In a resource-poor country, mutation identification has the potential to reduce the cost of family management for hereditary nonpolyposis colorectal cancer.

PURPOSE

Colonoscopic surveillance of family members at risk of hereditary nonpolyposis colorectal cancer is difficult in a resource-poor country because of its expense. For family members who live in remote areas, poor communication and limited access to sophisticated medical care make surveillance even more difficult. The identification of the mutation causing the disease will simplify surveillance. Our aim was to assess the impact of mutation analysis on the management of a South African family with more than 150 members at risk for hereditary nonpolyposis colorectal cancer.

METHODS

We studied a family that met the Amsterdam criteria for hereditary nonpolyposis colorectal cancer. Colorectal cancer affected 27 members in three generations (evidence from histology in 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 six family members was studied for microsatellite instability. DNA from all available family members was then screened for mutations in the hMLH1 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 with the disorder in members of this kindred. Test results of 100 chromosomes from population-matched controls were negative. Sixty family members between the ages of 16 and 50 years are at 50 percent risk for colon cancer by pedigree analysis, but of these, only 26 (43 percent) have the mutation.

CONCLUSION

A mutation in the DNA repair gene hMLH1 was found in family members with hereditary nonpolyposis colorectal cancer and in some unaffected relatives previously at 50 percent risk, but not in unrelated subjects. The blood test for the mutation will simplify management, counseling, and surveillance and help to establish prophylactic colectomy.