCs of all 9 patients. While 7 patients had a high degree of concordance among UCs, in 2 the UCs shared only a few similar alterations. Genetic and epigenetic abnormalities were frequently found in normal urothelial samples.
  
  
  CONCLUSIONS
  Multiple UCs in each patient appeared to arise from a single clone. The molecular order of tumor development varied from the timing of clinical presentation and suggested that residual malignant cells persist in the urinary tract despite apparent curative surgery. These cells lead to subsequent tumor relapse and new methods are required to detect and eradicate them.
authors.affiliation: Academic Urology Unit, University of Sheffield, Sheffield, United Kingdom. J.Catto@sheffield.ac.uk
authors.forename: James W F
authors.initials: JW
authors.lastname: Catto
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.forename: Robert
authors.initials: R
authors.lastname: Stoehr
authors.forename: Emma
authors.initials: E
authors.lastname: Bolderson
authors.forename: Ishtiaq
authors.initials: I
authors.lastname: Rehman
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Rosario
authors.forename: Freddie C
authors.initials: FC
authors.lastname: Hamdy
authors.forename: Mark
authors.initials: M
authors.lastname: Meuth
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019175:DNA Methylation; D005260:Female; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D014571:Urologic Neoplasms / Q000235:genetics* / Q000556:secondary*; D019459:Urothelium