The Founder Mutation MSH2*1906G→C Is an Important Cause of Hereditary Nonpolyposis Colorectal Cancer in the Ashkenazi Jewish Population

Abstract

Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by mutations in the mismatch-repair genes. We report here the identification and characterization of a founder mutation in MSH2 in the Ashkenazi Jewish population. We identified a nucleotide substitution, MSH2*1906G-->C, which results in a substitution of proline for alanine at codon 636 in the MSH2 protein. This allele was identified in 15 unrelated Ashkenazi Jewish families with HNPCC, most of which meet the Amsterdam criteria. Genotype analysis of 18 polymorphic loci within and flanking MSH2 suggested a single origin for the mutation. All colorectal cancers tested showed microsatellite instability and absence of MSH2 protein, by immunohistochemical analysis. In an analysis of a population-based incident series of 686 Ashkenazi Jews from Israel who have colorectal cancer, we identified 3 (0.44%) mutation carriers. Persons with a family history of colorectal or endometrial cancer were more likely to carry the mutation than were those without such a family history (P=.042), and those with colorectal cancer who carried the mutation were, on average, younger than affected individuals who did not carry it (P=.033). The mutation was not detected in either 566 unaffected Ashkenazi Jews from Israel or 1,022 control individuals from New York. In hospital-based series, the 1906C allele was identified in 5/463 Ashkenazi Jews with colorectal cancer, in 2/197 with endometrial cancer, and in 0/83 with ovarian cancer. When families identified by family history and in case series are included, 25 apparently unrelated Ashkenazi Jewish families have been found to harbor this mutation. Although this pathogenic mutation is not frequent in the Ashkenazi Jewish population (accounting for 2%-3% of colorectal cancer in those whose age at diagnosis is <60 years), it is highly penetrant and accounts for approximately one-third of HNPCC in Ashkenazi Jewish families that fulfill the Amsterdam criteria.

Phenotypic and genotypic heterogeneity in the Lynch syndrome: diagnostic, surveillance and management implications

“…In Finns, a genomic deletion of exon 16 of MLH1 probably dates back 1000 years or more and in parts of Finland accounts for 450% of all Lynch syndrome. 11,12 Other highly enriched founder mutations have been documented in Ashkenazi Jews (MSH2 1906G-C; accounting for B20% of Lynch syndrome 13 ) and other genetically isolated populations (for review see de la Chapelle 14 ).…”

Localization of breast cancer susceptibility loci by genome‐wide SNP linkage disequilibrium mapping

“…Formally, such results could have been caused by real associations, such as with modifier genes. However, with a similar analytical strategy using samples from Ashkenazi Jewish colon cancer families, we also obtained several significant associations outside of the MSH2 region [Mitra et al, 2004] that contains a founder mutation in Ashkenazi Jews [Foulkes et al, 2002]. Consequently, even after adjustments are made for multiple testing, regions could be identified with putatively significant Pvalues that are false positives.…”

A unique MSH2 exon 8 deletion accounts for a major portion of all mismatch repair gene mutations in Lynch syndrome families of Sardinian origin

“…5,8,[17][18][19][20][21][22][23][24] In a genetic isolate, such as Sardinia used to be (Sardinia currently counts about 1 673 000 inhabitants), a haplotype may be highly frequent because of genetic drift. Therefore, a mutation occurred on a particular haplotype can be traced in many individuals with a common ancestor.…”