This thesis aims to improve our understanding of the genetic and clinical aspects of inherited syndromes associated with adenomatous polyposis in order to optimize surveillance and management and... Show moreThis thesis aims to improve our understanding of the genetic and clinical aspects of inherited syndromes associated with adenomatous polyposis in order to optimize surveillance and management and to improve life expectancy of these patients. Hereditary polyposis syndromes are a group of syndromes characterized by the development of multiple colorectal polyps and a high risk of developing colorectal cancer at an early age. Familial adenomatous polyposis (FAP) is the most common polyposis syndrome characterised by development of hundreds to thousands of adenomatous polyps. MUTYH-associated polyposis (MAP) is found in 10-20% of patients with polyposis. In the first part of this thesis, we examined genetic modifiers of cancer risk on the phenotype of FAP. In addition, we studied the occurrence of extracolonic malignancies and whether these malignancies are an important cause of death. We also studied the prevalence of Barret’s Oesophagus in a large cohort of patients with MAP and FAP. Patients with Constitutional mismatch-repair deficiency syndrome (CMMRD) develop a wide spectrum of malignancies beginning in childhood. In the second part, we developed a surveillance program to detect the most common cancers in patients with CMMRD and assessed the effectiveness of this surveillance program and discussed possible improvements of the protocol. Show less
In conclusion, this thesis describes several new insights into polyposis, particularly MUTYH-associated polyposis. This recessive inheritable disease represents approximately 10-20% of all... Show moreIn conclusion, this thesis describes several new insights into polyposis, particularly MUTYH-associated polyposis. This recessive inheritable disease represents approximately 10-20% of all polyposis patients with a wide variety in the phenotype and significant genotype-phenotype correlations. Organ systems outside the gastrointestinal tract seem to be relatively spared in MAP patients. Colorectal carcinoma in MAP patients have some specific molecular and histological features, which are similar to MSI-high and Lynch-associated CRCs, such as a preferential proximal location, mucinous histotype, and increased presence of TILs. These TILs could be associated with higher activated immune response, which leads to reduced tumour growth and reduced metastasis. Indeed, better survival in MAP carcinomas was found in a European MAP cohort. Furthermore, it was shown that APC deletion and APC mosaicism represent a substantial number of the discovered APC mutations. The remaining APC and MUTYH negative polyposis patients might have the following: mutations in high penetrance CRC associated genes that are yet to be discovered, mutations in non-scanned parts of the MUTYH or APC genes, or a combination of low penetrance alleles. Show less
