Skip to main content
Article thumbnail
Location of Repository

Gastrointestinal Polyposis Syndromes : Clinical and molecular aspects of Familial Adenomatous Polyposis and Juvenile Polyposis

By L.A.A. Brosens


Colorectal cancer (CRC) is an important cause death. In the Netherlands, approximately 10.000 patients are diagnosed with CRC each year. Rare hereditary gastrointestinal polyposis syndromes predisposing to CRC, including familial adenomatous polyposis (FAP), juvenile polyposis (JPS) and Peutz-Jeghers syndrome (PJS), have provided a model for the investigation of cancer initiation and progression in the general population. Many insights in the molecular genetic basis of CRC have emerged from studying these syndromes. The first part of this thesis is about duodenal polyposis in FAP and chemoprevention with NSAIDs. With improved management of colorectal disease and increased life expectancy of FAP patients, duodenal polyps and adenocarcinoma have become major health problems in these patients. Surveillance, endoscopic and surgical treatment and the value of NSAID chemoprevention for duodenal polyposis are reviewed. Results of NSAIDs on regression or prevention of duodenal adenomas in FAP appear disappointing. Expression of the main target of NSAIDs, cyclooxygenase-2 (COX-2) was studied and compared between colorectal and duodenal adenomas from patients with FAP. Levels of COX-2 appeared to be significantly higher in the duodenum than in the colorectum of FAP patients, which may explain the poorer response of duodenal adenomas to COX-2 inhibition, suggesting that higher dosages of COX-2 inhibitors are needed for treatment of duodenal adenomas. The second part of this thesis focuses on clinical and molecular aspects of JPS. We performed person-year analysis to define the magnitude of risk for gastrointestinal cancer in JPS. A relative risk of colorectal cancer of 34 and a cumulative life-time risk of 38.7% in JPS was found. JPS is caused by germline mutation of the SMAD4 or BMPR1A gene, but a germline mutation is found in only 30-40% of patients. Likely, alternative ways of inactivation of these genes exist. Therefore, we used MLPA to investigate whether germline deletion of these genes may cause JPS. By combining sequencing and MLPA, a germline defect in SMAD4 or BMPR1A was found in almost 50% of the patients. Nine mutations (33.3%) were detected by direct sequencing, whereas four germline hemizygous large genomic deletion (14.8%) were found using MLPA. Prevention of polyp and neoplasia development in juvenile polyposis using chemoprevention may be useful in the treatment of these patients. We measured expression of COX-2 in juvenile polyps to investigate the potential value of chemoprevention by COX-2 inhibition. Increased levels of COX-2 were found in juvenile polyps from JPS patients, suggesting that chemoprevention using COX-2 inhibition can be beneficial in JPS. Lastly, we studied molecular aspects of juvenile polyps from patients with a SMAD4 germline defect. Focal reduction or loss of SMAD4 expression was present in the epithelium of about half of the juvenile polyps from SMAD4 mutation carriers. LOH or somatic mutation of the wild type SMAD4 allele was found in cases with aberrant SMAD4 protein expression. These findings do not support a “landscaper” mechanism for SMAD4, although stromal haploinsufficiency or loss of SMAD4 may still have a role in polyp initiation and epithelial loss may only occur at a later stage in polyp progression. Surprisingly, loss of epithelial SMAD4 immunostaining did not correlate with dysplasia in polyps, suggesting that loss of the wild type allele is not obligatory for dysplastic change in juvenile polyps, not fitting with the typical tumor-suppressor/“gatekeeper” role for SMAD4, as previously suggested

Publisher: Utrecht University
Year: 2008
OAI identifier:
Download PDF:
Sorry, we are unable to provide the full text but you may find it at the following location(s):
  • (external link)
  • Suggested articles

    To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.