Mutational context and diverse clonal development in early and late bladder cancer

Cell Rep. 2014 Jun 12;7(5):1649-1663. doi: 10.1016/j.celrep.2014.04.038. Epub 2014 May 15.


Bladder cancer (or urothelial cell carcinoma [UCC]) is characterized by field disease (malignant alterations in surrounding mucosa) and frequent recurrences. Whole-genome, exome, and transcriptome sequencing of 38 tumors, including four metachronous tumor pairs and 20 superficial tumors, identified an APOBEC mutational signature in one-third. This was biased toward the sense strand, correlated with mean expression level, and clustered near breakpoints. A>G mutations were up to eight times more frequent on the sense strand (p<0.002) in [ACG]AT contexts. The patient-specific APOBEC signature was negatively correlated to repair-gene expression and was not related to clinicopathological parameters. Mutations in gene families and single genes were related to tumor stage, and expression of chromatin modifiers correlated with survival. Evolutionary and subclonal analyses of early/late tumor pairs showed a unitary origin, and discrete tumor clones contained mutated cancer genes. The ancestral clones contained Pik3ca/Kdm6a mutations and may reflect the field-disease mutations shared among later tumors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • APOBEC-1 Deaminase
  • Carcinoma / genetics*
  • Carcinoma / pathology
  • Class I Phosphatidylinositol 3-Kinases
  • Clonal Evolution*
  • Cytidine Deaminase / genetics
  • Cytidine Deaminase / metabolism
  • DNA Repair
  • DNA, Antisense / genetics
  • Humans
  • Phosphatidylinositol 3-Kinases / genetics
  • Point Mutation*
  • Transcriptome
  • Urinary Bladder Neoplasms / genetics*
  • Urinary Bladder Neoplasms / pathology


  • DNA, Antisense
  • Phosphatidylinositol 3-Kinases
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • APOBEC-1 Deaminase
  • APOBEC1 protein, human
  • Cytidine Deaminase