Hampel H et al. (2005) Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 352: 1851–1860

Mutations in the mismatch repair genes MLH1, MSH2, MSH6 and PMS2 are associated with the Lynch syndrome (hereditary nonpolyposis colorectal cancer), with heterozygosity for a mutation conferring a strong propensity to cancer. As there is a need to improve diagnostic strategies for the Lynch syndrome, Hampel and colleagues investigated the frequency of these mutations in 1,066 patients with newly diagnosed colorectal cancer and compared the efficacy of two pre-screening methods for mismatch-repair deficiency.

Patients were genotyped according to five or six polymorphic markers in tumor and normal tissue to ascertain microsatellite instability. In total, 208 participants were classed as positive for microsatellite instability and were thus sequenced for MLH1, MSH2, MSH6 and PMS2 gene mutations, and underwent immunohistochemical staining and deletion analysis.

Of the 1,066 tumors, 135 had high-frequency microsatellite instability and 73 had low-frequency instability. Deleterious mutations leading to the Lynch syndrome were identified in 23 probands and the families of 21 of these patients were also screened, revealing Lynch syndrome mutations in 52 out of 117 relatives tested. Two probands were missed by both genotyping for microsatellite instability and immunohistochemical staining techniques.

In this study, the authors demonstrated the feasibility of large-scale screening of colorectal cancer patients and suggested that screening for mismatch-repair gene mutations by means of immunohistochemical analysis might be equally as effective as genotyping for microsatellite instability. The authors concluded that establishing the status of mismatch-repair proteins in colorectal cancer patients could have implications for prognosis and treatment of the condition.