IN A RESOURCE-POOR COUNTRY, MUTATION IDENTIFICATION HAS THE POTENTIALTO REDUCE THE COST OF FAMILY MANAGEMENT FOR HEREDITARY NONPOLYPOSIS COLORECTAL-CANCER

Colonoscopic surveillance of family members at risk of hereditary nonp olyposis colorectal cancer is difficult in a resource-poor country bec ause of its expense. For family members who live in remote areas, poor communication and limited access to sophisticated medical care make s urveillance even more difficult. The identification of the mutation ca using the disease will simplify surveillance. Our aim was to assess th e impact of mutation analysis on the management of a South African fam ily with more than 150 members at risk for hereditary nonpolyposis col orectal cancer. METHODS: We studied a family that met the Amsterdam cr iteria for hereditary nonpolyposis colorectal can cer. Colorectal canc er affected 27 members in three generations (evidence from histology i n 12, barium enema in 1, and family statements in 14 family members). Leukocyte DNA from family members was tested for linkage to candidate loci for colorectal cancer, and DNA from formalin-fixed cancers from s ix family members was studied for microsatellite instability. DNA from all available family members was then screened for mutations in the h MLH1 gene. The number of individuals at 50 percent risk was calculated by family pedigree and compared with the number who have the mutation . RESULTS: A disease-causing mutation in exon 13 of hMLH1 segregated w ith the disorder in members of this kindred. Test results of 100 chrom osomes from population-matched controls were negative. Sixty family me mbers between the ages of 16 and 50 years are at 50 percent risk for c olon cancer by pedigree analysis, but of these, only 26 (43 percent) h ave the mutation. CONCLUSION: A mutation in the DNA repair gene hMLH1 was found in family members with hereditary nonpolyposis colorectal ca ncer and in some unaffected relatives previously at 50 percent risk, b ut not in unrelated subjects. The blood test for the mutation will sim plify management, counseling, and surveillance and help to establish p rophylactic colectomy.