Association of hereditary nonpolyposis colorectal cancer-related tumors displaying low microsatellite instability with MSH6 germline mutations

Hereditary nonpolyposis colorectal cancer (HNPCC) (Amsterdam criteria) is o ften caused by mutations in mismatch repair (MMR) genes, and tumors of pati ents with HNPCC show microsatellite instability (MSI-high phenotype), Germl ine mutations of MMR genes have rarely been found in families that have HNP CC or suspected HNPCC and that do not show microsatellite instability (MSI- low phenotype). Therefore, an MSI-high phenotype is often used as an inclus ion criterion for mutation testing of MMR genes. Correction of base-base mi smatches is the major function of MSH6. Since mismatches present with an MS I-low phenotype, we assumed that the phenotype in patients with HNPCC-relat ed tumors might be associated with MSH6 germline mutations. We divided 36 p atients with suspected HNPCC into an MSI-low group (n = 18) and an MSI-high group (n = 18), on the basis of the results of MSI testing. Additionally, three unrelated patients from Amsterdam families with MSI-low tumors were i nvestigated. All patients were screened for MSH2, MLH1, and MSH6 mutations. Four presumably causative MSH6 mutations were detected in the patients (22 %) who had suspected HNPCC and MSI-low tumors. Furthermore, we detected one frameshift mutation in one of the three patients with HNPCC and MSI-low tu mors. In the MSI-high group, one MSH6 missense mutation was found, but the same patient also had an MLH1 mutation, which may explain the MSI-high phen otype. These results suggest that MSHG may be involved in a substantial pro portion of patients with HNPCC or suspected HNPCC and MSI-low tumors. Our d ata emphasize that an MSI-low phenotype cannot be considered an exclusion c riterion for mutation testing of MMR genes in general.