Evolution of bladder cancer investigated using exome sequencing

Özkurt, Ezgi
New genome sequencing technologies today allow the study of cancer evolution within individual tissues. In bladder cancer, it is commonly observed that multiple tumours co-occur in a tissue. However, whether these tumours are related (clonal hypothesis) or develop independently but synchronously (field effect hypothesis), was yet unknown. In this study, exome sequencing data was utilized to reveal the origin of multifocal tumours. The data was generated in an experiment where samples from bladder tumour (3 tumour samples per patient) and neighbouring normal mucosa (1 normal sample per patient) from 3 patients were collected and sequenced. The tumour samples were composed of apex and base sections of the tumours. Thousands of single nucleotide variants (SNV) were called in each patient. The phylogenetic trees constructed by SNV datasets of the 2 patients showed a topology consistent with clonal origin hypothesis, with a long shared tumour branch, indicating that the tumours derive from the same origin. The third patient's samples were suspected to be contaminated with neoplastic material, and thus not included in the rest of the analysis. An analysis of SNV types with respect to sequence context revealed that TpC* mutations were particularly enriched on the shared tumour branch, indicative of activity of APOBEC enzymes (single stranded DNA/RNA editing proteins) causing accumulation of TpC* mutations. Thus, it is hypothesized that a period of APOBEC activity led to accumulation of TpC* mutations, some of which included driver mutations that led to tumour formation, and subsequent separation of the tumours in 2 patients.
Citation Formats
E. Özkurt, “Evolution of bladder cancer investigated using exome sequencing,” M.S. - Master of Science, Middle East Technical University, 2015.