Prevalence of germline mutations of hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6 genes in 75 French kindreds with nonpolyposis colorectal cancer

Abstract

Hereditary nonpolyposis colorectal cancer (HNPCC) is a syndrome characterized by familial predisposition to colorectal carcinoma and extracolonic cancers of the gastrointestinal, urological, and female reproductive tracts. This dominant disorder is caused by germline defects in one of at least five DNA mismatch repair (MMR) genes: hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6 (GTBP). Germline mutations of hMSH2 and hMLH1 are also frequently identified in families not fulfilling all the Amsterdam criteria, thereby demonstrating that the involvement of these genes is not confined to typical HNPCC. To evaluate the respective involvement of the various MMR genes in typical and incomplete HNPCC syndromes, we have performed an analysis of the hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6 genes in a large series of French kindreds (n=75) with colorectal tumors and/or aggregation of extracolonic cancers belonging to the HNPCC spectrum. Mutational analysis has been performed in all families, without preselection for the tumor phenotype. We have detected 26 pathogenic germline mutations of the hMLH1 and hMSH2 genes and several novel variants of the hPMS1, hPMS2, and hMSH6 genes. Our data confirm that, regardless of the type of families and the tumor phenotype, hPMS1, hPMS2, and hMSH6 germline mutations are rare in familial aggregation of colorectal cancers. Furthermore, they suggest that the presence of multiple primary malignancies in a single individual and the observation of extracolonic tumors in relatives of a colorectal cancer patient should be included among the guidelines for referring patients for genetic testing.

Elevated mutant frequencies and increased C : G→T : A transitions in Mlh1−/− versus Pms2−/− murine small intestinal epithelial cells

“…Although a speci®c biochemical function for hMutLb has not yet been demonstrated in vitro (Raschle et al, 1999), it remains possible that this complex participates in some aspect of MMR in vivo. This is consistent with the ®nding of a hPMS1 mutation in an HNPCC kindred, which raises the possibility that hPMS1 does play an important role in the maintenance of genome stability (Prolla, 1998;Toft and Arends, 1998;Wang et al, 1999b). An additional mammalian MutL ortholog, MLH3, was recently cloned from humans and mice (Lipkin et al, 2000).…”

“…Mutations in one of ®ve di erent mismatch repair genes, primarily hMSH2 and hMLH1, and to a lesser extent hPMS2, hPMS1 and hMSH6, account for most cases of the autosomal dominant familial cancer syndrome, hereditary nonpolyposis colorectal cancer (HNPCC) (Kolodner, 1995;Prolla, 1998;Toft and Arends, 1998;Wang et al, 1999b). In most instances a ected individuals inherit a germline mutation on one allele and associated with a loss of heterozygosity develop predominantly colon, endometrial, and ovarian tumors, as well as malignancies of the stomach, pancreas, small intestine, skin, breast and urinary tract (Prolla, 1998;Toft and Arends, 1998;Wang et al, 1999b).…”

“…In most instances a ected individuals inherit a germline mutation on one allele and associated with a loss of heterozygosity develop predominantly colon, endometrial, and ovarian tumors, as well as malignancies of the stomach, pancreas, small intestine, skin, breast and urinary tract (Prolla, 1998;Toft and Arends, 1998;Wang et al, 1999b). Homozygous germline inactivation of a MMR gene was reported recently in two families.…”

Estimating cancer risk in HNPCC by the GRL method

“…As this study did not involve any additional intervention, it was exempt under French law from ethical review board approval. Blood samples were subjected to germline mutation screening of MLH1 (NM_000249 for cDNA and NC_000003 for genomic DNA) and MSH2 (NM_000251 for cDNA and NC_000002 for genomic DNA) genes using genomic DNA sequencing 19 . Of the 161 index cases meeting one of the selection criteria, 42 were found to carry a deleterious mutation of MLH1 or MSH2.…”

Mouse models for colorectal cancer

“…The Mlh1 tumors displayed a RER+ phenotype. Recently human MLH1 kindred that carried a homozygous MLH1 mutation were reported (Wang et al, 1999;Ricciardone et al, 1999). These patients died at a very young age and developed leukemias and/or lymphomas and neuro®bromatosis type I.…”