Geno- and phenotypical characteristics of gastrointestinal polyposis syndromes

Intestinal cancer research has focussed on understanding the process of tumour formation for which hereditary disorders have proven to be valuable models. Although much is known about the genetic events that occur during the adenoma-carcinoma sequence, little is known about the genetic events that take place before the visible histopathological changes, a process called pre-tumour progression. This is mainly because many mutations are compatible with a histologically normal phenotype which allows adenomas, in general, to appear relatively late in life after the age of 50. Expanding knowledge of (pre) tumour progression in Familial Adenomatous Polyposis (FAP), Juvenile Polyposis (JPS) and Peutz-Jeghers (PJS) syndrome patients allows an increased understanding of cancer development as a whole and to potentially predict an individuals’ susceptibility to tumour development. Our research provides evidence for the presence of pre-tumour progression in FAP patients; FAP patients reveal an increase in methylation patterns diversity which can be used as a read-out for enhanced stem cell longevity. Since intestinal cancer seems to be a disease of the stem cell, altered stem cell dynamics is essential in cancer development. As such, an increase in survival allows stem cells to have more time to accumulate the mutations required to initiate tumour formation. The increase in stem cell longevity seems to be caused by an imbalance in stem cell division due to the APC germline mutation carried by FAP patients. Interestingly, similar results are found in PJS patients; PJS also reveals enhanced stem cell survival, possibly due to the LKB1 germline mutation which they carry. JPS patients carry a SMAD4 or a BMPR1A germline mutation; we have been able to provide evidence that different genotypes result in different phenotypes. Polyps with a predominant stromal compartment are found in BMPR1Amutation carriers, while a more epithelial polyp variant is found in SMAD4 mutation carriers. Interestingly, when determining methylation pattern diversity to be able to establish the presence or absence of pre-tumour progression, BMPR1A mutation carriers reveal enhanced stem cell longevity and an expansion of the stem cell pool while in SMAD4 mutation carriers, hyperproliferation is seen. Both result in tumourigenesis but along different routes. Interestingly, literature has shown SMAD4 mutations to play a central role in the adenoma-carcinoma sequence suggesting that JPS SMAD4 mutation carriers develop tumours through the conventional adenoma-carcinoma sequence. However, by conducting APC, SMAD4 and K-ras mutation analysis and p53, SMAD4 and β-catenin immunohistochemistry, we have been able to contradict this theory. In conclusion, our research has provided evidence that multiple pathways lead to neoplasia in polyposis syndrome patients where aberrant stem cell dynamics seems to play an essential role.