MUTATIONS PREDISPOSING TO HEREDITARY NONPOLYPOSIS COLORECTAL-CANCER -DATABASE AND RESULTS OF A COLLABORATIVE STUDY

Background & Aims: Germline mutations in four DNA mismatch repair gene s are known to cause susceptibility to hereditary nonpolyposis colorec tal cancer (HNPCC). The rapidly increasing information about these mut ations needs to be collected and appropriately stored to facilitate fu rther studies on the biological and clinical significance of the findi ngs. Methods: The International Collaborative Group on HNPCC has estab lished a database of DNA mismatch repair gene mutations and polymorphi sms. In this report, 126 predisposing mutations were analyzed. Results : A majority of the mutations affected either the Mut L homologue (MLH ) 1 (n = 75) or the Mut S homologue (MSH) 2 (n = 48) and were quite ev enly distributed, with some clustering in MSH2 exon 12 and MLH1 exon 1 6. Most MSH2 mutations consisted of frameshift (60%) or nonsense chang es (23%), whereas MLH1 was mainly affected by frameshift (40%) or miss ense alterations (31%). Although most mutations were unique, a few com mon recurring mutations were identified, Of the families studied (n = 202), 82% met the Amsterdam criteria and 15% did not; the general muta tion profile was similar in both groups. Conclusions: The construction of mutation profiles will facilitate the development of diagnostic st rategies in HNPCC.