Determining the origin of synchronous multifocal bladder cancer by exome sequencing. Issue 1 (December 2015)

• Record Type: Journal Article
• Authors: Acar, Ömer; Özkurt, Ezgi; Demir, Gulfem; Saraç, Hilal; Alkan, Can; Esen, Tarık; Somel, Mehmet; Lack, Nathan
• Is Part Of: BMC cancer. Volume 15:Issue 1(2015)
• Page Start: 1
• Page End: 7
• Publication Date: 2015-12
• Subjects: Multifocal bladder cancer -- Next-generation sequencing, Population genetics, APOBEC deaminase; Cancer -- Periodicals; 616.994005
• DOI: 10.1186/s12885-015-1859-8
• Languages: English
• ISSNs: 1471-2407

Abstract

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 testp < 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.