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Title: APC mutation spectra and microsatellite instability in colorectal cancer and their relationship with dietary and other lifestyle factors
Author: Gay, L. J.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2009
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Mutation analysis of the mutation cluster region (MCR) of APC (codons 1276-1556) and MSI analysis was performed on 185 tumour samples from participants of the European Prospective Investigation into Cancer and Nutrition (EPIC) Norfolk Study, with the aim of relating the molecular changes to dietary and lifestyle information collected at the start of the study. For the APC analysis, genomic DNA was extracted from formalin-fixed archival tissue, amplified and sequenced. Repeat analysis identified mutations that were consistently found (confirmed), from those that were not (unconfirmed). Overall, 43% of cancers had a confirmed mutation with hotspots at codons 1276, 1306, 1415, 1450 and 1556. Comparison of APC mutations by clinico-pathological features (sex, age, BMI, tumour site and Dukes’ stage) revealed that proximal colon tumours had more confirmed point mutations, whereas distal tumours had more transversions (P = 0.04). Negative MLH1 protein expression, high MLH1 promoter methylation (>50%) and MSI-High tumours were more likely to be from female cases, proximal in location and early Dukes’ stage (P = 0.03, 0.02 and 0.001 respectively). Case analysis of APC and MSI patterns by smoking status, red and processed meat consumption revealed that cases with processed meat intake above the mean (>26 g/day) were more likely to have confirmed GC to AT transitions (P = 0.05). In summary, this detailed study of APC and MSI patterns showed that the APC mutation spectra differed by tumour site, possibly due to the different physiological environments in the colon. MSI-H tumours were distinct, highlighting the different MSI pathway. The association of CRC with processed meat consumption suggests a mechanistic link between dietary alkylating agents, such as N-Nitroso compounds, and GC to AT transitions.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available