Hereditary nonpolyposis colorectal cancer (HNPCC) is a common autosomal dominant cancer-susceptibility condition characterized by early onset colorectal cancer. Germ-line mutations in one of four DNA mismatch repair (MMR) genes, hMSH2, hMLH1, hPMS1, or hPMS2, are known to cause HNPCC. Although many mutations in these genes have been found in HNPCC kindreds complying with the so-called Amsterdam criteria, little is known about the involvement of these genes in families not satisfying these criteria but showing clear-cut familial clustering of colorectal cancer and other cancers. Here, we applied denaturing gradient-gel electrophoresis to screen for hMSH2 and hMLH1 mutations in two sets of HNPCC families, one set comprising families strictly complying with the Amsterdam criteria and another set in which at least one of the criteria was not satisfied. Interestingly, hMSH2 and hMLH1 mutations were found in 49% of the kindreds fully complying with the Amsterdam criteria, whereas a disease-causing mutation could be identified in only 8% of the families in which the criteria were not satisfied fully. In correspondence with these findings, 4 of 6 colorectal tumors from patients belonging to kindreds meeting the criteria showed microsatellite instability, whereas only 3 of 11 tumors from the other set of families demonstrated this instability. Although the number of tumors included in the study admittedly is small, the frequencies of mutations in the MMR genes show obvious differences between the two clinical sets of families. These results also emphasize the practical importance of the Amsterdam criteria, which provide a valid clinical subdivision between families, on the basis of their chance of carrying an hMSH2 or an hMLH1 mutation, and which bear important consequences for genetic testing and counseling and for the management of colorectal cancer families.

MGC Department of Human Genetics Medical Genetics Center Leiden University The Netherlands

See more in PubMed

Hum Mol Genet. 1995 Feb;4(2):237-42 PubMed

Hum Mol Genet. 1994 Dec;3(12):2257-60 PubMed

Cancer Res. 1995 Dec 1;55(23):5548-50 PubMed

Am J Hum Genet. 1996 Feb;58(2):300-7 PubMed

Nat Med. 1996 Feb;2(2):169-74 PubMed

Hum Mol Genet. 1996 Jun;5(6):763-9 PubMed

Hum Mol Genet. 1996 Sep;5(9):1245-52 PubMed

Am J Hum Genet. 1995 May;56(5):1060-6 PubMed

Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463-7 PubMed

Methods Enzymol. 1987;155:501-27 PubMed

Dis Colon Rectum. 1991 May;34(5):424-5 PubMed

Genomics. 1992 Aug;13(4):1162-8 PubMed

Cancer. 1993 Feb 1;71(3):677-85 PubMed

Gastroenterology. 1993 May;104(5):1535-49 PubMed

Science. 1993 May 7;260(5109):812-6 PubMed

Science. 1993 May 7;260(5109):816-9 PubMed

Nature. 1993 Jun 10;363(6429):558-61 PubMed

Cancer Res. 1993 Nov 1;53(21):5087-9 PubMed

Cancer Res. 1993 Nov 1;53(21):5100-3 PubMed

Cell. 1993 Dec 3;75(5):1027-38 PubMed

Cell. 1993 Dec 17;75(6):1215-25 PubMed

Science. 1994 Mar 18;263(5153):1625-9 PubMed

Oncogene. 1994 Apr;9(4):1163-6 PubMed

Cancer Res. 1994 Apr 1;54(7):1645-8 PubMed

Nat Genet. 1994 Feb;6(2):152-6 PubMed

Hum Mutat. 1994;3(2):83-94 PubMed

Nature. 1994 Sep 1;371(6492):75-80 PubMed

Cancer Res. 1995 Jan 15;55(2):242-8 PubMed

Science. 1995 Jun 2;268(5215):1336-8 PubMed