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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

Predicting the effects of nucleotide substitutions in human splice sites has been based on analysis of consensus sequences. We used a graphic representation of sequence conservation and base frequency, the sequence logo, to demonstrate that a change in a splice acceptor of hMSH2 (a gene associated with familial nonpolyposis colon cancer) probably does not reduce splicing efficiency. This confirms a population genetic study that suggested that this substitution is a genetic polymorphism. The information theory-based sequence logo is quantitative and more sensitive than the corresponding splice acceptor consensus sequence for detection of true mutations. Information analysis may potentially be used to distinguish polymorphisms from mutations in other types of transcriptional, translational, or protein-coding motifs.
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PMID:Using information content and base frequencies to distinguish mutations from genetic polymorphisms in splice junction recognition sites. 755 Feb 36

Hereditary Non-polyposis Colon Cancer Syndrome (HNPCC) is the most common cause of familial colorectal cancer. Molecular genetic studies of HNPCC have shown evidence of locus heterogeneity, and mutations in four genes (hMSH2, hMLH1, hPMS1, and hPMS2) which encode components of the mismatch enzyme repair system may cause HNPCC. To determine the extent and nature of locus heterogeneity in HNPCC, we performed genetic linkage studies in 14 HNPCC families from eastern and north-western England. Linkage to hMLH1 was excluded in six families, each of which were likely to be linked to hMSH2 (lod score > 1.0 in each family and total lod score for all six families = 7.64). Linkage to hMSH2 was excluded in three families, each of which were likely to be linked to hMLH1 (lod score > 1.0 in each family and total lod score at hMLH1 for all three families = 3.93). In the remaining five families linkage to hMSH2 or hMLH1 could not be excluded. These results confirm locus heterogeneity in HNPCC and suggest that, in the population studied, most large families with HNPCC will have mutations in hMSH2 or hMLH1. We did not detect any correlation between clinical phenotype and the genetic linkage results, but a Muir-Torre syndrome family excluded from linkage to hMLH1 was likely to be linked to hMSH2 and showed microsatellite instability in a tumour from an affected relative.
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PMID:Genetic linkage analysis in hereditary non-polyposis colon cancer syndrome. 761 41

All cancer types exhibit familial clustering, suggestive of a significant inherited component; however, to date only a few of the genes responsible have been identified and the inherited component, if any, underlying most common cancers has not been well defined. Amongst the important known susceptibility genes are those dominant genes conferring a high risk of breast and ovarian cancer (BRCA1), colon cancer (hMSH2 and hMLH1), and melanoma (MLM). All these genes confer a high lifetime risk of the disease concerned, but are rare and only account for a small minority (less than 5%) of cases. However, there are also commoner genes conferring lower risks but accounting for a more substantial fraction of cancer cases; those so far identified include the ataxia-telangiectasia gene and the HRAS1 minisatellite locus.
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PMID:The inherited component of cancer. 798 39

Hereditary nonpolyposis colorectal cancer (HNPCC) represents the most common form of genetic predisposition to colon cancer. Even in kindreds with several affected members it is, however, difficult to rule out chance clustering and other nonhereditary factors since colon cancer is so common in the general population. Similarly, it is impossible to distinguish individual patients with HNPCC from sporadic cases on clinical grounds since neither have polyposis or other specific physical signs. The localization of an HNPCC gene on chromosome 2 in May 1993 provided formal proof that HNPCC is a single gene (Mendelian) disorder. Instability at short tandem repeat sequences (microsatellites) was found to characterize HNPCC tumours. Positional and functional cloning strategies resulted in the identification of the HNPCC gene in December 1993. Interspecies homology suggests that the gene, hMSH2, functions in DNA mismatch repair. These findings provide a theoretical basis as well as practical tools to detect susceptibility to HNPCC cancers.
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PMID:Genetic basis of hereditary nonpolyposis colorectal carcinoma (HNPCC). 807 40

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.
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PMID:Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. 814 27

Hereditary nonpolyposis colorectal cancer is caused by heritable defects in the DNA mismatch repair genes hMLH1, hMSH2, hPMS1, and hPMS2. We have used denaturing gradient gel electrophoresis to analyze the 19 exons and exon-intron borders of hMLH1 in 39 Swedish hereditary nonpolyposis colorectal cancer families. Germline mutations were found in eight of these families: two splice mutations affecting exons 3 and 7, respectively, and six missense mutations, of which, four were in exon 2 and one each were in exons 1 and 16. The relatively high number of missense mutations raises several important clinical and technical issues. Such alterations can be identified only when using methods that target DNA or mRNA sequence alteration because they do not cause protein truncations detected by in vitro translation assays. Furthermore, the relationship between these missense mutations and the predisposition to colon cancer is difficult to determine without additional information; thus, genetic counseling based on mutation data is difficult.
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PMID:Mutation screening in the hMLH1 gene in Swedish hereditary nonpolyposis colon cancer families. 852 98

Selection of cells for resistance to cisplatin, a well-recognized mutagen, could result in mutations in genes involved in DNA mismatch repair and thereby to resistance to DNA-alkylating agents. Parental cells of the human ovarian adenocarcinoma cell line 2008 expressed hMLH1 when analyzed with immunoblot. One subline selected for resistance to cisplatin (2008/A) expressed no hMLH1, whereas another (2008/C13*5.25) expressed parental levels. Microsatellite instability was readily demonstrated in 2008/A cells but not in 2008 and in 2008/C13*5.25 cells. In addition, the 2008/A cells were 2-fold resistant to methyl-nitro-nitrosoguanidine and had a 65-fold elevated mutation rate at the HPRT locus as compared to 2008 cells, both of which are consistent with the loss of DNA mismatch repair in these cells. To determine whether the loss of DNA mismatch repair itself contributes to cisplatin resistance, studies were carried out in isogenic pairs of cell lines proficient or defective in this function. HCT116, a human colon cancer cell line deficient in hMLH1 function, was 2-fold resistant to cisplatin when compared to a subline complemented with chromosome 3 and expressing hMLH1. Similarly, the human endometrial cancer cell line HEC59, which expresses no hMSH2, was 2-fold resistant to cisplatin when compared to a subline complemented with chromosome 2 that expresses hMSH2. Therefore, the selection of cells for resistance to cisplatin can result in the loss of DNA mismatch repair, and loss of DNA mismatch repair in turn contributes to resistance to cisplatin.
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PMID:Loss of DNA mismatch repair in acquired resistance to cisplatin. 867 66

The phenomenon of alkylation tolerance has been observed in cells that are deficient in some component of the DNA mismatch repair (MMR) system. An alkylation-induced cell cycle arrest had been reported previously in one MMR-proficient cell line, whereas a MMR-defective clone derived from this line escapes from this arrest. We examined human cancer cell lines to determine if the cell cycle arrest were dependent upon the MMR system. Growth characteristics and cell cycle analysis after MNNG treatment were ascertained in seven MMR-deficient and proficient cell lines, with and without confirmed mutations in hMLH1 or hMSH2 by an in vitro transcription/translation assay. MMR-proficient cells underwent growth arrest in the G2 phase of the cell cycle after the first S phase, whereas MMR-deficient cells escaped an initial G2 delay and resumed a normal growth pattern. In the HCT116 line corrected for defective MMR by chromosome 3 transfer, the G2 phase arrest lasted more than five days. In another MMR-proficient colon cancer cell line, SW480, cell death occurred five days after MNNG treatment. A competent MMR system appears to be necessary for G2 arrest or cell death after alkylation damage, and this cell cycle checkpoint may allow the cell to repair damaged DNA, or prevent the replication of mutated DNA by prohibiting clonal expansion.
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PMID:Competency in mismatch repair prohibits clonal expansion of cancer cells treated with N-methyl-N'-nitro-N-nitrosoguanidine. 869 Jul 94

DNA instability, reflected in altered patterns of short tandem repeat sequences (microsatellites) in dividing cells, has been described in hereditary non-polyposis colon cancer (HNPCC) and in other tumor types. Ovarian cancer (OC), although most often a sporadic cancer, can recur, with HNPCC, as part of the Lynch cancer family syndrome. In an investigation of microsatellite instability (MIN) in 90 OC cases, we found MIN in 3/28 (11%) OC cases with, and 8/62 (13%) without, a family history of cancer. For 2/3 MIN+ OC cases with family cancer history consistent with the Lynch cancer family syndrome, we found additional bands in the microsatellite patterns in tumor versus normal tissue (HNPCC-type of MIN), but no germline mutations in two DNA mismatch repair genes, hMSH2 and hMLH1. In 7/8 MIN+ sporadic OC cases distinct MIN patterns not commonly reported in HNPCC were found. These are characterized by partial or total band shifting, leading to fewer bands and/or changes in the intensity of individual bands restricted to the tumor. In only one case was a germline change in hMSH2 or hMLH1 identified: this was subsequently found to be a polymorphism. An apparent hMLH1 somatic change confined to the tumor was found in another case. The fact that we found no germline pathologic mutations in hMSH2 and hMLH1 (predominant sites of mutation in HNPCC) in MIN+ OC cases, suggests that the genetic basis of MIN in OC can be different from that in HNPCC; our finding that distinct microsatellite banding patterns largely distinguish sporadic from familial OC, may reflect the involvement of different DNA repair genes in MIN in individual OC cases.
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PMID:Microsatellite instability differences between familial and sporadic ovarian cancers. 882 98


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