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Lipton, Lara R
01/2006Dissertation
Colorectal cancer in the commonest internal malignancy in western society today. At least a third of the incidence is likely to be due entirely or in part to inherited genetic factors. Over the last 15 years several genes have been described in which germline mutation leading to increased colorectal cancer risk may occur. The commonest are Hereditary Non-Polyposis Colorectal Cancer (HNPCC), which accounts for around 1-4% of colorectal cancer diagnosis without polyposis and is caused by mutations in mismatch repair genes and Familial Adenomatous Polyposis caused by mutations in the AFC gene. In this thesis two related themes are addressed. Firstly I examine clinical, pathologic and molecular genetic information in kindreds recruited from family cancer clinics in order to investigate several relevant clinical problems relating to decisions regarding genetic testing and clustering of non-HNPCC families. Secondly, the group of individuals and families with multiple colorectal polyps without known genetic cause are investigated in several ways. A candidate gene analysis is undertaken looking for germline changes, an analysis of adenomas from such individuals for informative somatic changes is performed and I describe a new inherited syndrome of colorectal cancer and polyposis, MYH associated polyposis as well as the pathway of tumourigenesis in affected individuals.
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