Gastrointestinal polyposis syndromes are characterized by the development of gastrointestinal polyps and an increased risk for neoplastic transformation. Peutz-Jeghers syndrome is a polyposis syndrome characterized by the development of gastrointestinal hamartomas; the molecular and histopathological origin of these polyps is unclear and hence the pre-malignant potential, if any, of these polyps remains unresolved. Current follow-up protocols mandate removal of polyps to decrease risk of intussusception as well as to decrease risk of neoplastic transformation. The current thesis investigates the premalignant potential of these polyps and proposes that in fact the polyps are an epiphenomenon to the malignant condition. Polyp removal therefore does not necessarily reduce cancer risk. Furthermore we show that abnormalities can be demonstrated in normal (id est unaffected) epithelia in Peutz-Jeghers syndrome that may suggest protracted clonal evolution at the level of the intestinal stem cell niche. Altered clonal evolution in the crypt would jointly explain the development of the benign gastrointestinal hamartomas as well as an increased risk for neoplastic transformation in these patients. Lastly, we show that the linchpin component of the Wnt signalling pathway, beta-catenin, appears on the plasma membrane upon Wnt treatment in Wnt-responsive cells. This suggests a previously unappreciated step in a signalling pathway frequently deregulated in familial and sporadic forms of colorectal cancer
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