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Results for “DNA Mismatch Repair”

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PubMed1993

Destabilization of tracts of simple repetitive DNA in yeast by mutations affecting DNA mismatch repair.

The genomes of all eukaryotes contain tracts of DNA in which a single base or a small number of bases is repeated. Expansions of such tracts have been associated with several human disorders including the fragile X syndrome. In addition, simple repeats are unstable in certain forms of colorectal cancer, suggesting a defect in DNA replication or repair. We show here that mutations in any three yeast genes involved in DNA mismatch repair (PMS1, MLH1 and MSH2) lead to 100- to 700-fold increases in tract instability, whereas mutations that eliminate the proof-reading function of DNA polymerases have little effect. The meiotic stability of the tracts is similar to the mitotic stability. These results suggest that tract instability is associated with DNA polymerases slipping during replication, and that some types of colorectal cancer may reflect mutations in genes involved in DNA mismatch repair.

DNA Repair↗

PubMed2000

Comparative study of the expression of DNA mismatch repair genes, the adenomatous polyposis coli gene and growth arrest DNA damage genes in melanoma recurrences and metastases.

The main goal of this study was to examine the expression of DNA mismatch repair genes (MLH1, MSH2, PMS1 and PMS2), the adenomatous polyposis coli (APC) gene and growth arrest DNA damage inducible (GADD) genes (GADD34, GADD45 and GADD153) in the different stages of melanoma recurrences and metastases, and to identify any mutual consistencies in their expression pattern. All the cases of primary melanoma examined showed a reduced expression of DNA repair genes. These results demonstrate that disturbances of DNA repair begin in the early stages of melanoma. No significant differences were found in the expression of these markers between cutaneous melanomas and their recurrences and metastases (P> 0.05). Eighteen significant correlations between markers were found in the primary melanomas, and 10 significant correlations were observed in the first recurrences of melanoma. In contrast, 27 statistically significant relationships were demonstrated in metastatic lymph nodes. The different correlations found in primary and metastatic tumours confirmed the hypothetical difference in marker interaction in the diagnostic groups investigated. Our results suggest that DNA repair genes may play an important role in the recurrence and metastasis of melanomas.

Adaptor Proteins, Signal Transducing↗

PubMed1998

Four new mutations in the DNA mismatch repair gene MLH1 in colorectal cancers with microsatellite instability. Mutations in brief no. 157. Online.

Hereditary nonpolyposis colorectal cancer (HNPCC) is frequently associated with inherited mutation in one of four DNA mismatch repair genes. Somatic mutations in the same genes are also found in a subset of sporadic colorectal cancers. A defect in DNA mismatch repair results in a RER (replication error) tumor phenotype. We screened 110 archival and 11 prospectively acquired colorectal cancers for the RER phenotype. A total of 22 cancers were RER-positive. RER-positive tumors were investigated for mutations in the DNA mismatch repair gene MLH1 using single-strand-conformation-polymorphism (SSCP) analysis. We identified four previously undescribed mutations in four different samples. Three mutations were exonic: a point mutation at codon 69 (AGG-->AAG(arg-->lys]); a single base pair deletion at codon 42/43 (GCAAAATCC-->GCAAATCC) leading to a new stop codon downstream; and a point mutation at codon 757 (TAA-->TAT [termination-->tyr] which extend the MLH1 peptide by 36 ammino acids. The fourth mutation was a 1 base pair insertion six base pairs 5' to the start of exon 14 (tttgtttt-->tttggtttt). The mutations were not seen in the patients' constitutional DNA. The somatic MLHI mutations identified appear to be causally associated with the RER phenotype.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Improved survival with an intact DNA mismatch repair system in endometrial cancer.

OBJECTIVE: To correlate survival and surgical-pathologic factors with DNA mismatch repair status in patients with endometrial cancer. METHODS: Specimens from 336 patients with endometrial cancer were used to create a tissue microarray. Immunohistochemistry with antibodies against the mismatch repair genes MLH1, MSH2, MSH6, and PMS2 were used to stain the tissue microarray. Clinical, pathologic, and survival data were collected and correlated with the immunohistochemistry results. RESULTS: Mismatch repair deficiency was seen in 29% (84 of 294) of cases. Correlation was noted between lack of expression of MLH1 and an increased risk for lymphvascular space involvement (32% versus 21%, P=.05) and cervical involvement (26% versus 14%, P=.02). Lack of expression of either MLH1 or MSH2 was associated with thinner patients (85% had a body mass index less than 40 versus 73% of patients with normal expression, P=.02), as well as with the absence of a history of previous primary malignancy (0 verus 13 cases [4%], P=.023). The estimated disease-free survival is 88%; despite a small number of recurrences, there was a nonsignificant improvement in disease-free survival in tumors with an intact mismatch repair system (P=.1). Significantly improved disease-free survival was seen in patients with normal MLH1 and MSH2 expression compared with those with abnormal expression (92% versus 81%, P=.035). CONCLUSION: Defects in DNA mismatch repair in endometrial cancer is correlated with negative prognostic factors and worse progression-free survival (without a difference in overall survival) compared with tumors with an intact mismatch repair system. LEVEL OF EVIDENCE: II-3.

Adaptor Proteins, Signal Transducing↗

PubMed1994

Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer.

The human DNA mismatch repair gene homologue hMSH2, on chromosome 2p is involved in hereditary non-polyposis colon cancer (HNPCC). On the basis of linkage data, a second HNPCC locus was assigned to chromosome 3p21-23 (ref. 3). Here we report that a human gene encoding a protein, hMLH1 (human MutL homologue), homologous to the bacterial DNA mismatch repair protein MutL, is located on human chromosome 3p21.3-23. We propose that hMLH1 is the HNPCC gene located on 3p because of the similarity of the hMLH1 gene product to the yeast DNA mismatch repair protein, MLH1, the coincident location of the hMLH1 gene and the HNPCC locus on chromosome 3, and hMLH1 missense mutations in affected individuals from a chromosome 3-linked HNPCC family.

Adaptor Proteins, Signal Transducing↗

PubMed2000

[The expression of DNA mismatch repair genes and detection of DNA ploidy in young patients with colorectal carcinoma].

OBJECTIVE: To investigate the clinicopathologic characters and carcinogentic pathways of young (age < 36) colorectal carcinomas (CRCs) in Guangzhou, China. METHODS: Immunohistochemistry and flow cytometry methods were used to detect the expression of hMSH(2) and hMLH(1), status of DNA ploidy in 63 cases of young CRCs from Guangzhou, China, and analyze their correlations with patient's clinicopathological characters. RESULTS: Of the 63 young CRCs studied, forty-four (69.8%) tumors were non-mucinous carcinomas, thirty-nine (61.9%) patients were in Dukes' C or D stage. Of the 59 CRCs which were successfully detected by immunohistochemistry and flow cytometry, ten (16.9%) CRCs lost either hMSH(2) or hMLH(1) and showed DNA diploid or near-diploid, while twenty-six (44.1%) had aneuploid DNA content and all with the normal expression of hMSH(2) and hMLH(1). In addition, there existed a significant percentage (23/59, 39%) of young CRCs showing no loss of either of these two mismatch repair proteins and having a diploid or near diploid DNA content. CONCLUSION: The overall percentage of young CRCs in Guangzhou is significantly higher than those in Caucasian predominant countries and about seventy percent of young CRCs in Guangzhou are conventional carcinomas. 39% of young CRCs in Guangzhou showed no evidence of either chromosomal instability or microsatellite instability carcinogentic pathway, indicating that there must be at least a third pathway which triggers the CRCs in these special subgroups of young patients in Guangzhou, China.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Expression of the DNA mismatch repair proteins (hMLH1 and hMSH2) in infiltrating pancreatic cancer and its relation to some phenotypic features.

UNLABELLED: DNA mismatch repair system defects cause microsatellite instability (MSI) and form an alternative pathway in cancer development. Germline mutations of DNA mismatch repair genes account for hereditary nonpolyposis colorectal cancer, which has a different morphology and biology than sporadic cancers. MSI has also been found in sporadic neoplasms and some inflammatory conditions (chronic pancreatitis, ulcerative colitis). The purpose of the present study was to evaluate the expression of hMLH1 and hMLH2 proteins in infiltrating pancreatic cancer and to find out whether there is a relationship between some phenotypic manifestations and expression of MMR genes. We studied 30 cases of infiltrating pancreatic cancer and apart from hMLH1 and hMLH2 expression cytokeratin 7 and chromogranin were measured as markers of ductal and endocrine differentiation, respectively. All ductal pancreatic cancers expressed cytokeratin 7. In most cases the expression was strong, present in 50-100% of cells in moderately differentiated cancers and in 80-100% of cells in poorly differentiated cancers. Chromogranin expression was seen in 5 moderately differentiated cancers and in 6 poorly differentiated cancers (up to 20% of positive cells). In all cases DNA mismatch repair genes expression was present. CONCLUSION: Ductal pancreatic carcinomas express hMLH1 and hMLH2 proteins irrespective of their differentiation. The expression of cytokeratin 7 is typical of ductal pancreatic carcinoma and its level is related to cancer differentiation. Some ductal pancreatic carcinomas irrespective of their differentiation show the expression of chromogranin, which is associated with the expression of hMSH2 gene.

Adaptor Proteins, Signal Transducing↗

PubMedDate not supplied

Altered expression and new mutations in DNA mismatch repair genes MLH1 and MSH2 in melanoma brain metastases.

Brain metastases, including those of malignant melanoma (known for its high genomic instability), are the most common intracranial tumors. The main objective of this study was to investigate expression and mutation in the DNA mismatch repair system in melanoma brain metastases. Expression of MLH1, MSH2, PMS1 and PMS2 was investigated immunohistochemically in 31 melanoma metastatic tumors. Mutational analysis of MLH1 and MSH2 was performed in 17 melanoma brain metastases. Loss of MLH1 and MSH2 expression was found in 10/31 and 12/31 tumors. PMS1 (27/31) and PMS2 (28/31) expression was preserved in the majority of lesions. Potential missense mutation was found in MSH2 (exon 13) in 2/17 melanomas. Mutation in the intron sequence between exon 14 and 15 of MLH1 (exon 15) was observed in 4/17 cases. Our results indicate that the two major DNA mismatch repair genes, MLH1 and MSH2, are more frequently affected by alterations in the DNA mismatch repair system than the helper genes PMS1 and PMS2. The presence of mutations of MSH2 and MLH1 in melanoma brain metastases, which has not been found in primary melanomas, indicates the high genomic instability of melanoma brain metastases.

Adaptor Proteins, Signal Transducing↗

PubMed2000

Steady-state regulation of the human DNA mismatch repair system.

Steady-state levels of human DNA mismatch repair (MMR) transcripts and proteins were measured in MMR-proficient and -deficient cell lines by the newly developed competitive quantitative reverse transcription- polymerase chain reaction and Western analysis normalized with purified proteins. In MMR-proficient cells, hMSH2 is the most abundant MMR protein and is expressed 3 to 5 times more than hMLH1. The hMLH1 protein was expressed 1.5 to 2.5 times more than hPMS2. Steady-state levels of mRNA expression correlated well with protein expression. hMSH2-mutated LoVo cells did not express detectable hMSH3 or hMSH6 proteins. Similarly, hMLH1-mutated HCT116 cells did not express detectable hMLH1 or hPMS2 protein, whereas in hMLH1-restored HCT116+ch3 cells, hPMS2 protein was re-expressed. In hMSH6-mutated HCT15 cells, both hMSH3 protein and mRNA were increased. In SV40-transformed lung fibroblasts, all MMR mRNAs and proteins examined were expressed at levels 1.5-5-fold higher than in their nontransformed counterpart. The steady-state levels of MMR proteins indicate that substantially more hMutS proteins, which are involved in DNA mismatch recognition, are present in comparison with the hMutL proteins. Stability of hMSH3 and hMSH6 proteins appears to depend upon the presence of the hMSH2 protein, and, similarly, the stability of the hPMS2 protein depends upon hMLH1. When the hMSH6 is mutationally inactivated, hMSH3 increases by both transcriptional up-regulation and enhanced protein stability. A balanced up-regulation of all of the components was seen after viral transformation in a fibroblast model. Quantitative changes of the MMR components are a potential mechanism to modify the DNA MMR capabilities of a cell.

Cell Transformation, Viral↗

PubMed1997

Role of DNA mismatch repair in the cytotoxicity of ionizing radiation.

The DNA mismatch repair (MMR) system in mammalian cells not only serves to correct base mispairs and other replication errors, but it also influences the cellular response to certain forms of DNA damage. Cells that are deficient in MMR are relatively resistant to alkylation damage because, in wild-type cells, the MMR system is thought to promote toxicity via futile repair of alkylated mispairs. Conversely, MMR-deficient cells are sensitive to UV light, possibly due to the requirement for MMR factors in transcription-coupled repair of active genes. MMR deficiency has been associated with familial and sporadic carcinomas of the colon and other sites, and so, we sought to determine the influence of MMR status on cellular response to ionizing radiation, an agent commonly used for cancer therapy. Fibroblast cell lines were established from transgenic mice carrying targeted disruptions of one of three MMR genes in mammalian cells: Pms2, Mlh1, or Msh2. In comparison to wild-type cell lines from related mice, the Pms2-, Mlh1-, or Msh2-nullizygous cell lines were found to exhibit higher levels of clonogenic survival following exposure to ionizing radiation. Because ionizing radiation generates a variety of lesions in DNA, the differences in survival may reflect a role for MMR in processing a subset of these lesions, such as damaged bases. These results both identify a new class of DNA-damaging agents whose effects are modulated by the MMR system and may help to elucidate pathways of radiation response in cancer cells.

Animals↗

PubMed1995

DNA mismatch repair and cancer.

The genetic basis of cancer involves certain classes of genes, particularly oncogenes, tumor-suppressor genes, and DNA mismatch repair genes. Originally identified in bacteria and yeast, the human homologues of DNA mismatch repair genes have been implicated in the pathogenesis of the hereditary nonpolyposis colorectal cancer syndromes, as well as a variety of different sporadic cancers. An appreciation of their role in cancer is predicated on an understanding of their function in the processes of DNA repair. This article reviews the recent developments and advances in the biology of the human DNA mismatch repair genes and their involvement in the pathogenesis of cancer.

Colonic Neoplasms↗

PubMed2004

Cadmium inhibits human DNA mismatch repair in vivo.

The heavy metal cadmium (Cd) is a human carcinogen that inhibits DNA repair activities. We show that DNA mismatch repair (MMR)-mediated cell cycle arrest after alkylation damage is suppressed by exposure to Cd and that this effect is reversed by preincubation with excess of zinc (Zn). We show that Cd-mediated inactivation of MMR activity is not caused by disruption of complex formation between the MMR proteins hEXO1-hMutS alpha and hEXO1-hMutL alpha nor does Cd inhibit 5'-exonuclease activity of hEXO1 in vitro. Thus, our studies show that exposure of human cells to Cd suppresses MMR activity, a repair activity known to play an important role in colon cancer and that this effect can be reversed by Zn treatment.

Alkylation↗

PubMed2001

DNA mismatch repair genes hMLH1, hMSH2, and hMSH6 are not inactivated in bronchioloalveolar carcinomas of the lung.

BACKGROUND: Defective DNA mismatch repair (MMR) appears to be rare in nonsmall cell carcinomas of the lung. Defective DNA MMR results from genetic or epigenetic alterations that inactivate the DNA MMR genes hMLH1 or hMSH2, and rarely hMSH6. The loss of normal DNA MMR is thought to promote tumorigenesis by accelerating the accumulation of mutations in oncogenes and tumor suppressor genes. Inactivation of hMLH1, hMSH2, and hMSH6 is observed as a loss of expression of these proteins by immunohistochemistry. Bronchioloalveolar carcinoma is a subtype of adenocarcinoma with distinctive clinical and pathologic features. MATERIALS AND METHODS: An immunohistochemical study was performed on paraffin embedded sections of 33 bronchioloalveolar carcinomas (20 nonmucinous and 13 mucinous) for hmlh1, hmsh2, and hmsh6 proteins. RESULTS All the tumors showed normal expression of hmlh1, hmsh2, and hmsh6. CONCLUSIONS: These findings suggest that defective DNA MMR due to inactivation of hMLH1, hMSH2, or hMSH6 does not play a significant role in the pathogenesis of bronchioloalveolar carcinomas.

Adaptor Proteins, Signal Transducing↗

PubMed1997

Cancer risk associated with germline DNA mismatch repair gene mutations.

The autosomal dominant syndrome of Hereditary Nonpolyposis Colorectal Cancer (HNPCC) is due to germline DNA mismatch repair gene mutations in most cases. However, the penetrance of such mutations outwith classical HNPCC kindreds is unknown because families studied to date have been specifically selected for research purposes. Using a population-based strategy, we have calculated the lifetime cancer risk associated with germline DNA mismatch repair gene mutations, irrespective of their family history. We identified 67 gene carriers whose risk to age 70 for all cancers was 91% for males and 69% for females. The risk of developing colorectal cancer was significantly greater for males than for females (74% versus 30%, P= 0.006). The risk of uterine cancer (42%) exceeded that for colorectal cancer in females, emphasising the need for uterine screening. Our findings give further insight into the biological effect of defective DNA mismatch repair. We have demonstrated a systematic approach to identifying individuals at high risk of cancer but who may not be part of classical HNPCC families. The risk estimates derived from these analyses provide a rational basis on which to guide genetic counselling and to tailor clinical surveillance.

Colorectal Neoplasms, Hereditary Nonpolyposis↗

PubMed2002

Expression of hMSH2 and hMLH1 proteins of the human DNA mismatch repair system in salivary gland tumors.

BACKGROUND: The human DNA mismatch repair (hMMR) system plays an important role in reducing mutation and maintaining genomic stability. The MMR system in human cells is composed of at least six genes (hMSH2, hMLH1, hMSH3, hPMS1, hPMS2 and GTBP/hMSH6). In particular, hMSH2 and hMLH1 are expressed in cells undergoing rapid renewal; their reduced expression has been reported in several tumors. METHODS: We examined the expression of hMSH2 and hMLH1 by immunohistochemistry in tumor specimens from 43 patients with primary tumors. RESULTS: All carcinomas (n = 20) expressed these proteins. In addition, when compared to pleomorphic adenomas, malignant tumors contained significantly (P < 0.01) higher proportions of hMSH2 (56.1 +/- 31.5 vs. 31.1 +/- 22.6) and hMLH1 (27.9 +/- 26.0 vs. 14.0 +/- 12.6) positive cells. Warthin's tumors showed no specific nuclear staining of tumor cells for both hMSH2 and hMLH1. CONCLUSIONS: These data suggest a minor, if any, role for a defect in the hMMR system in the pathogenesis of malignant salivary gland tumors.

Adaptor Proteins, Signal Transducing↗

PubMed2001

The interaction of DNA mismatch repair proteins with human exonuclease I.

Exonucleolytic degradation of DNA is an essential part of many DNA metabolic processes including DNA mismatch repair (MMR) and recombination. Human exonuclease I (hExoI) is a member of a family of conserved 5' --> 3' exonucleases, which are implicated in these processes by genetic studies. Here, we demonstrate that hExoI binds strongly to hMLH1, and we describe interaction regions between hExoI and the MMR proteins hMSH2, hMSH3, and hMLH1. In addition, hExoI forms an immunoprecipitable complex with hMLH1/hPMS2 in vivo. The study of interaction regions suggests a biochemical mechanism of the involvement of hExoI as a downstream effector in MMR and/or DNA recombination.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Warthin tumors do not have microsatellite instability and express normal DNA mismatch repair proteins.

CONTEXT: Warthin tumors are controversial entities with a poorly understood etiology. Although some investigators have suggested a neoplastic origin, others have supported a developmental anomaly. A recent study described the absence of staining for hMLH1 and hMSH2 proteins in the epithelial component of Warthin tumors, suggesting that they arise secondary to defects in the DNA mismatch repair system. OBJECTIVE: To determine if Warthin tumors exhibit evidence of DNA mismatch repair defects. DESIGN: Immunostains for hMLH1 and hMSH2 were performed using a standard approach. Microdissection of the epithelial component was followed by DNA extraction from the tissue fragments. Polymerase chain reaction and capillary electrophoresis analyses were performed for the following 5 National Cancer Institute-recommended microsatellites: D2s123, D5s346, D17s250, BAT25, and BAT26. PATIENTS: Twelve patients with Warthin tumors were included. RESULTS: The immunostains for hMLH1 and hMSH2 showed preserved expression in the nuclei of the epithelial component of all Warthin tumors. No microsatellite instability was detected, and no loss of heterozygosity was seen. CONCLUSIONS: These results are not concordant with previously reported results showing loss of expression of the hMLH1 and hMSH2 DNA mismatch repair enzymes in the epithelial component of Warthin tumors. Furthermore, no microsatellite instability was detected in the 5 loci tested for each tumor in this series. These data demonstrate that Warthin tumors do not have evidence of DNA mismatch repair defects at the genomic or protein expression level.

Adaptor Proteins, Signal Transducing↗

PubMedDate not supplied

Expression of DNA mismatch repair proteins hMSH2 and hMLH1 and the cyclin G1 inhibitor, p21(waf1/cip1) in pediatric tumors: correlation with response to therapy.

The expression of the DNA mismatch repair proteins hMSH2 and hMLH1 and p21(waf1) the cyclin G1 inhibitor, may determine response of adult cancers to anti-cancer drugs, that include alkylating agents and platinum-based drugs. The role of DNA mismatch repair proteins (hMSH2 and hMLH1) and p21(waf1) in pediatric tumor responses to chemotherapy and irradiation is described in the present study of 23 pediatric solid cancers (4 wilms' tumors, 9 neuroblastomas, 3 hepatoblastomas, 3 lymphomas and 4 sarcomas) using immunohistochemical methods. Immunostaining was scored for intensity (0-3) and extent (0-3). Most tumors stained strongly for hMSH2 and weakly or negative for hMLH1. All the hMLH1 negative tumors (1 wilms', 1 hepatoblastoma, 1 sarcoma, 2 lymphomas and 2 neuroblastomas) achieved complete response. p21(waf1) negative and positive tumors achieved relatively similar treatment response. The results suggest that the expression of DNA mismatch repair proteins hMLH1 and hMSH2, and p21(waf1) do not influence individual cancer responses to treatment and the results may reflect the use of multiple drugs and irradiation that cause many different types of DNA damage.

Adaptor Proteins, Signal Transducing↗