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Title: Mutation detection in normal mucosa and early lesions of colorectal cancer
Author: Sutton, Kate Marie
ISNI:       0000 0004 5358 7650
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2014
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Colorectal cancer (CRC) has a relatively poor prognosis when detected at a later stage, therefore understanding its development to allow prevention or early detection is key to improving outcomes. Bowel cancer screening allows for the detection of tumours and precursor lesions. Even earlier changes could potentially be detected; genetic aberrations within the normal bowel before phenotypic changes occur. Early lesions may develop independently throughout the bowel or through a cancer field effect. FAP adenomas are a useful model due to adenomas developing within the same environment and all incurring the same first “hit” within APC. Using next generation sequencing the genetic profiles of FAP adenomas can be compared to better understand the development of these lesions. Firstly the sensitivity of pyrosequencing and NGS was determined as was the value of PCR-based mutant enrichment techniques. Samples of carcinoma, adenoma and their associated normals alongside normal mucosa from patients with normal colonoscopies were tested for mutations in commonly mutated genes in CRC using NGS. Multiple FAP adenomas from four patients were also tested with this mutation panel. Alongside this, copy number analysis was performed. The mutational and copy number data was used to ascertain the pattern of adenoma development throughout the bowel. Mutations were detected in carcinoma associated normal in APC, KRAS, CTNNB1 and SMAD4. The KRAS mutations in carcinoma associated normal differed to the KRAS mutation in the matched tumour. No mutations were detected in oncogenes in adenoma associated normal or normal mucosa from patients with normal colonoscopies. Studying mutations and copy number aberrations in FAP adenomas revealed that some adenomas shared specific lesions, indicating that they were clonally related. These results have confirmed previously findings of KRAS mutations in carcinoma associated normal mucosa as well as describing mutations in APC, CTNNB1 and SMAD4. This combined with the large amount of similarity in terms of mutations and copy number seen in adenomas from the same patient provides evidence for the cancer field theory.
Supervisor: Quirke, Phil Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available