hMLH1, hMSH2 and hMSH6 mutations in hereditary non-polyposis colorectal cancer families from Southern Sweden

We have screened 17 Southern Sweden individuals/families with suspected her editary non-polyposis colorectal cancer (HNPCC) for mutations in the DNA-mi smatch repair genes hMLH1, hMSH2 and hMSH6 using denaturing gradient gel el ectrophoresis, protein truncation test and direct DNA sequencing. The famil ies were selected on the basis of a family history of HNPCC-related tumors or the occurrence of metachronous colorectal cancer/endometrial cancer at y oung age in an individual with a weak family history of cancer. Furthermore , we required that tumor tissue from at least one individual in the family had to display microsatellite instability. We identified germ-line mutation s in 9 individuals from 8 families. Five families had mutations in hMLH1, 4 of which were splice site mutations, 2 had frameshift mutations in hMSH2 a nd I patient with metachronous endometrial and rectal cancer but with a wea k family history of cancer had a nonsense mutation in hMSH6, Our results pr esent novel germ-line DNA-repair gene mutations, one of these in hMSH6 and demonstrate the diversified mutation spectrum in Sweden, where no founder m utation has so far been identified. (C) 1999 Wiley-Liss, Inc.