BACKGROUND: Synchronous multifocal @entity5 are commonly observed in @entity189 of the bladder. The origin of these physically independent @entity5 has been proposed to occur by either intraluminal migration (clonal) or spontaneous transformation of multiple cells by carcinogens (field effect). It is unclear which model is correct, with several studies supporting both hypotheses. A potential cause of this uncertainty may be the small number of genetic mutations previously used to quantify the relationship between these @entity5 . METHODS: To better understand the genetic lineage of these @entity5 we conducted exome sequencing of synchronous multifocal pTa @entity150 at a high depth, using multiple samples from three @entity1 . RESULTS: Phylogenetic analysis of high confidence single @entity4334 variants (SNV) demonstrated that the sequenced multifocal @entity150 arose from a clonal origin in all three @entity1 (bootstrap value 100 %). Interestingly, in two @entity1 the most common type of @entity5 -associated SNVs were cytosine mutations of @entity33874 @entity2354 (Fisher's exact test p   <   10(-41)), likely caused by APOBEC-mediated deamination. Incorporating these results into our clonal model, we found that @entity33874 type mutations occurred 2-5* more often among SNVs on the ancestral branches than in the more recent private branches (p   <   10(-4)) suggesting that @entity33874 mutations largely occurred early in the development of the @entity5 . CONCLUSIONS: These results demonstrate that synchronous multifocal @entity150 frequently arise from a clonal origin. Our data also suggests that APOBEC-mediated mutations occur early in the development of the @entity5 and may be a driver of tumourigenesis in non-muscle invasive @entity150 .

Determining the origin of synchronous multifocal XXXX by exome sequencing.

@entity1 :: ('9606', 'Species') :: ['patients'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumours', 'tumour'] @entity189 :: ('MESH:D002277', 'Disease') :: ['urothelial carcinomas'] @entity2354 :: ('CHEBI:47885', 'Chemical') :: ['dinucleotides'] @entity150 :: ('MESH:D001749', 'Disease') :: ['urothelial bladder cancers', 'bladder cancers', 'urothelial bladder cancer'] @entity4334 :: ('D009711', 'Chemical') :: ['nucleotide'] @entity33874 :: ('60386', 'Gene') :: ['TpC*']
@entity150 :: (MESH:D001749,Disease) :: ['bladder cancer']
