The Genetics of Hereditary Non-Polyposis Colorectal Cancer

2003 ◽  
Vol 1 (1) ◽  
pp. 137-144 ◽  
Author(s):  
Stephen B. Gruber ◽  
Wendy Kohlmann
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Molecular Diagnostic ◽  
Repair System ◽  
Molecular Fingerprint ◽  
Dna Mismatch ◽  
Repair Protein ◽  
Mismatch Repair System ◽  
Defective Mismatch Repair

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant condition accounting for 3% to 5% of all colorectal cancer. HNPCC is caused by germline mutations in the mismatch repair system and is recognized by a characteristic clinical phenotype as well as a hallmark of the tumors termed “microsatellite instability.” Microsatellite instability serves as a molecular fingerprint for defective mismatch repair and has proven to be useful in the molecular diagnostic workup for HNPCC. The crystal structure of the DNA mismatch repair protein MutS has been solved, providing insight into the molecular basis of defective mismatch repair. Genetic testing has become a key component of the treatment of patients and families with HNPCC, and enhanced surveillance for HNPCC has been shown to reduce the rate of colorectal cancer by more than half and improve 10-year survival from 68% to 93%.

Warthin Tumors Do Not Have Microsatellite Instability and Express Normal DNA Mismatch Repair Proteins

2006 ◽  
Vol 130 (1) ◽  
pp. 52-56 ◽  
Author(s):  
Jennifer L. Hunt
Keyword(s):  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Repair System ◽  
Dna Mismatch ◽  
Epithelial Component ◽  
Repair Enzymes ◽  
Dna Mismatch Repair System ◽  
Mismatch Repair System ◽  
Polymerase Chain

Abstract 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.

Oxidative stress induces inactivation of the DNA mismatch repair system and causes microsatellite instability

2000 ◽  
Vol 118 (4) ◽  
pp. A707
Author(s):  
Christoph Gasche ◽  
Christina L. Chang ◽  
Jennifer Rhees ◽  
Ajay Goel ◽  
Luigi Ricciardiello ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Repair System ◽  
Dna Mismatch ◽  
Dna Mismatch Repair System ◽  
Mismatch Repair System

Frequency of Defective Mismatch Repair System in a Series of Consecutive Cases of Colorectal Cancer in a National Cancer Center

2018 ◽  
Vol 49 (3) ◽  
pp. 379-384 ◽  
Author(s):  
Patricia E. López-Correa ◽  
Leonardo S. Lino-Silva ◽  
Armando Gamboa-Domínguez ◽  
César Zepeda-Najar ◽  
Rosa A. Salcedo-Hernández
Keyword(s):  
Colorectal Cancer ◽  
Mismatch Repair ◽  
Cancer Center ◽  
Repair System ◽  
Mismatch Repair System ◽  
Defective Mismatch Repair

Functional Specifics of the MutL Protein of the DNA Mismatch Repair System in Different Organisms

2020 ◽  
Vol 46 (6) ◽  
pp. 875-890
Author(s):  
M. V. Monakhova ◽  
M. A. Milakina ◽  
R. M. Trikin ◽  
T. S. Oretskaya ◽  
E. A. Kubareva
Keyword(s):  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Repair System ◽  
Dna Mismatch ◽  
Dna Mismatch Repair System ◽  
Mismatch Repair System

scholarly journals Saturation of DNA Mismatch Repair and Error Catastrophe by a Base Analogue in Escherichia coli

Genetics ◽  
2002 ◽  
Vol 161 (4) ◽  
pp. 1363-1371
Author(s):  
Kazuo Negishi ◽  
David Loakes ◽  
Roel M Schaaper
Keyword(s):  
Escherichia Coli ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Repair System ◽  
Mutagenic Action ◽  
Wild Type ◽  
Dna Mismatch ◽  
Cell Counts ◽  
Error Catastrophe ◽  
Mismatch Repair System

Abstract Deoxyribosyl-dihydropyrimido[4,5-c][1,2]oxazin-7-one (dP) is a potent mutagenic deoxycytidine-derived base analogue capable of pairing with both A and G, thereby causing G · C → A · T and A · T → G · C transition mutations. We have found that the Escherichia coli DNA mismatch-repair system can protect cells against this mutagenic action. At a low dose, dP is much more mutagenic in mismatch-repair-defective mutH, mutL, and mutS strains than in a wild-type strain. At higher doses, the difference between the wild-type and the mutator strains becomes small, indicative of saturation of mismatch repair. Introduction of a plasmid containing the E. coli mutL+ gene significantly reduces dP-induced mutagenesis. Together, the results indicate that the mismatch-repair system can remove dP-induced replication errors, but that its capacity to remove dP-containing mismatches can readily be saturated. When cells are cultured at high dP concentration, mutant frequencies reach exceptionally high levels and viable cell counts are reduced. The observations are consistent with a hypothesis in which dP-induced cell killing and growth impairment result from excess mutations (error catastrophe), as previously observed spontaneously in proofreading-deficient mutD (dnaQ) strains.

scholarly journals Antagonism of Ultraviolet-Light Mutagenesis by the Methyl-Directed Mismatch-Repair System of Escherichia coli

Genetics ◽  
2000 ◽  
Vol 154 (2) ◽  
pp. 503-512 ◽  
Author(s):  
Hongbo Liu ◽  
Stephen R Hewitt ◽  
John B Hays
Keyword(s):  
Escherichia Coli ◽  
Mismatch Repair ◽  
Excision Repair ◽  
Spontaneous Mutation ◽  
Repair System ◽  
Uv Mutagenesis ◽  
Repair Protein ◽  
Mismatch Repair System

Abstract Previous studies have demonstrated that the Escherichia coli MutHLS mismatch-repair system can process UV-irradiated DNA in vivo and that the human MSH2·MSH6 mismatch-repair protein binds more strongly in vitro to photoproduct/base mismatches than to “matched” photoproducts in DNA. We tested the hypothesis that mismatch repair directed against incorrect bases opposite photoproducts might reduce UV mutagenesis, using two alleles at E. coli lacZ codon 461, which revert, respectively, via CCC → CTC and CTT → CTC transitions. F′ lacZ targets were mated from mut+ donors into mutH, mutL, or mutS recipients, once cells were at substantial densities, to minimize spontaneous mutation prior to irradiation. In umu+ mut+ recipients, a range of UV fluences induced lac+ revertant frequencies of 4–25 × 10−8; these frequencies were consistently 2-fold higher in mutH, mutL, or mutS recipients. Since this effect on mutation frequency was unaltered by an Mfd− defect, it appears not to involve transcription-coupled excision repair. In mut+ umuC122::Tn5 bacteria, UV mutagenesis (at 60 J/m2) was very low, but mutH or mutL or mutS mutations increased reversion of both lacZ alleles roughly 25-fold, to 5–10 × 10−8. Thus, at UV doses too low to induce SOS functions, such as Umu2′D, most incorrect bases opposite occasional photoproducts may be removed by mismatch repair, whereas in heavily irradiated (SOS-induced) cells, mismatch repair may only correct some photoproduct/base mismatches, so UV mutagenesis remains substantial.

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

2000 ◽  
Vol 275 (37) ◽  
pp. 29178
Author(s):  
Dong Kyung Chang ◽  
Luigi Ricciardiello ◽  
Ajay Goel ◽  
Christina L. Chang ◽  
C. Richard Boland
Keyword(s):  
Steady State ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
State Regulation ◽  
Repair System ◽  
Dna Mismatch ◽  
Human Dna ◽  
Dna Mismatch Repair System ◽  
Mismatch Repair System
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