Mononucleotide microsatellite instability and germline MSH6 mutation analysis in early onset colorectal cancer

Germline mutations in the MSH2 and MLH1 mismatch repair genes account for m ost cases of hereditary non-polyposis colon cancer syndrome (HNPCC). In add ition, germline MSH2 and MLH1 mutations have been detected in patients with non-HNPCC early onset colorectal cancer. Germline MSH6 mutations appear to be rare in classical HNPCC families, but their frequency in young colorect al cancer cases has not been studied previously. In a population based stud y of early onset colorectal cancer (<50 years) investigated for tumour micr osatellite instability (MSI), we identified a subgroup of tumours with MSI for mono- but not dinucleotide repeat markers (m-MSI+ group). In contrast t o tumours with classical MSI for dinucleotide markers (d-MSI+), the m-MSIgroup cancers were mainly left sided (6/7). As MSH6 mutations in yeast and human cell lines are associated with weak (and preferential mononucleotide) MSI, the complete MSH6 gene coding region was sequenced in blood DNA from the five m-MSI+ cases available for analysis. A germline nonsense mutation was identified in an isolated case of early onset colorectal cancer (age 43 years). These results support previous findings that germline MSH6 mutatio ns may not be associated with classical MSI and suggest a role for germline MSH6 mutations in isolated early onset colorectal cancer.