Background: It is now known that a proportion of cases of hereditary non-polyposis colorectal cancer (HNPCC) is caused by mutations in the human homologue of the yeast DNA mismatch repair gene MSH2. A proline to leucine change due to a C to T transition in codon 622 of hMSH2 has been identified in a large HNPCC family of over 240 individuals.
Aim: To develop an assay to detect the family-specific mutation and apply the findings to genetic screening.
Methods: The C to T change in codon 622 creates a new Mae I site (CTAG) allowing a simple, non-radioactive assay to be developed in order to detect this mutation. The assay was applied to affected members of the family and their first degree relatives (siblings and offspring) between the ages of 17 and 77 years, a total of 75 subjects within two generations (IV and V).
Results: 13/13 (100%) subjects with cancer were mutation positive, 7/7 (100%) elderly subjects from generation IV and with no evidence of cancer were mutation negative, 23/57 (40%) subjects from generation V were mutation positive and 0/50 (100%) unrelated subjects were mutation negative. Following the demonstration of perfect segregation of the disease with the mutation, family members were invited to receive the results of the test. Sixty-three (84%) responded within six weeks of receiving the invitation. Genetic screening and counselling members of HNPCC families was perceived as beneficial overall, allowing non-carriers of the mutant gene (as well as their descendants) to be removed from a programme of colonoscopic surveillance.