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Determining the origin of synchronous multifocal bladder cancer by exome sequencing | BMC Cancer
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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.
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Keywords {🔍}
snvs, tumours, cancer, samples, mutations, tumour, bladder, patients, additional, article, tpc, shared, multifocal, file, pubmed, analysis, origin, normal, data, clonal, sequencing, table, sample, patient, google, scholar, genetic, results, genome, cas, synchronous, snv, urothelial, mutation, cancers, demonstrated, test, study, mucosa, human, reference, indels, exome, number, field, phylogenetic, fishers, exact, found, early,
Topics {✒️}
x-chromosomal inactivation patterns article download pdf apobec-mediated mutations occurred produced conflicting reports paired-end illumina sequencing neighbor-joining algorithm suggested multifocal bladder cancer exact test p-values urothelial bladder carcinoma related subjects upper urinary tract late bladder cancer privacy choices/manage cookies bladder cancer lesion apobec-mediated deamination full access intrinsic genetic instability article acar apobec-mediated mutations gatk quality filter strict filtering criteria gatk quality score creative commons license low/high grade intratumoural mutation heterogeneity paired-end mode [8] bmc cancer 15 metachronous multifocal tumours reflect synchronous tumours single nucleotide polymorphisms apobec3 cytidine deaminases urothelial cancer initiation nj algorithm based comprehensive molecular characterization physically independent tumours tissue- specific variants apobec mutations occur reference human genome human reference genome population genetic analysis clin cancer res multiple human cancers results exome sequencing tarık esen high technical noise previous studies results strongly support classic work characterizing genome analysis toolkit normal bladder mucosa
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headline:Determining the origin of synchronous multifocal bladder cancer by exome sequencing
description: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. 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. 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. 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.
datePublished:2015-11-09T00:00:00Z
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Multifocal bladder cancer
Next-generation sequencing, Population genetics, APOBEC deaminase
Cancer Research
Oncology
Surgical Oncology
Health Promotion and Disease Prevention
Biomedicine
general
Medicine/Public Health
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headline:Determining the origin of synchronous multifocal bladder cancer by exome sequencing
description: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. 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. 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. 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.
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Multifocal bladder cancer
Next-generation sequencing, Population genetics, APOBEC deaminase
Cancer Research
Oncology
Surgical Oncology
Health Promotion and Disease Prevention
Biomedicine
general
Medicine/Public Health
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