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Title: Mitomycin C induced genetic alterations and tumour evolution in non-muscle-invasive bladder cancer
Author: Astley, Rebecca Jane
ISNI:       0000 0004 7966 9515
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2019
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Bladder cancer (BC) is the ninth most common cancer in the world. There are two main forms of the disease; non-muscle-invasive BC (NMIBC) and muscle-invasive BC (MIBC). NMIBC commonly recurs and multiple tumours may be resected from the same patient over many years. This provides a unique opportunity to study the molecular events that occur during disease evolution. Some patients receive intravesical courses of mitomycin-C (MMC) chemotherapy, which may provide a potent selective advantage during disease evolution. 67 tumours from 23 patients with recurrent NMIBC were analysed for copy number alterations (CNAs) using shallow-pass whole genome sequencing. Recurrent tumours from each patient tended to share CNAs and common changes seen in BC, such as loss of chromosome 9, suggestive of a monoclonal origin. Some patients received a course of MMC. However no CNAs that specifically related to treatment were identified. To better understand chemotherapy related events in NMIBC, 18 tumours from 8 patients who received a course of MMC were analysed using whole exome sequencing. A significant increase in non-synonymous mutations was identified posttreatment. Unique mutations post-treatment displayed a significant increase in the number of transversions, specifically C:G > A:T substitutions, as well as an increase in the number of tandem substitutions, specifically at CC or GG dinucleotides. This is consistent with the types of mutations induced by MMC experimentally. Analysis of the sequence context shows that MMC produces a signature similar to that seen by aflatoxin. Analysis of the clonality of the MMC-induced mutations demonstrates that these unique mutations tend to be subclonal. Overall this work shows that MMC can cause DNA damage that can be identified in post-treatment tumours and this could influence the evolutionary trajectory of the cancer. Further work is required to confirm this mutational signature and fully discern the effect of MMC treatment on the clonal dynamics of NMIBC.
Supervisor: Hurst, Carolyn ; Knowles, Margaret Sponsor: Cancer Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available