Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since 1993 four genes have been identified that, when mutated, confer predisposition to a form of hereditary colon cancer (hereditary nonpolyposis colorectal cancer [HNPCC]). These genes belong to the Mut-related family of DNA mismatch repair genes whose protein products are responsible for the recognition and correction of errors that arise during DNA replication. Mutational inactivation of both copies of a DNA mismatch repair gene results in a profound repair defect demonstrable by biochemical assays, and in vivo this defect is presumed to lead to progressive accumulation of secondary mutations throughout the genome, some of which affect important growth-regulatory genes and, hence, give rise to cancer. To date, more than 70 different germline mutations have been detected in DNA mismatch repair genes and shown to be associated with HNPCC. Current evidence suggests that two genes, MSH2 and MLH1, account for roughly equal proportions of HNPCC kindreds, together being responsible for a majority of these families, but striking interethnic differences occur. Most mutations lead to truncated protein products. Mutation screening is quite demanding in HNPCC since, with a few exceptions, the predisposing mutations typically vary from kindred to kindred and individual mutations are scattered throughout the genes. Knowledge of the predisposing mutations allows genotype-phenotype correlations and forms the basis for further studies clarifying the pathogenesis of this disorder. In at-risk individuals, it allows predictive testing for cancer susceptibility and, consequently, appropriate clinical management of mutation carriers and noncarriers.
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PMID:Mutations predisposing to hereditary nonpolyposis colorectal cancer. 911 64

The phenomenon of alternative splicing in the DNA mismatch repair genes MLH1 and MSH2 was extensively investigated by coupled reverse transcription-polymerase chain reaction in different human tissues, including 42 mononuclear blood cell samples--31 obtained from familial colon cancer patients or their at-risk relatives and 11 from healthy blood donors--7 normal colonic mucosae, 4 established human cancer cell lines, 8 colorectal tumors, and one sample each of ileum, liver, muscle, thymus, breast, and EBV-transformed lymphoblasts. Several isoforms were observed for each gene. Products of MLH1 alternative splicing included mRNAs lacking alternative exons 6/9, 9, 9/10, 9/10/11, 10/11, 12, 16, and 17. For MSH2, products lacking exons 5, 13, 2 through 7, and 2 through 8 were identified. The levels of expression were found to vary among different samples. All isoforms were found in a relevant fraction (43-100%) of the mononuclear blood cell samples, as well as in other tissues. The splicing variants were also detected in normal colonic mucosa, with the exceptions of the MLH1 -6/9 and -10/11 and the MSH2 -13 isoforms. Germline mutations of MLH1 and MSH2 confer constitutional predisposition to the development of colorectal cancer and other neoplasms. A substantial proportion of the mutations identified so far involve alterations of the normal splicing process. Knowledge of the existence of multiple alternative splicing events, not caused by genomic DNA changes, is important for the evaluation of the results of molecular diagnostic tests based on RNA analysis.
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PMID:Characterization of MLH1 and MSH2 alternative splicing and its relevance to molecular testing of colorectal cancer susceptibility. 949 Feb 93

MSH5 (MutS homologue 5) is a member of a family of proteins known to be involved in DNA mismatch repair. Germline mutations in MSH2, MLH1 and GTBP (also known as MSH6) cause hereditary non-polyposis colon cancer (HNPCC) or Lynch syndrome. Inactivation of Msh2, Mlh1, Gtmbp (also known as Msh6) or Pms2 in mice leads to hereditary predisposition to intestinal and other cancers. Early studies in yeast revealed a role for some of these proteins, including Msh5, in meiosis. Gene targeting studies in mice confirmed roles for Mlh1 and Pms2 in mammalian meiosis. To assess the role of Msh5 in mammals, we generated and characterized mice with a null mutation in Msh5. Msh5-/- mice are viable but sterile. Meiosis in these mice is affected due to the disruption of chromosome pairing in prophase I. We found that this meiotic failure leads to a diminution in testicular size and a complete loss of ovarian structures. Our results show that normal Msh5 function is essential for meiotic progression and, in females, gonadal maintenance.
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PMID:Mammalian MutS homologue 5 is required for chromosome pairing in meiosis. 991 5

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

Cancer predisposition in hereditary non-polyposis colon cancer (HNPCC) is caused by defects in DNA mismatch repair (MMR). Mismatch recognition is attributed to two heterodimeric protein complexes: MutSalpha (refs 2, 3, 4, 5), a dimer of MutS homologues MSH2 and MSH6; and MutSbeta (refs 2,7), a dimer of MSH2 and MSH3. These complexes have specific and redundant mismatch recognition capacity. Whereas MSH2 deficiency ablates the activity of both dimers, causing strong cancer predisposition in mice and men, loss of MSH3 or MSH6 (also known as GTBP) function causes a partial MMR defect. This may explain the rarity of MSH6 and absence of MSH3 germline mutations in HNPCC families. To test this, we have inactivated the mouse genes Msh3 (formerly Rep3 ) and Msh6 (formerly Gtmbp). Msh6-deficient mice were prone to cancer; most animals developed lymphomas or epithelial tumours originating from the skin and uterus but only rarely from the intestine. Msh3 deficiency did not cause cancer predisposition, but in an Msh6 -deficient background, loss of Msh3 accelerated intestinal tumorigenesis. Lymphomagenesis was not affected. Furthermore, mismatch-directed anti-recombination and sensitivity to methylating agents required Msh2 and Msh6, but not Msh3. Thus, loss of MMR functions specific to Msh2/Msh6 is sufficient for lymphoma development in mice, whereas predisposition to intestinal cancer requires loss of function of both Msh2/Msh6 and Msh2/Msh3.
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PMID:HNPCC-like cancer predisposition in mice through simultaneous loss of Msh3 and Msh6 mismatch-repair protein functions. 1054 54

Hereditary non-polyposis colon cancer (HNPCC) is a heterogeneous group of tumour predisposition syndromes caused by germline mutations in at least four different mismatch repair genes. HNPCC patients are prone to the development of carcinomas of the intestinal tract and other specific sites. Identification of presumptive HNPCC patients is primarily based on a positive family history of colorectal cancer in at least two generations. In the course of mutation screening of the MLH1 and MSH2 genes in patients manifesting a carcinoma of the HNPCC tumour spectrum before the age of 45 years, we identified a germline MSH2 344delA frameshift mutation in a male proband. This index patient, at the age of 25 years, initially developed a large rectal adenoma that was removed by polypectomy. Ten years later he was operated on for an invasive right sided colon carcinoma in the caecum (International Union Against Cancer (UICC) stage III). The mother and father, aged 61 and 66 years, respectively, were healthy and had no family history of colorectal cancer. Subsequent molecular analyses excluded the germinal MSH2 344delA alteration identified in their son and at the same time paternity was confirmed with a set of informative polymorphic markers. Thus, the genetic alteration identified in our patient definitely represented a de novo germline mutation in one of the major HNPCC genes. This case report of a patient with colorectal cancer at a relatively young age with no family history is intended to encourage mutation screening of the MSH2 and MLH1 genes in similar cases to find out whether this group of patients contains an increased proportion of de novo mutations in mismatch repair genes.
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PMID:A proven de novo germline mutation in HNPCC. 1059

Mutations in mismatch repair (MMR) genes predispose humans to cancer. Particularly prevalent are frameshift and point mutations in MSH2 and MLH1, two genes whose products are required for the early steps in MMR. In normal tissues of persons predisposed to hereditary non-polyposis colon cancer (HNPCC), these mutations are usually present in only one allele. In tumor cells of these patients, the second, wild type allele is typically found to be deleted or inactivated by point mutation. This suggests that loss of heterozygosity (LOH) results in a strong mutator phenotype that could eventually lead to the onset of disease. Here we demonstrate that diploid yeast strains that are heterozygous for MSH2 and MLH1 alleles have an elevated mutation rate. We further show that this effect results not from saturation of the MMR capacity of all cells in the population, but rather from loss of the wild type allele in a subpopulation of heterozygous cells. These results have implications for understanding the mechanisms of carcinogenesis in humans.
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PMID:Mutator phenotype due to loss of heterozygosity in diploid yeast strains with mutations in MSH2 and MLH1. 1072 Jul 37

A set of 90 nonpolypotic colon cancer families in which germ-line mutations of MSH2 and MLH1 had been excluded were screened for mutations in two additional DNA mismatch repair genes, MSH6 and MSH3. Kindreds fulfilling and not fulfilling the Amsterdam I criteria, showing early and late onset colorectal (and other) cancers, and having microsatellite stable and unstable tumors were included. Two partly parallel approaches were used: genetic linkage analysis (19 large families) and the protein truncation test (85, mostly smaller, families). Whereas MSH3 was not involved in any family, a large Amsterdam-positive, late-onset family showed a novel germ-line mutation in MSH6 (deletion of CT at nucleotide 3052 in exon 4). The mutation was identified through genetic linkage (multipoint lod score 2.4) and subsequent sequencing of MSH6. Furthermore, the entire MSH6 gene was sequenced exon by exon in families with frameshift mutations in the (C)8 tract in tumors, previously suggested as a predictor of MSH6 germ-line mutations; no mutations were found. We conclude that germ-line involvement of MSH6 and MSH3 is rare and that other genes are likely to account for a majority of MSH2-, MLH1-mutation negative families with nonpolypotic colon cancer.
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PMID:MSH6 and MSH3 are rarely involved in genetic predisposition to nonpolypotic colon cancer. 1124 74

Hereditary non-polyposis colon cancer (HNPCC), the most common form of hereditary colon cancer, is a syndrome of deficient DNA mismatch repair (MMR). Five, possibly six, human MMR genes have been identified that, when mutated in the germline, cause susceptibility to this syndrome. To date, more than 300 different predisposing mutations are known, mainly affecting the MMR genes MLH1 ( approximately 50%), MSH2 ( approximately 40%) and MSH6 ( approximately 10%). Genetically predisposed individuals carry a defective copy of an MMR gene in every cell. Somatic inactivation of the remaining wild-type copy in a target tissue, typically colon, gives rise to a profound repair defect, progressive accumulation of mutations and cancer. Instability at short tandem repeat sequences, microsatellites, is a typical manifestation of MMR deficiency and apart from HNPCC tumors, occurs in approximately 15% of sporadic colon and other tumors. The majority of the latter cases are attributable to one particular MMR gene, MLH1, and unlike HNPCC, an epigenetic rather than a genetic mechanism plays an important role in the inactivation of this gene. The present review provides an update of the genetics of HNPCC and more generally, of cancer development driven by deficient MMR. Recent discoveries suggest that apart from post-replication repair, MMR proteins have several other functions that are highly relevant to carcinogenesis. Knowledge of the complex interplay between the MMR system and other cellular pathways allows us to better understand the phenotypic manifestations of HNPCC and other cancers with deficient MMR.
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PMID:Deficient DNA mismatch repair: a common etiologic factor for colon cancer. 1125 6

DNA mismatch repair is of considerable scientific and medical importance because of its essential role in maintaining genomic integrity, and its association with hereditary non-polyposis colon cancer (HNPCC). Germline mutations in five mismatch repair genes (MLH1, MSH2, PMS1, PMS2, and MSH6) have been associated with HNPCC susceptibility. Our laboratory recently identified MLH3, a novel DNA mismatch repair gene. We screened the MLH3 coding sequence in 60 probands with increased genetic risk factors for colorectal cancer susceptibility and no mutations in the other candidate genes. No definite MLH3 germline mutations were found. We subsequently screened 36 colon tumors, and discovered an appreciable frequency of somatic MLH3 coding mutations in MSI-H tumors (25%). In four of six tumors, evidence of biallelic inactivation was noted. Furthermore, MLH3 nonsense mutations were identified in two of 12 microsatellite stable (MSS) tumors with 14q24 loss of heterozygosity. While our analyses do not exclude the existence of germline MLH3 mutations in patients with increased genetic risk factors for colorectal cancer susceptibility, they suggest such mutations are uncommon in this patient population. The finding of an appreciable frequency of somatic MLH3 mutations is consistent with a possible role for this gene in the progression of colorectal cancer tumorigenesis. Hum Mutat 17:389-396, 2001. Published 2001 Wiley-Liss, Inc.
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PMID:Germline and somatic mutation analyses in the DNA mismatch repair gene MLH3: Evidence for somatic mutation in colorectal cancers. 1131 54


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