Studies on familial adenomatous polyposis

Sammanfattning: Familial adenomatous polyposis (FAP) is a hereditary disorder caused by mutations in the adenomatous polyposis coli (APC) gene, which leads to adenoma formation and subsequently to cancer, predominantly in the colon and the rectum but also in the duodenum. The cancer morbidity and mortality can be decreased by presymtomatic screening and surgical treatment. We have therefore studied the epidemiology of the disease in the Swedish population over time and the effect of family screening. Data was obtained from the Swedish Polyposis Registry, which was set up in the late 1950s. The registry included 431 patients in 145 families at the end of 1996. The risk of having colorectal cancer (CRC) at diagnosis was very low in patients detected by screening. Moreover, females were diagnosed with symptoms and CRC significantly earlier than males. The most common surgical treatment for FAP has been colectomy and ileorectal anastomosis (IRA), but since the early 1980s, restorative proctocolectomy and ileal pouch-anal anastomosis (IPAA) has been an alternative to IRA. Patients with IRA remain at risk of rectal cancer. Therefore we investigated the risk of rectal cancer and rectal amputation after IRA and searched for risk factors that could predict the fate of the rectal stump. We also compared the surgical and functional outcome of IRA and IPAA. Rectal cancer occurred in almost 10% of IRA operated patients despite a high rectal excision rate. Dense polyposis was shown to be a risk factor for a malignant trait. However, the functional outcome was better after IRA, compared to IPAA. Duodenal cancer has become the second most common cause of death in FAP patients as screening and prophylactic treatment of CRC have improved. We assessed the risk of premalignant and malignant lesions in the periampullary region of the duodenum in 180 patients screened by upper endoscopy. The cumulative risk at age 60 of periampullary advanced adenomas and adenocarcinomas was 20% and 10%, respectively. We also investigated the APC gene mutations in families with these lesions. Mutations were found in 14 out of 16 families accessible for analysis and they were clustered between codons 1051- 1309 in exon 15 of the APC gene. The pathogenesis of intestinal adenomatosis in FAP is still unknown. Thus, we studied tenascin and alkaline sphingomyelinase, factors that have been implicated in the regulation of epithelial cell growth regulation. Tenascin, an extracellular matrix constituent, was found to be differently expressed in dysplastic and hyperplastic mucosa of rectal adenomas in FAP patients compared to surrounding normal mucosa and mucosa from controls. The sphingomyelinase activity was decreased both in adenomas and surrounding normal mucosa from FAP patients. In conclusion, a national screening program for FAP efficiently reduces the risk of CRC although patients operated with IRA are still at risk of rectal cancer, especially those with a high number of polyps at operation. It also demonstrates the influence of gender on the course of the disease. IPAA, although more radical than IRA, has the disadvantage of a poorer functional outcome. Duodenal cancer is a an increasing clinical problem and advanced periampullary adenomas together with genotype seem to be predictive of prognosis. Tenascin and alkaline sphingomyelinase may be involved in the pathogenesis of adenoma formation in FAR