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dc.contributor.authorMitchell, Rory J.en
dc.date.accessioned2019-02-15T14:37:27Z
dc.date.available2019-02-15T14:37:27Z
dc.date.issued2004en
dc.identifier.urihttp://hdl.handle.net/1842/35364
dc.description.abstracten
dc.description.abstractThe identification of people at increased genetic risk of colorectal cancer and the provision of appropriate clinical screening represents one approach to the prevention of colorectal cancer in the Scottish population. This thesis aims to contribute to current knowledge regarding the available tools for identifying those at increased genetic risk in a population, namely genetic testing and family history assessment.en
dc.description.abstractKey issues relating to the use of family history in this context were addressed through the analysis of a unique data set, comprising family history information reported by a colorectal cancer case or control subject at interview and the results of record linkage of this data to the Scottish Cancer Registry. Retrospective family history case-control analysis showed that individuals with an affected first-degree relative were at an increased risk of developing colorectal cancer (ORimh 2.14, 95% CI = 1.11, 4.14). Prevalence of such a family history in control subjects was 9.4% (95% CI = 4.9, 13.9). Substantial under-reporting of family history was evident, with sensitivity of interview as a means of determining a history of colorectal cancer in a first-degree relative being approximately 0.55 for both cases and controls. These studies illustrate the potential advantages of targeting people with a family history, but also highlight some of the limitations of such an approach.en
dc.description.abstractThe genetic epidemiology of the mismatch repair genes hMLH 1 and hMSH2 and their association with colorectal cancer was considered in a systematic literature review. Although conventional epidemiological studies are lacking, there is compelling evidence to implicate mutations in these genes in the aetiology of a sub-set of colorectal cancers, with penetrance of approximately 80% in males and 40% in females. A total of 550 different published gene variants were identified, and this high degree of heterogeneity was illustrated in a unique database. This review indicates that carriers of mismatch repair gene mutations merit particular consideration in the context of colorectal cancer prevention through targeting people at increased genetic risk.en
dc.description.abstractAccordingly, the challenge of identifying asymptomatic mismatch repair gene mutation carriers in Scotland was addressed through the development of a computer model of cascade genetic testing, a strategy in which a mutation is identified in one family member and systematically traced through a pedigree. The model predicts that application of cascade genetic testing to colorectal cancer cases < 55 years of age over a twenty- year period would involve testing 7142 patients and 849 relatives of known carriers, and would identify 321.2 (95%CI = 305.3, 337.1) asymptomatic mutation carriers, representing approximately 27% of the estimated 1209 carriers in Scotland. Model outcomes were highly sensitive to the prevalence and penetrance of mutations, and the participation rates of those offered testing. Overall, outcomes from this computer model suggest that cascade genetic testing is potentially a useful means of identifying asymptomatic mismatch repair gene mutation carriers in Scotland. Followup work should ensure that it is also of practical importance as a tool for planning research and health policy.en
dc.description.abstractIdentification and screening of mismatch repair gene mutation carriers is an important approach to colorectal cancer prevention, but is only relevant to a minority of people at increased genetic risk. Hence, despite inherent limitations, family history remains a crucial tool for genetic risk assessment in a population. An integrated approach to the prevention of colorectal cancer through targeting people at increased genetic risk can potentially provide substantial health benefits to a sub-group of the population, and thus contribute to the overall prevention of colorectal cancer in Scotland.en
dc.publisherThe University of Edinburghen
dc.relation.ispartofAnnexe Thesis Digitisation Project 2019 Block 22en
dc.relation.isreferencedbyAlready catalogueden
dc.titlePrevention of colorectal cancer in Scotland: strategies for those at increased genetic risken
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


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