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      • Department of Computer Engineering
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      Determining the origin of synchronous multifocal bladder cancer by exome sequencing

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      Author(s)
      Acar, Ö.
      Özkurt, E.
      Demir, G.
      Saraç, H.
      Alkan C.
      Esen, T.
      Somel, M.
      Lack, N. A.
      Date
      2015
      Source Title
      BMC Cancer
      Print ISSN
      1471-2407
      Publisher
      BioMed Central Ltd.
      Volume
      15
      Pages
      1 - 7
      Language
      English
      Type
      Article
      Item Usage Stats
      207
      views
      137
      downloads
      Abstract
      Background: Synchronous multifocal tumours are commonly observed in urothelial carcinomas of the bladder. The origin of these physically independent tumours 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 tumours. Methods: To better understand the genetic lineage of these tumours we conducted exome sequencing of synchronous multifocal pTa urothelial bladder cancers at a high depth, using multiple samples from three patients. Results: Phylogenetic analysis of high confidence single nucleotide variants (SNV) demonstrated that the sequenced multifocal bladder cancers arose from a clonal origin in all three patients (bootstrap value 100 %). Interestingly, in two patients the most common type of tumour-associated SNVs were cytosine mutations of TpC*dinucleotides (Fisher's exact test p < 10-41), likely caused by APOBEC-mediated deamination. Incorporating these results into our clonal model, we found that TpC*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 TpC*mutations largely occurred early in the development of the tumour. Conclusions: These results demonstrate that synchronous multifocal bladder cancers frequently arise from a clonal origin. Our data also suggests that APOBEC-mediated mutations occur early in the development of the tumour and may be a driver of tumourigenesis in non-muscle invasive urothelial bladder cancer.
      Keywords
      APOBEC deaminase
      Multifocal bladder cancer
      Population genetics
      Cytosine deaminase
      Dinucleotide
      Protein APOBEC3B
      Unclassified drug
      Adult
      Aged
      Bladder cancer
      Case report
      Clonal variation
      Controlled study
      Deamination
      Exome
      Gene sequence
      Genetic marker
      Genetic variability
      Genomic instability
      Human
      Human tissue
      Male
      Molecular model
      Multiple cancer
      Mutational analysis
      Next generation sequencing
      Single nucleotide variant
      Permalink
      http://hdl.handle.net/11693/26530
      Published Version (Please cite this version)
      http://dx.doi.org/10.1186/s12885-015-1859-8
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      • Department of Computer Engineering 1568
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