Determining the origin of synchronous multifocal bladder cancer by exome sequencing

dc.citation.epage7en_US
dc.citation.spage1en_US
dc.citation.volumeNumber15en_US
dc.contributor.authorAcar, Ö.en_US
dc.contributor.authorÖzkurt, E.en_US
dc.contributor.authorDemir, G.en_US
dc.contributor.authorSaraç, H.en_US
dc.contributor.authorAlkan C.en_US
dc.contributor.authorEsen, T.en_US
dc.contributor.authorSomel, M.en_US
dc.contributor.authorLack, N. A.en_US
dc.date.accessioned2016-02-08T11:01:09Z
dc.date.available2016-02-08T11:01:09Z
dc.date.issued2015en_US
dc.departmentDepartment of Computer Engineeringen_US
dc.description.abstractBackground: 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.en_US
dc.identifier.doi10.1186/s12885-015-1859-8en_US
dc.identifier.issn1471-2407
dc.identifier.urihttp://hdl.handle.net/11693/26530
dc.language.isoEnglishen_US
dc.publisherBioMed Central Ltd.en_US
dc.relation.isversionofhttp://dx.doi.org/10.1186/s12885-015-1859-8en_US
dc.source.titleBMC Canceren_US
dc.subjectAPOBEC deaminaseen_US
dc.subjectMultifocal bladder canceren_US
dc.subjectPopulation geneticsen_US
dc.subjectCytosine deaminaseen_US
dc.subjectDinucleotideen_US
dc.subjectProtein APOBEC3Ben_US
dc.subjectUnclassified drugen_US
dc.subjectAdulten_US
dc.subjectAgeden_US
dc.subjectBladder canceren_US
dc.subjectCase reporten_US
dc.subjectClonal variationen_US
dc.subjectControlled studyen_US
dc.subjectDeaminationen_US
dc.subjectExomeen_US
dc.subjectGene sequenceen_US
dc.subjectGenetic markeren_US
dc.subjectGenetic variabilityen_US
dc.subjectGenomic instabilityen_US
dc.subjectHumanen_US
dc.subjectHuman tissueen_US
dc.subjectMaleen_US
dc.subjectMolecular modelen_US
dc.subjectMultiple canceren_US
dc.subjectMutational analysisen_US
dc.subjectNext generation sequencingen_US
dc.subjectSingle nucleotide varianten_US
dc.titleDetermining the origin of synchronous multifocal bladder cancer by exome sequencingen_US
dc.typeArticleen_US
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