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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The haploid yeast Saccharomyces cerevisiae MW104-1B strain was disomic for chromosome III (n + 1) and carried DNA mismatches at three different heteroallelic loci; leu2 (leu2-1/leu2-27), thr4 (thr4-1/thr4-16) and his4 (his4-4/his4-519) (Williamson, 1984). We mutagenized the MW104-1B strain and identified seven mutant isolates that display elevated mitotic/meiotic prototrophs due to mismatch repair failures at heteroallelic loci. Three mutants (pms1, pms2 and pms3) isolated earlier from MW104-1B were shown to correct in vitro constructed plasmids with defined DNA mismatches (G/T, A/C, G/G, etc.) poorly (Kramer et al., 1989a). Complementation tests were performed by crossing all seven new mutant isolates to pms1 and pms2 mutants and assaying for mutant phenotype in the diploids. Four mutant isolates failed to complement the two known pms alleles (pms1-1 and pms2-1). Two other mutant isolates complemented the pms1-1 and pms2-1 alleles, but failed to complement each other and were named as the pms5-1 allele of an uncharacterized gene (PMS5). One other mutant isolate complemented the pms1-1, pms2-1 and pms5-1 alleles and was named as the pms6-1 allele of another uncharacterized gene (PMS6). Subsequently, the pms5-1 mutant allele was shown to be complemented by a plasmid borne yeast MSH2 gene, implying that it is an allele of MSH2 (PMS5). The human homologs (hMSH2 and hMLH1) of two yeast DNA mismatch repair genes (MSH2 and MLH1) have been cloned recently and shown to be responsible for hereditary nonpolypnosis colon cancer (HNPCC) (Fishel et al., 1993; Leach et al., 1993; Bronner et al., 1994; Papadopoulos et al., 1994).
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PMID:Mutagenesis of yeast MW104-1B strain has identified the uncharacterized PMS6 DNA mismatch repair gene locus and additional alleles of existing PMS1, PMS2 and MSH2 genes. 752 Oct 9

Alterations of the human MSH2 gene, a homologue of the bacterial MutS mismatch repair gene, co-segregate with the majority of hereditary non-polyposis colon cancer (HNPCC) cases. We have generated homozygous MSH2-/- mice. Surprisingly, these mice were found to be viable, produced offspring in a mendelian ratio and bred through at least two generations. Starting at two months of age homozygous-/- mice began, with high frequency, to develop lymphoid tumours that contained microsatellite instabilities. These data establish a direct link between MSH2 deficiency and the pathogenesis of cancer. These mutant mice should be good models to study the progression of tumours and also to screen carcinogenic and anti-cancer agents.
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PMID:MSH2 deficient mice are viable and susceptible to lymphoid tumours. 755 Mar 17

Genetic instability has been recently related to point mutations on genes involved in DNA repair pathway of errors produced during replication. These molecular alterations have been described in hereditary and sporadic colon carcinomas and related tumors. To examine genetic instability on lympho- and myeloproliferative processes, we analyzed the behaviour of 10 microsatellite markers and one VNTR on different chromosomes in 10 patients with non-Hodgkin lymphomas (NHL), one patient with acute lymphoblastic leukemia (ALL) and 10 patients with acute myeloid leukemia (AML). Mobility shifts were found in three of those cases. One of them showed genetic instability for several markers--microsatellites and VNTR- and the other two showed differences for only one marker. As a correlation between point mutations in MSH2 gene and the presence of genetic instability in hereditary non-polyposis colon cancer (HNPCC) and related tumors has been found, we analyzed the sequence of a conversed region of this gene in the cases showing this phenomenon. We only found a polymorphism, previously described, in 669 codon from cDNA.
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PMID:Genetic instability of microsatellites in hematological neoplasms. 759 85

Research on the genetic, molecular genetic, clinical features, and natural history of HNPCC has shown tremendous progress and evolution during the past 25 years. Specifically, HNPCC's autosomal dominant mode of genetic transmission has now been documented through linkage studies of the gene at 2p (MSH2) and at 3p (MLH1) with the cloning of these genes. Also, the tumor spectrum has increased, which now, in addition to carcinoma of the colon, endometrium, stomach, and ovary, includes transitional cell carcinoma of the ureter and renal pelvis, and adenocarcinomas of the small bowel and pancreas. Surveillance and management protocols for patients at high risk should include full colonoscopy since 70% of the colon cancers occur in the proximal colon. Because of the marked excess of synchronous and metachronous colorectal cancers (CRC), no less than a subtotal colectomy should be performed at the time of initial CRC. Women, in addition to colonoscopy, require endometrial aspiration biopsy. Should they develop CRC and if their procreation is completed, we recommend that they consider prophylactic hysterectomy and bilateral salpingo oophorectomy at the time of their subtotal colectomy. Now that the deleterious genes at 2p and 3p have been identified, we are offering candidates, in whom the MSH2 or MLH1 mutation has been verified, an option of prophylactic subtotal colectomy as opposed to annual life time colonoscopy. With the development of the International Hereditary Nonpolyposis Colorectal Cancer Collaborative Group, knowledge can be disseminated worldwide about the public health importance of HNPCC and the need to implement highly targeted surveillance and management strategies in all clinical practice settings.
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PMID:25 years of HNPCC. 797 96

Hereditary nonpolyposis colorectal cancer (HNPCC) (Lynch syndrome) accounts for a small proportion of the total colorectal cancer burden, yet represents the most common form of dominantly inherited colon cancer. Until recently, the diagnosis has been based on family history of colorectal and other intra-abdominal cancers. This has been problematic since chance clustering of such tumors cannot be excluded. On the other hand, not every HNPCC patients shows a dramatic family history of cancer. Genetic mapping of a locus for HNPCC to chromosome 2p and the observation that HNPCC tumors show instability of short tandem repeat sequences (replication errors, RER) rapidly led to the cloning of the predisposing gene, human MSH2 (hMSH2). Mutations of hMSH2 have been demonstrated to segregate in large HNPCC families with the cancer phenotype, thus providing convincing evidence that the gene indeed, when mutated, predisposes its carriers to colorectal and other intra-abdominal tumors. Localization of a second locus for HNPCC to chromosome 3p and the subsequent cloning of another predisposing gene, human MLH1 (hMLH1) give hope that a great majority of families can soon be diagnosed by molecular genetic methods.
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PMID:Genes involved in hereditary nonpolyposis colorectal carcinoma. 797 3

The predisposition to colon cancer is multigenetically controlled in animals and probably also in humans. We have analyzed the multigenic control of susceptibility to 1,2-dimethylhydrazine-induced colon tumors in mice by using a set of 20 homozygous CcS/Dem recombinant congenic strains, each of which contains a different random subset of approximately 12.5% of genes from the susceptible strain STS/A and 87.5% of genes from the relatively resistant strain BALB/cHeA. Some CcS/Dem strains received the alleles from the susceptible strain STS/A at one or more of the multiple colon tumor susceptibility loci and are susceptible, whereas others are resistant. Linkage analysis shows that these susceptibility genes are different from the mouse homologs of the genes known to be somatically mutated in human colon cancer (KRAS2, TP53, DCC, MCC, APC, MSH2, and probably also MLH1). Different subsets of genes control tumor numbers and size. Two colon cancer susceptibility genes, Scc1 and Scc2, map to mouse chromosome 2. The Scc1 locus has been mapped to a narrow region of 2.4 centimorgans (90% confidence interval).
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PMID:Fine mapping of colon tumor susceptibility (Scc) genes in the mouse, different from the genes known to be somatically mutated in colon cancer. 857 18

A great deal of the energy and time of a cell is invested in DNA repair activities. The first step in DNA repair pathways is recognition of the lesion on the DNA. The classical lesion-recognizing proteins interact with other repair proteins to form multiprotein complexes most notable of which are those that function in Nucleotide Excision Repair (NER). Proteins involved in lesion recognition include HMG1 and 2 recognizing cisplatin adducts but also maintaining active nucleosome structures and interacting with loops in cruciforms; HMG-box nuclear proteins; XPA and XPC lacking in xeroderma pigmentosum patients and involved in lesion recognition during NER; p53 recognizing strand breaks and insertion/deletion mismatches and causing arrest in the cell cycle; MSH2 mismatch repair protein identified as the human colon cancer gene product; and others including the transcription factor YB-1 that binds to depurinated DNA with a higher affinity compared with undamaged DNA. Other type of lesion-recognizing proteins are also repair enzymes like the O(6)-methylguanine-DNA methyltransferase and DNA glycosylases. Lesion recognition is an important process and might be the rate-limiting step in the overall repair process.
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PMID:DNA lesion-recognizing proteins and the p53 connection. 861 13

Germline mutations in four human mismatch repair genes (MSH2, MLH1, PMS1, and PMS2) have been reported to cause hereditary non-polyposis colon cancer syndrome (HNPCC). The identification of germline mutations in HNPCC kindreds allows precise diagnosis and accurate predictive testing. To investigate further the genetic epidemiology of HNPCC and the nature and frequency of germline mutations in this disorder, we studied 17 English HNPCC kindreds for germline mutations in MSH2 and MLH1. A previous genetic linkage study had suggested that most English HNPCC families will have mutations in one of these genes. Mutation analysis was performed in a three step process. (1) mRNA extracted from lymphoblastoid cell lines was analysed for gross rearrangements, (2) the in vitro transcription-translation (IVTT) assay was then performed to detect protein truncating mutations, and (3) partial cDNA sequencing of MSH2 or MLH1 was undertaken in families (n = 6) linked to MSH2 or MLH1 but without a detectable mutation. Seven different germline mutations were identified in eight of 17 (47%) kindreds (five in MSH2 and three in MLH1). In three cases there was a deletion of a single exon in MSH2 mRNA, three mutations resulted in a truncated protein product, and two missense mutations were identified by direct sequencing. Six mutations were novel. No precise correlation between genotype and phenotype was observed, although a MSH2 missense (Thr905Arg) mutation was associated with a susceptibility to multiple colorectal polyps. Age related risks for colorectal and uterine cancer were similar for MSH2 and MLH1 mutations.
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PMID:Mutation screening of MSH2 and MLH1 mRNA in hereditary non-polyposis colon cancer syndrome. 888 May 70

Alterations of the human mismatch repair genes have been linked to hereditary non-polyposis colon cancer (HNPCC) as well as to sporadic cancers that exhibit microsatellite instability. The human mismatch repair genes are highly conserved homologs of the Escherichia coli MutHLS system. Six MutS homologs have been identified in Saccharomyces cerevisiae and four MutS homologs have been identified in human cells. At least three of these eukaryotic MutS homologs are involved in the recognition/binding of mispaired nucleotides and nucleotide lesions. MSH2 plays a fundamental role in mispair recognition whereas MSH3 and MSH6 appear to modify the specificity of this recognition. The redundant functions of MSH3 and MSH6 explain the greater prevalence of hmsh2 mutations in HNPCC families.
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PMID:MutS homologs in mammalian cells. 902 26

Biochemical and genetic approaches have been used to demonstrate that basic elements of a DNA mismatch repair (MMR) pathway are conserved between bacteria, yeast and mammals. Recently, mutations in the human MMR genes MSH2, MLH1, PMS1 and PMS2 have been implicated in a common form of hereditary colon cancer and in sporadic tumors of various tissues. In order to better understand the consequences of MMR deficiency in mammalian organisms, mice deficient for the Pms2, Mlh1 and Msh2 MMR gene homologues have been generated. MMR deficient mice display a general increase in spontaneous mutation rate and develop tumors during the first year of life. Additionally, loss of MMR appears to accelerate tumorigenesis in an Apc deficient background.
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PMID:DNA mismatch repair deficient mice in cancer research. 911 Apr 1


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