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PubMed2002

The founder mutation MSH2*1906G-->C is an important cause of hereditary nonpolyposis colorectal cancer in the Ashkenazi Jewish population.

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.

Alanine↗

PubMed2005

Deletions account for 17% of pathogenic germline alterations in MLH1 and MSH2 in hereditary nonpolyposis colorectal cancer (HNPCC) families.

Hereditary nonpolyposis colorectal cancer (HNPCC) is due to defects in DNA mismatch repair (MMR) genes MSH2, MLH1, MSH6, and to a lesser extent PMS2. Of 466 suspected HNPCC families, we defined 54 index patients with either tumors of high microsatellite instability (MSI-H) and/or loss of expression for either MLH1, MSH2, and/or MSH6, but without a detectable pathogenic point mutation in these genes. This study cohort was augmented to 64 patients by 10 mutation-negative index patients from Amsterdam families where no tumors were available. Deletion/duplication screening using the multiplex ligation-dependent probe amplification (MLPA) revealed 12 deletions in MSH2 and two deletions in MLH1. These deletions constitute 17% of pathogenic germline alterations but elucidate the susceptibility to HNPCC in only 22% of the mutation-negative study cohort, pointing towards other mutation mechanisms for an inherited inactivation of MLH1 or MSH2. We describe here four novel deletions. One novel and one known type of deletion were found for three and two unrelated families, respectively. MLPA analysis proved a reliable method for the detection of genomic deletions in MLH1 and MSH2; however, sequence variations in the ligation-probe binding site can mimic single exon deletions.

Alu Elements↗

PubMed1999

Deficiency in Msh2 affects the efficiency and local sequence specificity of immunoglobulin class-switch recombination: parallels with somatic hypermutation.

During maturation of the immune response, IgM+ B cells switch to expression of one of the downstream isotypes (IgG, A or E). This class switching occurs by region-specific recombination within the IgH locus through an unknown mechanism. A lack of switch recombination in mice deficient in components of the DNA-dependent protein kinase (DNA-PK)-Ku complex has pointed to a role for non-homologous end joining. Here we characterize a switching defect in mice lacking a protein involved in DNA mismatch recognition. Mice deficient in Msh2 give diminished IgG (but not IgM) responses following challenge with both T cell-dependent and T cell-independent antigens. This appears to reflect a B cell-intrinsic defect since B cells from Msh2-deficient mice also exhibit impaired switching (but not blasting or proliferation) on in vitro culture with lipopolysaccharide. Furthermore, those switches that do occur in Msh2-deficient B cells reveal a shift in the distribution of recombination sites used: the breakpoints are more likely to occur in consensus motifs. These results, which intriguingly parallel the effects of Msh2 deficiency on hypermutation, suggest a role for Msh2 in the mechanics of class-switch recombination.

Animals↗

PubMed2001

Requirement for Msh6, but not for Swi4 (Msh3), in Msh2-dependent repair of base-base mismatches and mononucleotide loops in Schizosaccharomyces pombe.

The msh6 mismatch repair gene of Schizosaccharomyces pombe was cloned, sequenced, and inactivated. Strains bearing all combinations of inactivated msh6, msh2, and swi4 (the S. pombe MSH3 ortholog) alleles were tested for their defects in mitotic and meiotic mismatch repair. Mitotic mutation rates were similarly increased in msh6 and msh2 mutants, both for reversion of a base-base substitution as well as of an insertion of one nucleotide in a mononucleotide run. Tetrad analysis and intragenic two-factor crosses revealed that meiotic mismatch repair was affected in msh6 to the same extent as in msh2 background. In contrast, loss of Swi4 likely did not cause a defect in mismatch repair, but rather resulted in reduced recombination frequency. Consistently, a mutated swi4 caused a two- to threefold reduction of recombinants in intergenic crosses, while msh2 and msh6 mutants were not significantly different from wild type. In summary, our study showed that Msh6 plays the same important role as Msh2 in the major mismatch repair pathway of S. pombe, while Swi4 rather functions in recombination.

Amino Acid Sequence↗

PubMed2002

Phosphorylation of mismatch repair proteins MSH2 and MSH6 affecting MutSalpha mismatch-binding activity.

Mismatch repair (MMR) is involved in the removal of mispaired bases from DNA and thus plays an important role in the maintenance of genomic stability and the prevention of mutations and cancer. Moreover, MMR triggers genotoxicity and apoptosis upon processing of DNA lesions such as O6-methylguanine. Whereas the enzymology of MMR has been elucidated in great detail, only limited data are available concerning its regulation. Here we show that the major mismatch-binding proteins MSH2 and MSH6, forming the MutSalpha complex, are phosphorylated in vitro by protein kinase C and casein kinase II, but not by protein kinase A. Phosphorylation of MSH2 and MSH6 was also found within the cell, with MSH6 being more extensively phosphorylated than MSH2. Lack of MSH2 and MSH6 phosphorylation in vivo due to phosphate depletion, kinase inhibition (by H7 and quercetin) and treatment with phosphatases (CIP, SAP and lambda-PPase) significantly reduced mismatch-binding activity of MutSalpha. It also prevented methylation-induced nuclear translocation of the repair complex, indicating that nuclear translocation of MutSalpha upon mutagen treatment is dependent on protein phosphorylation. The finding that MSH2 and MSH6 are subject to phosphorylation resulting in increased mismatch binding by MutSalpha indicates a novel type of post-translational regulation of MMR which might be involved in the response of cells to genotoxic stress.

Active Transport, Cell Nucleus↗

PubMedDate not supplied

MSH2 splice site mutation and endometrial cancer.

Hereditary nonpolyposis colorectal cancer (HNPCC) is an inherited syndrome of cancer susceptibility caused by germ line mutations of genes participating in mismatch repair (MMR). Carriers of MMR gene mutations have an increased risk of colorectal cancers and cancer of other organs. Tumors of the endometrium represent the most frequent extracolonic malignancies in HNPCC. It has been suggested that women harboring MMR gene mutations have a higher risk of endometrial cancer than of colon cancer. Here, we describe an HNPCC patient with early-onset endometrial cancer and a strong familial history of endometrial tumors who harbored a germ line MSH2 splice site mutation (IVS9_2A>G). This mutation was responsible for abnormal messenger RNA processing, leading to the introduction of a premature stop signal and to the expression of a truncated MSH2 protein. In addition, the same mutation was associated with loss of MSH2 protein expression, high microsatellite instability, and PTEN inactivation. Although a direct relationship between the endometrial cancer susceptibility and the MSH2 mutation we found cannot be established, our observations, consistent with the work of other authors, suggest the involvement of germ line MSH2 abnormalities in endometrial tumor development and support the case for endometrial cancer screening in women from HNPCC families.

Adenocarcinoma↗

PubMed1999

Separation-of-function mutations in Saccharomyces cerevisiae MSH2 that confer mismatch repair defects but do not affect nonhomologous-tail removal during recombination.

Yeast Msh2p forms complexes with Msh3p and Msh6p to repair DNA mispairs that arise during DNA replication. In addition to their role in mismatch repair (MMR), the MSH2 and MSH3 gene products are required to remove 3' nonhomologous DNA tails during genetic recombination. The mismatch repair genes MSH6, MLH1, and PMS1, whose products interact with Msh2p, are not required in this process. We have identified mutations in MSH2 that do not disrupt genetic recombination but confer a strong defect in mismatch repair. Twenty-four msh2 mutations that conferred a dominant negative phenotype for mismatch repair were isolated. A subset of these mutations mapped to residues in Msh2p that were analogous to mutations identified in human nonpolyposis colorectal cancer msh2 kindreds. Approximately half of the these MMR-defective mutations retained wild-type or nearly wild-type activity for the removal of nonhomologous DNA tails during genetic recombination. The identification of mutations in MSH2 that disrupt mismatch repair without affecting recombination provides a first step in dissecting the Msh-effector protein complexes that are thought to play different roles during DNA repair and genetic recombination.

Alleles↗

PubMed2003

p53, mdm2, EGFR, and msh2 expression in paired initial and recurrent glioblastoma multiforme.

BACKGROUND: The clinical course of glioblastoma multiforme is characterised by invasive growth and regular recurrence. Many genetic alteration have been identified in the genesis of the disease. However, information about immunohistochemical expression in recurrent lesions is sparse. OBJECTIVES: To determine (1) whether the p53/mdm2/EGFR/msh2 expression pattern differs in initial v recurrent glioblastoma multiforme; (2) whether a possible change in expression correlates with prognostic variables (progression-free survival time, total survival time); and (3) whether chemotherapy in addition to surgery and radiotherapy influences the p53/mdm2/EGFR/msh2 expression profile. METHODS: 27 patients were studied. They met the following criteria: histologically confirmed diagnosis of glioblastoma multiforme (WHO IV); total tumour resection at initial craniotomy; at least one re-craniotomy for glioblastoma multiforme recurrence; age 21 years or older. All underwent radiotherapy of at least 54 Gy, and 17 received additional chemotherapy. Immunohistochemical staining of initial tumours and recurrences was done with the following monoclonal antibodies: anti-p53 (DO-1), anti-mdm2 (IF-2), anti-EGFR (H11), and anti-msh2 (AB-1). RESULTS: In comparison with the initial tumour, recurrent lesions were characterised by reduced expression of p53 (p < 0.0001) and msh2 (p = 0.0012), while the numbers of mdm2 (p = 0.02), EGFR (p < 0.0001), and msh2 positive specimens (p < 0.0001) were reduced. Chemotherapy was associated with reduced msh2 expression (p < 0.0001). Immunohistochemical variables were not associated with patient survival. CONCLUSIONS: There are significant differences in the p53/mdm2/EGFR/msh2 expression patterns in initial v recurrent glioblastoma multiforme. There may be interactions between chemotherapy and changes in the msh2 expression.

Adult↗

PubMed2006

Endometrial cancer risk is associated with variants of the mismatch repair genes MLH1 and MSH2.

Women with germ-line mutations in the mismatch repair genes (responsible for hereditary nonpolyposis colorectal cancer) face an increased risk of colonic and endometrial cancer. However, these germ-line mutations are rare and are responsible for fewer than 1% of endometrial cancers. Therefore, we examined whether or not common variants of the hereditary nonpolyposis colorectal cancer-associated genes might also be associated with an increased risk of endometrial cancer. Three single-nucleotide polymorphisms were selected in the MLH1 and MSH2 mismatch repair genes. All the various 672 women with endometrial cancer and 880 controls were genotyped. Each of these three single-nucleotide polymorphisms was associated with an increased risk of endometrial cancer. Carriers of the MLH1 nt-93 A allele were at a 1.5-fold increased risk of developing endometrial cancer compared with controls [95% confidence interval (95% CI), 1.2-2.0; P = 0.001]. The risk was higher for homozygote carriers [odds ratio (OR), 1.9; 95% CI, 1.2-3.2; P = 0.009]. For carriers of the MSH2 rs2303428 C allele, the OR was 1.4 (95% CI, 1.0-1.9; P = 0.05), and for carriers of the MSH2 rs2059520 G allele, the OR was 1.3 (95% CI, 1.0-1.7; P = 0.03). More than 9% of endometrial cancer cases carried a variant allele in both MLH1 and MSH2. For these women, the risk of endometrial cancer was particularly high (OR, 2.1; 95% CI, 1.2-3.6; P = 0.005). For patients younger than 50 years at diagnosis who carried both variants, the risk was even higher (OR, 3.4; 95% CI, 1.7-6.6; P = 0.0005). In summary, two common variant alleles of the MLH1 and MSH2 genes make a substantial contribution to endometrial cancer incidence in Ontario.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared with families with MLH1 or MSH2 mutations: the German Hereditary Nonpolyposis Colorectal Cancer Consortium.

PURPOSE: The aim of the study was the analysis of the involvement and phenotypic manifestations of MSH6 germline mutations in families suspected of hereditary nonpolyposis colorectal cancer (HNPCC). PATIENTS AND METHODS: Patients were preselected among 706 families by microsatellite instability, immunohistochemistry, and/or exclusion of MLH1 or MSH2 mutations and were subjected to MSH6 mutation analysis. Clinical and molecular data of MSH6 mutation families were compared with data from families with MLH1 and MSH2 mutations. RESULTS: We identified 27 families with 24 different pathogenic MSH6 germline mutations, representing 3.8% of the total of the families, and 14.7% of all families with DNA mismatch repair (MMR) gene mutations (n = 183). The median age of onset of colorectal cancer in putative mutation carriers was 10 years higher for MSH6 (54 years; 95% CI, 51 to 56) compared with MLH1 and MSH2 (44 years; 95% CI, 43 to 45; log-rank test, P = .0038). Relative to other malignant tumors, colorectal cancer was less frequent in MSH6 families compared with MLH1 and MSH2 families (Fisher's exact test, P < .001). In contrast, the frequency of non-HNPCC-associated tumors was increased (Fisher's exact test, P < .001). CONCLUSION: Later age of disease onset and lower incidence of colorectal cancer may contribute to a lower proportion of identified MSH6 mutations in families suspected of HNPCC. However, in approximately half of these families, at least one patient developed colorectal or endometrial cancer in the fourth decade of life. Therefore, a surveillance program as stringent as that for families with MLH1 or MSH2 mutations is recommended.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Genotype-phenotype comparison of German MLH1 and MSH2 mutation carriers clinically affected with Lynch syndrome: a report by the German HNPCC Consortium.

PURPOSE: Lynch syndrome is linked to germline mutations in mismatch repair genes. We analyzed the genotype-phenotype correlations in the largest cohort so far reported. PATIENTS AND METHODS: Following standard algorithms, we identified 281 of 574 unrelated families with deleterious germline mutations in MLH1 (n = 124) or MSH2 (n = 157). A total of 988 patients with 1,381 cancers were included in this analysis. RESULTS: We identified 181 and 259 individuals with proven or obligatory and 254 and 294 with assumed MLH1 and MSH2 mutations, respectively. Age at diagnosis was younger both in regard to first cancer (40 v 43 years; P < .009) and to first colorectal cancer (CRC; 41 v 44 years; P = .004) in MLH1 (n = 435) versus MSH2 (n = 553) mutation carriers. In both groups, rectal cancers were remarkably frequent, and the time span between first and second CRC was smaller if the first primary occurred left sided. Gastric cancer was the third most frequent malignancy occurring without a similarly affected relative in most cases. All prostate cancers occurred in MSH2 mutation carriers. CONCLUSION: The proportion of rectal cancers and shorter time span to metachronous cancers indicates the need for a defined treatment strategy for primary rectal cancers in hereditary nonpolyposis colorectal cancer patients. Male MLH1 mutation carriers require earlier colonoscopy beginning at age 20 years. We propose regular gastric surveillance starting at age 35 years, regardless of the familial occurrence of this cancer. The association of prostate cancer with MSH2 mutations should be taken into consideration both for clinical and genetic counseling practice.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Bcl-2 rescues the germinal center response but does not alter the V gene somatic hypermutation spectrum in MSH2-deficient mice.

Ab V genes in mice deficient for the postreplication mismatch repair factor MutS homolog (MSH2) have been reported to display an abnormal bias for hypermutations at G and C nucleotides and hotspots. We previously showed that the germinal center (GC) response is severely attenuated in MSH2-deficient mice. This suggested that premature death of GC B cells might preclude multiple rounds of hypermutation necessary to generate a normal spectrum of base changes. To test this hypothesis, we created MSH2-deficient mice in which Bcl-2 expression was driven in B cells from a transgene. In such mice, the elevated levels of intra-GC apoptosis and untimely GC dissolution characteristic of MSH2-deficient mice are suppressed. However, the spectrum of hypermutation is unchanged. These data indicate that the effects of MSH2 deficiency on GC B cell viability and the hypermutation process are distinct.

Animals↗

PubMed2006

[The analysis for mRNA mutation of MLH1, MSH2 genes and the gene diagnosis for hereditary nonpolyposis colorectal cancer].

OBJECTIVE: To identify hereditary nonpolyposis colorectal cancer (HNPCC) families based on the germline mutations of MLH1 and MSH2 mRNA. METHODS: RNA was extracted from the peripheral blood of the 14 members from 12 different families fulfilling Amsterdam Criteria II. The germline mutations of MLH1 and MSH2 mRNA were detected by cDNA sequencing analysis following reverse transcription-PCR(RT-PCR) with special primers, heat-resistance reverse transcriptase, and expand long template PCR. DNA was extracted from the peripheral blood of the 14 members, the corresponding exons, in which mutations were found using the above method, were amplified with Taq enzyme, sequencing analysis was followed. RESULTS: Six germline mutations were detected and identified from the 6 different families based on mRNA, 4 of them to be in MLH1, the other 2 in MSH2. The MLH1 mutations distribute in the exon 8, 12, 16, and 19. The MSH2 mutations distribute in exons 1 and 2. The 6 mutations were identified from the corresponding exons respectively in genomic DNA sequencing analysis. The mutation types involve in 4 missense, 1 silent, and 1 non-coding area mutations. Five out of the 6 mutations have not been reported previously. Five out of the 6 mutations were pathological, involving in 5 different families. The five families were identified to HNPCC families. CONCLUSION: HNPCC family can be identified with RNA-based sequencing of MLH1 and MSH2 from peripheral blood, which has the advantages of both cost, time saving and high sensitivity.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Novel and recurrent germline alterations in the MLH1 and MSH2 genes identified in hereditary nonpolyposis colorectal cancer patients in Slovakia.

Hereditary non-polyposis colorectal cancer (HNPCC) is associated with germline mutations in DNA mismatch repair genes, predominantly MSH2 and MLH1. Mutation carriers develop cancers in the colorectum, endometrium, ovary, stomach, small intestine and the upper urinary tract. We describe here the results of a mutational analysis of 11 unrelated HNPCC patients by direct genomic sequencing of MLH1 and MSH2. The alterations found include 7 novel changes and 4 different pathogenic mutations described previously in Poland, Moldavia, Finland, Germany, France and USA. Four novel pathogenic mutations in the MLH1 gene include two frameshift mutations (c.1150delG and c.1210_1211delCT), one missense mutation (c.793C>A) and one intron-exon border mutation (c.546- 2A>C). The last change resulted in the skipping of exon 7, as shown by sequencing of RT-PCR products. The only novel MSH2 pathogenic change was a nonsense mutation c.1129C>T. The novel intronic change c.381-41A>G in MLH1 was found in a patient carrying a previously-described mutation in the MSH2 gene. Interestingly, two unrelated patients carried also a novel change in the promoter region of MLH1 in one of the CpG islands (c.-269C>G). However, this alteration does not abrogate transcription, as shown by RT-PCR analysis. In summary, most (approximately 80%) pathogenic germline mutations detected in the studied group of patients by direct genomic sequencing of MLH1 and MSH2 were located in the MLH1 gene. These and previous data indicate that the majority of germline point mutations and small deletions/insertions in HNPCC families in Slovakia affect the MLH1 locus.

Adaptor Proteins, Signal Transducing↗

PubMed2004

A founder mutation of the MSH2 gene and hereditary nonpolyposis colorectal cancer in the United States.

CONTEXT: Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is caused by mutations in the mismatch repair genes and confers an extraordinarily high risk of colorectal, endometrial, and other cancers. However, while carriers of these mutations should be identified, counseled, and offered clinical surveillance, at present the mutations are not tested for in mutation analyses. OBJECTIVE: To describe the prevalence of a large genomic deletion encompassing exons 1 to 6 of the MSH2 gene that is widespread in the US population as a result of a founder effect. DESIGN, SETTING, AND PATIENTS: Ongoing genealogical and historical study conducted to assess the origin and spread of an MSH2 mutation previously identified in 9 apparently unrelated families with putative HNPCC and living in widely different geographic locations in the United States. MAIN OUTCOME MEASURES: Classification of family members as carriers or noncarriers of the MSH2 mutation; spread of the mutation across the continental United States. RESULTS: To date, 566 family members of the 9 probands have been identified to be at risk and counseled; 137 of these have been tested, and 61 carry the founder mutation. Three families have been genealogically shown to descend from a German immigrant family that arrived and first settled in Pennsylvania in the early 1700s. Movements of branches of the family from Pennsylvania through North Carolina, Alabama, Kentucky, Missouri, Iowa, Nebraska, Utah, Texas, and California have been documented, and carriers of the mutation have already been diagnosed in 14 states. In contrast, the deletion was not found among 407 European and Australian families with HNPCC. CONCLUSION: The postulated high frequency and continent-wide geographic distribution of a cancer-predisposing founder mutation of the MSH2 gene in a large, outbred (as opposed to genetically isolated) population, and the ease with which the mutation can be detected, suggest that the routine testing of individuals at risk for HNPCC in the United States should include an assay for this mutation until more is learned about its occurrence.

Colorectal Neoplasms, Hereditary Nonpolyposis↗

PubMed1997

Characterization of MSH2 and MLH1 mutations in Italian families with hereditary nonpolyposis colorectal cancer.

Mismatch repair genes MSH2 and MLH1 are considered to be the two major genes that are responsible for hereditary nonpolyposis colorectal cancer (HNPCC). Germline heterozygous inactivating mutations of MSH2 and MLH1 have been identified previously in a substantial fraction of individuals who are predisposed genetically to colorectal carcinoma (CRC) and other tumors of the HNPCC spectrum. With the aim of determining the relevance of these two genes in the Italian population, we submitted to mutational analysis a set of 17 HNPCC families, all of which fulfilled the "Amsterdam criteria." A combination of different techniques, including reverse transcription-polymerase chain reaction (RT-PCR) of long fragments and single-strand conformation polymorphism (SSCP) on cDNA and genomic DNA, allowed the identification of ten molecular variants, seven of which are predicted to inactivate mismatch repair function. The mutated predisposing gene was MSH2 in two families and MLH1 in five other families. All of the mutations were characterized by DNA sequencing and appeared to involve different molecular mechanisms, such as short in-frame and out-of-frame deletions, splicing errors, and nonsense mutations. This study also demonstrates that, in the Italian population, a considerable fraction of HNPCC families (at least 41%) is linked to MSH2 and MLH1 mutations.

Adaptor Proteins, Signal Transducing↗

PubMed1997

Mutational analysis of MLH1 and MSH2 in 25 prospectively-acquired RER+ endometrial cancers.

Mutations in the DNA mismatch repair (MMR) genes MLH1 and MSH2 have been linked to several human cancers which display the replication error (RER) phenotype. Germline mutations in these two genes have been implicated in about 90% of families with hereditary nonpolyposis colorectal cancer (HNPCC). A significant proportion of endometrial cancers, the second most common malignancy of the HNPCC syndrome, also exhibit RER. We screened 125 primary endometrial adenocarcinomas with seven microsatellite markers and identified 25 specimens with RER (20%). We used single-strand conformation variant analysis to search for mutations in MLH1 and MSH2. Direct sequencing of variants revealed only one germline mutation in MLH1 and a single somatic mutation in MSH2. However, six previously unreported sequence polymorphisms in MLH1 were identified. Four of these polymorphisms show clear population-based differences in allele frequency. In addition, a highly informative marker for MLH1 was characterized. The low frequency of mutations in MLH1 and MSH2 in this large series of cancers suggests that other MMR genes are responsible for the RER phenotype in endometrial cancers.

Adaptor Proteins, Signal Transducing↗

PubMed2000

Novel germline mutation (300-305delAGTTGA) in the human MSH2 gene in hereditary non-polyposis colorectal cancer (HNPCC).

Hereditary non-polyposis colorectal cancer (HNPCC) is a common hereditary syndrome characterized by the high incidence and early onset of colorectal cancer. The majority of the HNPCC families carry germline mutations in either the MSH2 or the MLH1 mismatch repair gene. A 46 year-old female patient whose family history fulfilled the Amsterdam criteria for HNPCC was diagnosed with undifferentiated adenocarcinoma of the transverse colon. Recognizing the Lynch 2 syndrome (the existance of multiple HNPCC related cancers in a pedigree), we used polymerase chain reaction followed by direct sequencing to screen the coding regions of both the MSH2 and the MLH1 genes for germline mutations in DNA from the patient. We detected a novel germline mutation (300-305delAGTTGA) in exon 2 of human MSH2. We noted microsatellite instability in four microsatellite loci. Immunohistochemistry showed a lack of expression of the MSH2 gene product in the tumor, suggesting that the mutation is a disease-causing mutation.

Base Pair Mismatch↗