Microsatellite instability - a useful diagnostic tool to select patients at high risk for hereditary non-polyposis colorectal cancer: a study in different groups of patients with colorectal cancer

Background-Clinical diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) is based on a typical family history. As molecular genetic testing is predominantly restricted to these families, gene carriers not meeting t he clinical criteria may be missed. Aims-To examine the value of microsatellite instability (MSI) as a tool to increase the likelihood for uncovering a mismatch repair germline mutation in patients with colorectal cancer and to identify a genotype-phenotype rel ation in families with verified mutations. Methods-Systematic search for germline mutations (hMSH2 and hMLH1 genes) wa s performed in 96 patients: 57 fulfilled the Amsterdam criteria (group 1) a nd 12 the looser HNPCC criteria (group 2). Seventeen patients showed famili al clustering of cancers (group 3) and 10 patients under 50 years had spora dic cancer (group 4), the latter of whom all exhibited MSI+ tumours. Results-A similar proportion of germline mutations was found in patients wh o fulfilled the clinical criteria of HNPCC and had MSI+ tumours (groups 1 a nd 2; 15/39) compared with patients who did not meet these clinical criteri a but who had MSI+ tumours (groups 3 and 4; 8/27 patients). Affected relati ves of patients with hMLH1 mutations showed a significantly higher frequenc y of colorectal cancer but a lower frequency of endometrium cancer than tho se with hMSH2 mutations. Conclusions-MSI in tumour tissue is a useful criterion for selecting patien ts who should be tested for germline mutations in the mismatch repair genes hMSH2 and hMLH1 irrespective of their family history. Among carriers of hM SH2 mutations the tumour spectrum was broader than among carriers of hMLH1 mutations.