Population-based molecular detection of hereditary nonpolyposis colorectal cancer.

PURPOSE: Cancer morbidity and mortality can be dramatically reduced by colonoscopic screening of individuals with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, creating a need to identify HNPCC. We studied how HNPCC identification should be carried out on a large scale in a sensitive and efficient manner. PATIENTS AND METHODS: Colorectal cancer specimens from consecutive newly diagnosed patients were studied for microsatellite instability (MSI). Germline mutations in the MLH1 and MSH2 genes were searched for in MSI(+) individuals. RESULTS: Among 535 colorectal cancer patients, 66 (12%) were MSI(+). Among these, 18 (3.4% of the total) had disease-causing germline mutations in MLH1 or MSH2. Among these 18 patients, five were less than 50 years old, seven had a previous or synchronous colorectal or endometrial cancer, and 15 had at least one first-degree relative with colorectal or endometrial cancer. Notably, 17 (94%) of 18 patients had at least one of these three features, which were present in 22% of all 535 patients. Combining these data with a previous study of 509 patients, mutation-positive HNPCC accounts for 28 (2.7%) of 1,044 cases of colorectal cancer, predicting a greater than one in 740 incidence of mutation-positive individuals in this population. CONCLUSION: Large-scale molecular screening for HNPCC can be done by the described two-stage procedure of MSI determination followed by mutation analysis. Efficiency can be greatly improved by using three high-risk features to select 22% of all patients for MSI analysis, whereby only 6% need to have mutation analysis. Sensitivity is only slightly impaired by this procedure.

Microsatellite instability in adenomas as a marker for hereditary nonpolyposis colorectal cancer.

Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common of the well-defined colorectal cancer syndromes, accounting for at least 2% of the total colorectal cancer burden and carrying a greater than 80% lifetime risk of cancer. Significant reduction in cancer morbidity and mortality can be accomplished by appropriate clinical cancer screening of HNPCC patients with mutations in mismatch repair (MMR) genes. Thus, it is desirable to identify individuals who are mutation-positive. In individuals with cancer, mutation detection can be accomplished relatively efficiently by germline mutation analysis of individuals whose cancers show microsatellite instability (MSI). This study was designed to assess the feasibility of screening colorectal adenoma patients for HNPCC in the same manner. Among 378 adenoma patients, six (1.6%) had at least one MSI adenoma. Five out of the six patients (83%) had a germline MMR gene mutation. We conclude that MSI analysis is a useful method of prescreening colorectal adenoma patients for HNPCC.

Frequency of hereditary nonpolyposis colorectal cancer. A prospective multicenter study in Finland.

PURPOSE: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant cancer syndrome characterized by early onset of colorectal carcinomas (CRC). Recently, two HNPCC genes have been mapped and cloned, one in the short arm of chromosome 2 and another in the short arm of chromosome 3. There has been a major controversy about the frequency of HNPCC. The few estimates available have been based on series selected by age or series representing local area. The purpose of the present study was to design a nonselected, prospective, multicenter study, taking into account the family background and other risk factors of CRC. METHODS: The proportion of HNPCC of all (N = 406) CRC cases was evaluated in a prospective multicenter study. Family history and other risk factors were investigated over a 12-month period for all new CRC patients in ten hospitals. These cases constituted 23 percent of all CRCs diagnosed in Finland during the study period. RESULTS: Three (0.7 percent) cases of verified and seven (1.7 percent) cases of suspected HNPCC were identified, following the evaluation of all families with features indicative of susceptibility to cancer. The proportion of identifiable risk factors of CRC was 5.8-7.5 percent (HNPCC, 0.7-2.4 percent; previous CRC, 3.4 percent; ulcerative colitis, 1.0 percent; familial adenomatous polyposis coli, 0.7 percent). CONCLUSION. This prospective multicenter study revealed that the frequency of hereditary colorectal cancer is lower than in some previous studies, when diagnosis is based on extensive pedigree analysis. This result with recent findings of common ancestral founding mutation in Finnish HNPCC families indicates that there may be geographic differences in the occurrence of HNPCC. However, this does not change the fact that identification of HNPCC--perhaps one of the most common inherited diseases identified in humans--has become a question of vital importance now when diagnosis of the syndrome and large-scale screening of gene carriers using specific tests are on the horizon.