Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0009402 (colorectal cancer)
53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many human tumours have length alterations in repetitive sequence elements. Although this microsatellite instability has been attributed to mutations in four DNA mismatch repair genes in hereditary nonpolyposis colorectal cancer (HNPCC) kindreds, many sporadic tumours exhibit instability but no detectable mutations in these genes. It is therefore of interest to identify other genes that contribute to this instability. In yeast, mutations in several genes, including RTH and MSH3, cause microsatellite instability. Thus, we screened 16 endometrial carcinomas with microsatellite instability for alterations in FEN1 (the human homolog of RTH) and in MSH3 (refs 12-14). Although we found no FEN1 mutations, a frameshift mutation in MSH3 was observed in an endometrial carcinoma and in an endometrial carcinoma cell line. Extracts of the cell line were deficient in repair of DNA substrates containing mismatches or extra nucleotides. Introducing chromosome 5, encoding the MSH3 gene, into the mutant cell line increased the stability of some but not all microsatellites. Extracts of these cells repaired certain substrates containing extra nucleotides, but were deficient in repair of those containing mismatches or other extra nucleotides. A subsequent search revealed a second gene mutation in HHUA cells, a missense mutation in the MSH6 gene. Together the data suggest that the MSH3 gene encodes a product that functions in repair of some but not all pre-mutational intermediates, its mutation in tumours can result in genomic instability and, as in yeast, MSH3 and MSH6 are partially redundant for mismatch repair.
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PMID:Mutation of MSH3 in endometrial cancer and evidence for its functional role in heteroduplex repair. 878 29

DNA-mismatch repair removes mismatches from the newly replicated DNA strand. In humans, mutations in the mismatch repair genes hMSH2, hMLH1, hPMS1 and hPMS2 result in hereditary non-polyposis colorectal cancer (HNPCC) [1-8]. The hMSH2 (MSH for MutS homologue) protein forms a complex with a 160 kDa protein, and this heterodimer, hMutSalpha, has high affinity for a G/T mismatch [9,10]. Cell lines in which the 160 kDa subunit of hMutSalpha is mutated are specifically defective in the repair of base-base and single-nucleotide insertion/deletion mismatches [9,11]. Genetic studies in S. cerevisiae have suggested that MSH2 functions with either MSH3 or MSH6 in mismatch repair, and, in the absence of the latter two genes, MSH2 is inactive [12,13]. MSH6 encodes the yeast counterpart of the 160 kDa subunit of hMutSalpha [12,13]. As in humans, yeast MSH6 forms a complex with MSH2, and the MSH2-MSH6 heterodimer binds a G/T mismatch [14]. Here, we find that MSH2 and MSH3 form another stable heterodimer, and we purify this heterodimer to near homogeneity. We show that MSH2-MSH3 has low affinity for a G/T mismatch but binds to insertion/deletion mismatches with high specificity, unlike MSH2-MSH6.
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PMID:Binding of insertion/deletion DNA mismatches by the heterodimer of yeast mismatch repair proteins MSH2 and MSH3. 880 66

DNA mismatch repair plays a key role in the maintenance of genetic fidelity. Mutations in the human mismatch repair genes hMSH2, hMLH1, hPMS1, and hPMS2 are associated with hereditary nonpolyposis colorectal cancer. The proliferating cell nuclear antigen (PCNA) is essential for DNA replication, where it acts as a processivity factor. Here, we identify a point mutation, pol30-104, in the Saccharomyces cerevisiae POL30 gene encoding PCNA that increases the rate of instability of simple repetitive DNA sequences and raises the rate of spontaneous forward mutation. Epistasis analyses with mutations in mismatch repair genes MSH2, MLH1, and PMS1 suggest that the pol30-104 mutation impairs MSH2/MLH1/PMS1-dependent mismatch repair, consistent with the hypothesis that PCNA functions in mismatch repair. MSH2 functions in mismatch repair with either MSH3 or MSH6, and the MSH2-MSH3 and MSH2-MSH6 heterodimers have a role in the recognition of DNA mismatches. Consistent with the genetic data, we find specific interaction of PCNA with the MSH2-MSH3 heterodimer.
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PMID:Evidence for involvement of yeast proliferating cell nuclear antigen in DNA mismatch repair. 891 Apr 4

We have cloned and characterized the human orthologue of the Saccharomyces cerevisiae MutS homologue 5 (MSH5) cDNA, as well as the human gene that encodes the MSH5 cDNA, as a step toward understanding the molecular genetic mechanisms involved in the biological function of this novel human protein. The identified cDNA contains a 2505-bp open reading frame (ORF) that encodes an 834-amino-acid polypeptide with a predicted molecular mass of 92.9 kDa. The amino acid sequence encoded by this cDNA includes sequence motifs that are conserved in all known MutS homologues existing in bacteria to humans. The cDNA appears, on the basis of amino acid sequence analysis, to be a member of the MutS family and shares 30% sequence identity with that of S. cerevisiae MSH5, a yeast gene that plays a critical role in facilitating crossover during meiosis. Northern blot analysis demonstrated the presence of a 2.9-kb human MSH5 mRNA species in all human tissues tested, but the highest expression was in human testis, an organ containing cells that undergo constant DNA synthesis and meiosis. The expression pattern of human MSH5 resembled that of the previously identified human MutS homologues MSH2, MSH3, and MSH6-genes that are involved in the pathogenesis of hereditary nonpolyposis colorectal cancer (HNPCC). In an effort to expedite the search for potential disease association with this new human MutS homologue, we have also determined the chromosomal location and structure of the human MSH5 locus. Sequence and structural characterization demonstrated that MSH5 spans approximately 25 kb and contains 26 exons that range in length from 36 bp for exon 8 to 254 bp for exon 25. MSH5 has been mapped to human chromosome band 6p21.3 by fluorescence in situ hybridization. Knowledge of the sequence and gene structure of MSH5 will now enable studies of the possible roles MSH5 may play in meiosis and/or DNA replicative mismatch repair.
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PMID:Cloning, structural characterization, and chromosomal localization of the human orthologue of Saccharomyces cerevisiae MSH5 gene. 974 Jun 71

Genetic instability of microsatellite repeat sequences [microsatellite instability (MI)] is commonly seen in tumors associated with the hereditary nonpolyposis colorectal cancer syndrome and is a result of inactivating mutations in any of several genes involved in a particular pathway of DNA mismatch repair. Sporadic (i.e., nonhereditary) manifestations of several tumor types, including colorectal, gastric, and endometrial carcinomas, also exhibit MI in a significant fraction of cases. Many MI+ sporadic colorectal carcinomas are associated with somatic mutations of mismatch repair genes, and several genes with coding region microsatellites are frequently mutated as a result in these cancers. The molecular causes and consequences of MI in sporadic endometrial carcinomas remain obscure, however. The aims of this study were: (a) to identify a series of sporadic endometrial carcinomas with clear evidence of MI; (b) to determine the extent to which somatic alterations in mismatch repair genes are associated with this MI; and (c) to establish whether the genes containing coding region microsatellite repeats that are known to be disrupted in MI+ gastrointestinal cancers are also disrupted in MI+ endometrial carcinomas. Matched pairs of normal and tumor DNA from 57 consecutive cases of endometrial carcinoma were examined for evidence of MI using a consensus panel of microsatellite markers. Fourteen cases (25%) displayed unequivocal evidence of MI, consistent with previously published estimates of the incidence of MI+ sporadic endometrial carcinoma. These cases were subjected to a mutation screen of the coding regions and exon-intron boundaries of the mismatch repair genes MSH2 and MLH1. Although several polymorphisms were detected, no clearly deleterious mutations were found in either of these genes. Notably, however, hypermethylation of the MLH1 promoter region was identified in 10 of 14 (71%) MI+ cases. Somatic mutations in coding region microsatellite repeats in the TGFbetaIIR, IGFIIR, BAX, E2F4, MSH3, MSH6, BRCA1, and BRCA2 genes were generally rare. Four MI+ tumors (29%) contained somatic mutations in the PTEN gene, only one of which was likely the result of MI. These data indicate that somatic mutational inactivation of known mismatch repair genes does not account for the great majority of sporadic endometrial carcinomas with MI and that a significant fraction of these cases may instead be causally associated with hypermethylation of the MLH1 promoter. Furthermore, genes with coding region microsatellites that are frequently mutated in MI+ gastrointestinal cancers are rarely mutated in MI+ endometrial cancers, implying the existence of alternative molecular targets for the tumorigenic effects of MI in this tumor type.
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PMID:Causes and consequences of microsatellite instability in endometrial carcinoma. 992 63

Hereditary nonpolyposis colorectal cancer (Lynch syndrome) is an autosomal dominant disease caused by mutations in the mismatch repair genes in particular in MLH1, MSH2 and MSH6. The disease is characterized by the development of colorectal, endometrial cancer and several other cancers. There is evidence that the clinical expression of the disease varies from one country to another. This variation might affect not only the application of criteria proposed to identify families but also clinical risk factors reported to predict the outcome of genetic testing. Data on site of the cancer, age at diagnosis and pathology were collected from 155 families with suspected HNPCC known at the Korean and Dutch HNPCC registries. DGGE, SSCP and DNA-sequencing were performed to identify MSH2, MLH1 and MSH6 mutations. A total of 33 Korean and 42 Dutch families met the clinical criteria for HNPCC. Germline mutations in the MMR-genes were found in 23 Korean and 24 Dutch families. In families that met the Amsterdam criteria, and also in those associated with MLH1 mutations, more cancers of the stomach and pancreas were observed in the Korean families than in the Dutch HNPCC families; in relative terms, the incidence of cancers of the endometrium in the Korean families was lower. Multivariate analysis showed that an early age at diagnosis, and the occurrence of pancreatic cancer were independent predictive factors of germline mutations in MLH1, MSH2 and MSH6 in the Korean subset of families.
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PMID:Gene-environment interaction in hereditary nonpolyposis colorectal cancer with implications for diagnosis and genetic testing. 1040 64

Mutations affecting human mismatch repair (MMR) genes (MLH1, MSH2, PMS1, PMS2, and MSH6) cause tumour predisposition in hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, and an association has been demonstrated with the replication error (RER) phenotype in most colorectal and some extracolonic neoplasms. A pathogenetic model for RER+ tumours through inactivation of suppressor genes has been hypothesised, and TGF beta RII, BAX and IGFIIR genes have recently been proposed as targets of such inactivating mutations. In this study, a series of 47 tumours developed in patients with known MLH1/MSH2 status and a family history of HNPCC and/or early onset colorectal cancer were characterised for the RER phenotype through microsatellite analysis. The RER phenotype, displayed by 17 tumours, was then correlated with the presence of insertions/deletions at the TGF beta RII, IGFIIR and BAX gene stretches, confirming that the TGF beta RII inactivation may be particularly critical for the RER-associated tumorigenesis. RER+ colorectal cancers (CRCs) developed more frequently in patients from HNPCC families (72.7%) than in those from families not fulfilling the Amsterdam criteria (33.3% in suspected HNPCC and 20.8% in early onset CRC patients). A consistent fraction of either Amsterdam and non-Amsterdam patients developed RER- CRCs, pointing to the involvement of other genes not related to the MMR system. The RER phenotype was associated with younger age at diagnosis in familial cases, and there was a trend for an association with proximal CRC localisation and early Dukes' stages. The RER status was also correlated with the presence and type of MLH1 and MSH2 alteration.
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PMID:Evaluation of the replication error phenotype in relation to molecular and clinicopathological features in hereditary and early onset colorectal cancer. 1044 73

Germline mutations in the MSH2 and MLH1 mismatch repair genes account for most cases of hereditary non-polyposis colon cancer syndrome (HNPCC). In addition, germline MSH2 and MLH1 mutations have been detected in patients with non-HNPCC early onset colorectal cancer. Germline MSH6 mutations appear to be rare in classical HNPCC families, but their frequency in young colorectal cancer cases has not been studied previously. In a population based study of early onset colorectal cancer (<50 years) investigated for tumour microsatellite instability (MSI), we identified a subgroup of tumours with MSI for mono- but not dinucleotide repeat markers (m-MSI+ group). In contrast to tumours with classical MSI for dinucleotide markers (d-MSI+), the m-MSI+ group cancers were mainly left sided (6/7). As MSH6 mutations in yeast and human cell lines are associated with weak (and preferential mononucleotide) MSI, the complete MSH6 gene coding region was sequenced in blood DNA from the five m-MSI+ cases available for analysis. A germline nonsense mutation was identified in an isolated case of early onset colorectal cancer (age 43 years). These results support previous findings that germline MSH6 mutations may not be associated with classical MSI and suggest a role for germline MSH6 mutations in isolated early onset colorectal cancer.
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PMID:Mononucleotide microsatellite instability and germline MSH6 mutation analysis in early onset colorectal cancer. 1050 23

Hereditary nonpolyposis colorectal cancer (HNPCC) (Amsterdam criteria) is often caused by mutations in mismatch repair (MMR) genes, and tumors of patients with HNPCC show microsatellite instability (MSI-high phenotype). Germline mutations of MMR genes have rarely been found in families that have HNPCC or suspected HNPCC and that do not show microsatellite instability (MSI-low phenotype). Therefore, an MSI-high phenotype is often used as an inclusion criterion for mutation testing of MMR genes. Correction of base-base mismatches is the major function of MSH6. Since mismatches present with an MSI-low phenotype, we assumed that the phenotype in patients with HNPCC-related tumors might be associated with MSH6 germline mutations. We divided 36 patients with suspected HNPCC into an MSI-low group (n=18) and an MSI-high group (n=18), on the basis of the results of MSI testing. Additionally, three unrelated patients from Amsterdam families with MSI-low tumors were investigated. All patients were screened for MSH2, MLH1, and MSH6 mutations. Four presumably causative MSH6 mutations were detected in the patients (22%) who had suspected HNPCC and MSI-low tumors. Furthermore, we detected one frameshift mutation in one of the three patients with HNPCC and MSI-low tumors. In the MSI-high group, one MSH6 missense mutation was found, but the same patient also had an MLH1 mutation, which may explain the MSI-high phenotype. These results suggest that MSH6 may be involved in a substantial proportion of patients with HNPCC or suspected HNPCC and MSI-low tumors. Our data emphasize that an MSI-low phenotype cannot be considered an exclusion criterion for mutation testing of MMR genes in general.
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PMID:Association of hereditary nonpolyposis colorectal cancer-related tumors displaying low microsatellite instability with MSH6 germline mutations. 1052 Dec 94

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.
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PMID:Separation-of-function mutations in Saccharomyces cerevisiae MSH2 that confer mismatch repair defects but do not affect nonhomologous-tail removal during recombination. 1052 44


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