Ann Med

Hirschsprungs disease genes and the development of the enteric nervous system.

Year 1998
Wartiovaara K. Salo M. Sariola H.
Institute of Biotechnology, Developmental Biology Research Programme, University of Helsinki, Hospital for Children and Adolescents, Finland. kawrtiov@helsinki.fi
Hirschsprung's disease or aganglionic megacolon causes chronic, congenital obstipation at an incidence of 1 per 5000 live births. Two approaches have been vital to the present understanding of the pathogenesis and genetic background of the disease: disease linkage analyses and mouse models of aganglionic megacolon. Because the increasing number of transgenic or natural mouse strains with congenital megacolon has led to mutation screening in Hirschsprung's disease patients, almost every second patient could now receive a genetic explanation for his/her disease. The known disease genes include tyrosine kinase receptor Ret, endothelin receptor B and its ligand endothelin 3. In addition, mutations have been found in the gene encoding the glial cell line-derived neurotrophic factor, the ligand for Ret, but these may only have a modifier effect. The mouse models have also provided insight into the developmental mechanisms of the normal intestinal innervation. We combine here the present clinical data on the gene mutations in Hirschsprung's disease with the experimental molecular biology data, and formulate a hypothesis on the pathogenesis of this multigenic-multifactorial disease.

Prognosis of colorectal cancer varies in different high-risk conditions.

Year 1998
Aarnio M. Mustonen H. Mecklin JP. Jarvinen HJ.
Department of Surgery, Helsinki University Central Hospital, Finland.
Variation in prognosis between different colorectal cancer (CRC) patient groups was studied by comparing the survival rates of patients belonging to three cancer predisposition groups with those with sporadic CRC. The high-risk groups included 43 members of hereditary nonpolyposis colorectal cancer (HNPCC) families, 25 patients with familial adenomatous polyposis (FAP) and 33 patients with underlying ulcerative colitis (UC). The control group included 122 consecutive sporadic CRC patients. Cumulative 5-year survival was highest in HNPCC (86%), which is significantly better than in sporadic colorectal cancer (59%, hazard ratio 0.41, P = 0.02). Cancer associated with UC had a 5-year survival rate of 39%, which is significantly less than in sporadic cancer (hazard ratio 1.83, P = 0.03). There was no significant difference in the survival between patients with FAP and patients with sporadic CRC (hazard ratio 1.27, P = 0.5). Exclusion of cases detected by screening examinations slightly reduced the survival rates; 85% for HNPCC, 53% for FAP and 28% for UC. However, the differences between the groups remained significant. The survival of patients with HNPCC was found to be better than that among other groups in this study, which probably relates to the specific tumourigenesis involving DNA mismatch repair dysfunction.