The first part of this thesis evaluates the proportion of germline APC and MUTYH pathogenic variants in colorectal polyposis patients and subsequently identifies the substantial proportion... Show moreThe first part of this thesis evaluates the proportion of germline APC and MUTYH pathogenic variants in colorectal polyposis patients and subsequently identifies the substantial proportion polyposis patients remaining unexplained. Part II of this thesis elucidates the significance of APC mosaicism in these unexplained polyposis patients. Analysis of more than 400 patients resulted in a suggestion for both testing and surveillance guidelines. Moreover, chapter 4 describes the interesting finding of multiple APC mosaicism cases in one family with the family members having distinct mosaic patterns and phenotypes. The last part of this thesis assesses another explanation for the development of colorectal adenomatous polyps, namely the presence of pks+ E. coli and colibactin-associated mutational signatures. In this part we describe the common c.835-8A>G APC splice variant as fitting the mutational signature caused by colibactin, which is produced by pks+ E. coli. Moreover, we examine this mutational signature and fecal pks genes in a random selection of our cohort. Show less
Notwithstanding the hereditary colorectal cancer (CRC) syndromes where the underlying genetic defects have been characterized, for the vast majority of familial cases (15-20%) the disease-causing... Show moreNotwithstanding the hereditary colorectal cancer (CRC) syndromes where the underlying genetic defects have been characterized, for the vast majority of familial cases (15-20%) the disease-causing genes remain unknown, posing serious problems for genetic counselling and patient management of individuals at risk. Aiming to improve the molecular classification of familial CRC, an omics-based approach employing BAC (aCGH), cDNA microarrays and distinct in silico analytical strategies were used to study both the genomic and expression profiles generated from a large collection of colorectal adenomatous polyps. Though the overall results showed a high degree of similarity shared by genomic and expression profiles of familial colonic adenomas, which casts several serious doubts on the classification of hereditary CRC syndromes by omics technologies, the presented findings also argue in favour of a common molecular basis for CRC formation and contribute to the elucidation of the early events associated with colorectal tumorigenesis, namely the early occurrence of CIN and of the complex cross-talk between signalling pathways, in hereditary and in sporadic CRC and even across-species, and additionally in highlighting the power of integrated approaches in the discovery and prioritization of putative targets involved in colorectal tumorigenesis. Show less
