Sieber, Oliver; (2004) The genetic basis of the multiple colorectal adenoma phenotype. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Multiple adenoma patients are characterised by 3-100 colorectal adenomas, resulting in an increased risk of colorectal cancer. The disease can be inherited as a Mendelian trait, either autosomal dominant or recessive, or occur sporadically. Approximately 10% of multiple adenoma patients carry a truncating mutation in the APC gene, usually in exons 1-4, exon 9 or the 3'-half of exon 15, producing a diagnosis of AAPC. Two APC missense variants, I1307K and E1317Q, have also been associated with the disease, and some whole-gene deletions have been reported. However, these latter associations have been inconsistent. In contrast, germline mutations in the central region of APC cause classical FAP, a dominant predisposition to hundreds or thousands of colorectal adenomas, resulting in a near 100% risk of cancer. The molecular mechanisms underlying these genotype-phenotype correlations are poorly understood. The genetic basis of multiple adenomas in patients without APC mutation remains to be identified. In this thesis, I have excluded a major role of whole-gene APC deletions in causing AAPC/multiple adenomas. Instead, individuals with such mutations were found to develop classical FAP. I have refined the relationship between germline and somatic mutations at the APC locus in AAPC and classical FAP to show that somatic mutations are constrained by selection for an optimal level of Wnt signalling and that this at least partly determines disease severity. In support of this view, I have provided evidence against a role of truncating APC mutations in causing chromosomal instability. I have shown that the genetic basis underlying multiple adenomas is heterogeneous, by establishing the importance of recessive germline mutations in the base excision repair gene MYH. Some individuals with such mutations were also found to develop classical polyposis. I provide evidence that multiple adenomas are not generally attributable to germline mutations in the Wnt and TGFβ/BMP signalling pathways.

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