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.

Figure 1

Representative families with the MSH2*1906G→C mutation. Carriers of MSH2*1906G→C are indicated by “+/−”; tested noncarriers are indicated by “+/+”; all other individuals are untested. Notably, none of these families fulfil the Amsterdam criteria but, nevertheless, a priori are very likely to carry germline mutations in mismatch-repair genes.

Figure 2

Immunohistochemical staining of MSH2 (A) and MSH6 (B), in the woman in family 3 who has colorectal cancer and carries the MSH2*1906G→C mutation (tables 1 and 2) and in control samples from colorectal tumors in which MSH2 (C) and MSH6 (D) are expressed. The colonic adenocarcinoma is moderately differentiated, with relatively well-formed glands infiltrating the stromal tissue. Positive immunoreactivity with antibodies to MSH2 and MSH6 is represented by the presence of brown staining in the nuclei. There is a complete absence of nuclear staining of both MSH2 and MSH6 in the tumor cells, whereas a few scattered small lymphocytes show brown labeling in their nuclei (arrow). The presence of nuclear staining in lymphocytes serves as an internal positive control. The stain for MSH6 shows some cytoplasmic labeling both in the tumor cells and in some stromal cells. The significance of such cytoplasmic staining in this patient is unclear but is likely a reflection of nonspecific background staining.

Figure 3

Schematic representation of MSH2 and surrounding regions of chromosome 2. Marker loci and genetic distances are shown. This map is based on information provided by The Genome Database and the National Center for Biotechnology Information (see the “Single Nucleotide Polymorphism” Web page). We used the “BLAST Search Genome” Web page (August 2001 freeze) of the University of California, Santa Cruz, to obtain the relative genetic positions of these markers. The relative positions of some markers have been published elsewhere (Green et al. ; Desai et al. 2000), but some of that positional information was erroneous. Single-nucleotide polymorphisms (SNPs) were identified by use of “The SNP Consortium Ltd.” Web site. The MSH2 map was designed in accordance with data provided by the ICG-HNPCC. Intragenic markers have been described elsewhere (Desai et al. 2000). Alongside the vertical portion of the ideogram, we have indicated the positions of markers, according to the recombination map presented by Kong et al. (2002). Note that the positions of D2S391 and Rs1374749 with respect to surrounding markers are uncertain. According to data available at the Golden Path Web site (see the “UCSC Genome Informatics” Web page), Rs1374749 is centromeric of D2S391, whereas according to the recombination map presented by Kong et al. it is telomeric; Kong et al.'s recombination map also places Rs919883 telomeric of D2S391. There are discrepancies between the recombination map and the physical map presented by Kong et al. If the true map order is tel–D2S391-Rs1347479-Rs896213-Rs919883-cen (based primarily on physical data), then all markers from MSH2 up to and including Rs1347479 are completely conserved, whereas D2S391 and markers beyond it are not. At this time, it is not possible to synthesize all of the available mapping data into one consistent marker order. For further details, see the Electronic-Database Information and Results sections.

Figure 4

Schematic map of chromosome 2, showing extent of potential haplotype sharing. Sixteen unrelated families were studied. The position of MSH2 is indicated, and the positions of markers are as shown in figure 3. “D” denotes distance (in Mb). The double-headed vertical arrows indicate the extent of the possible haplotype sharing in different groups of mutation carriers, and the ends of the arrows indicate the last marker that is conserved in the indicated fraction of probands studied; for example, probands from 9 of 15 families share a haplotype that could extend over a maximum of ∼10.3 Mb. The proportion of families sharing the same haplotype increases from left to right. For details, see the text.