Linkage analysis identifies gene carriers among members of families with hereditary nonpolyposis colorectal cancer.

Background & Aims: Uncertainty about genetic risk in hereditary nonpolyposis colorectal cancer (HNPCC) may lead to unnecessary screening. The aims of this study were to show how gene linkage findings can elucidate who is at risk and requires intensive screening and how cancer control can be enhanced by screening high-risk family members. This information can be useful given the public health magnitude of HNPCC.

Methods: An extended family with HNPCC was studied using formal linkage analysis with DNA extraction from blood samples, followed by genotyping with polymerase chain reaction technique for microsatellite markers. Sixty-one blood relatives of a family with HNPCC, 5 of whom had colorectal cancer, and 12 unrelated family members underwent DNA sampling for genetic analysis.

Results: Linkage analysis showed that all 5 affected individuals had a haplotype with the same alleles 10/7/9, which was also detected in 13 first-degree healthy gene carriers and absent in the remaining 43 non-gene carriers. In the asymptomatic subjects screened, one incidental colorectal cancer and four adenomas were detected in 3 of 6 gene carriers. An adenoma was found in 1 of 17 noncarriers; the remaining 16 noncarriers have undergone 67 unnecessary colonoscopies.

Conclusions: Linkage analysis can differentiate gene carriers from non carriers. Colorectal cancer screening should be restricted to gene carriers.