Sequence analysis of the mismatch repair gene hMSH6 in the germline of patients with familial and sporadic colorectal cancer

To evaluate the involvement of hMSH6 in colorectal cancer, the complete cod ing sequence and flanking intron regions of the gene were analyzed by DNA s equencing in 10 patients fulfilling Bethesda Guidelines for colorectal tumo rs and 10 patients with sporadic colorectal carcinoma, In addition, 10 mono - and 10 dinucleotide repeat markers were analyzed for microsatellite insta bility. A protein-truncating T insertion at codon 218 was identified in the index person of a hereditary non-polyposis colorectal cancer (HNPCC)-like kindred and was accompanied by a somatic T deletion in the tumor, The tumor of this patient was positive for mono- but negative for dinucleotide repea t instability and lacked allelic losses at loci frequently affected in colo rectal carcinomas. A novel amino acid change, F340S, was found in a patient with sporadic colon and breast cancer and leukemia but was not detected in 246 chromosomes from healthy anonymous blood donors. In addition, we descr ibe 2 silent and 15 intronic sequence variants not previously reported, Alt hough the frequency is low, we present further evidence for hMSH6 germline mutations Chat: predispose patients to HNPCC-like phenotypes and suggest th at mono- and dinucleotide repeat instability testing may be useful for dist inguishing between individuals harboring an hMSH2 or hMLH1 mutation and a m utation of the hMSH6 gene. (C) 2000 Wiley-liss, Inc.