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)

Germ-line mutations in MLH1 and MSH2 genes predispose to hereditary non-polyposis colorectal cancer (HNPCC) syndrome, but they do not predict a specific phenotype of the disease. We speculated that the ataxia-telangiectasia mutated gene (ATM) was a candidate gene to modulate the phenotypic expression of HNPCC, as heterozygous individuals for germ-line ATM mutations have been considered at higher risk of developing epithelial malignancies. The frequency of the ATM D1853N polymorphism was evaluated in 167 individuals from 20 HNPCC families in which MLH1 or MSH2 germ-line mutations co-segregated with the disease. Among the 67 MLH1 or MSH2 mutation carriers, the ATM 1853N variant was associated with a significantly higher incidence of colorectal and other HNPCC-related cancers, when compared with individuals carrying the ATM 1853D variant [12/13 (92%) vs. 31/54 (57.5%); p = 0.02]. MLH1 and MSH2 mutation carriers who concomitantly carried the ATM 1853N variant, had an 8 times increased risk of developing colorectal and other HNPCC-related cancers (OR: 8.9; p = 0.02), when compared with MLH1 or MSH2 mutation carriers with the ATM 1853D variant. Our results suggest that the ATM D1853N polymorphism modulates the penetrance of MLH1 and MSH2 germ-line mutations.
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PMID:A polymorphism in the ATM gene modulates the penetrance of hereditary non-polyposis colorectal cancer. 1109 16

PMS2 is one of a complex of genes encoding DNA repair proteins that includes MSH2, MLH1, MSH6 and MSH3. Mutation of any of these DNA mismatch repair genes leads to impairment of DNA repair and can lead to tumorigenesis. Germline mutation of PMS2 has been reported as a rare cause of hereditary nonpolyposis colorectal cancer (HNPCC) and Turcot's syndrome. The PMS2 gene is located on chromosome 7p22 and consists of 15 exons. Within exon 11 of PMS2 is a coding repeat of eight adenosines. This study reports on the finding of a nonexpressed pseudogene that is highly homologous to the PMS2 gene in this region. The pseudogene is polymorphic for two alterations in the repeat region: a 3 bp delAAA at a site corresponding to nucleotide 1231 in PMS2; and an AA-->GG change at nucleotide 1238. Due to the high homology in both intronic and exonic sequences, polymorphisms in this pseudogene could be mistaken for mutations in the PMS2 gene and erroneously thought to be a cause of HNPCC and/or Turcot's syndrome.
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PMID:Polymorphisms in a pseudogene highly homologous to PMS2. 1110 87

The most sensitive technique for the detection of germline mutations is exon by exon sequencing of the gene under investigation using genomic DNA as a template for analysis. This approach, however, has cost and sensitivity limitations that can, at least in part, be overcome by RNA-based analysis. Germline mutations of MLH1 and MSH2 are the most frequent cause of the inherited susceptibility to colorectal and other epithelial cancers known as hereditary non-polyposis colorectal cancer (HNPCC). We compared the analysis of the MLH1 and MSH2 genes using mRNA and genomic DNA as starting material from 21 HNPCC patients. All samples were investigated by RT-PCR, sequencing of cDNA and simultaneous sequencing of genomic DNA. The cDNA was generated using specific primers complementary to the ends of MLH1 and MSH2 genes, respectively. Mutations in MLH1 and MSH2 were detected in 11 out of 21 unrelated patients. In 10 out of 11 cases, mutations were detected independently of the type of primers used for reverse transcription (RT). One novel missense mutation (K751R) in MLH1 was detected using this method. One nonsense mutation (E205X) in MSH2 was only detectable when RT was performed using MSH2 gene-specific primers. Shorter PCR products indicative of alternatively spliced transcripts were not observed when MLH1 or MSH2 specific cDNA RT primers were employed to generate template, except in one case where exon skipping was observed for exons 9 and 10. In this report we demonstrate that primers specific for RT of MLH1 and MSH2 are crucial for increasing the sensitivity of cDNA analysis. DNA sequencing using RNA as a basis for template construction may be a valuable and economical alternative to genomic DNA sequencing.
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PMID:Optimization of experimental conditions for RNA-based sequencing of MLH1 and MSH2 genes. 1113 42

A woman is described who developed an ovarian adenocarcinoma, 3 metachronous colorectal adenocarcinomas, and a primary adrenocortical adenocarcinoma. Genetic investigation of the mismatch repair genes MLH1 and MSH2 showed a germline mutation in MSH2. Colorectal and ovarian carcinoma belong to the tumor spectrum of hereditary nonpolyposis colorectal cancer (HNPCC). Adrenocortical adenocarcinoma, however, has never been described as 1 of the HNPCC-associated tumors. To investigate whether the adrenocortical adenocarcinoma in this patient was caused by the MSH2 germline mutation, determination of microsatellite instability (MSI) and immunohistochemical analysis were performed on 1 of the colorectal tumors and the adrenocortical adenocarcinoma. MSI and general loss of MSH2 protein expression could be seen in the colorectal tumor but not in the adrenocortical adenocarcinoma. Therefore, it is highly unlikely that the adrenocortical adenocarcinoma found in this patient was due to her genetic predisposition for HNPCC. HUM PATHOL 31:1522-1527.
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PMID:Adrenocortical adenocarcinoma in an MSH2 carrier: coincidence or causal relation? 1115 Mar 79

Mismatch repair (MMR) gene mutations cause hereditary nonpolyposis colorectal cancer (HNPCC), a common form of familial colorectal cancer. Among MMR genes, germline MSH6 mutations are often observed in HNPCC-like families with an increased frequency of endometrial cancer. We have previously shown that a proportion of women affected with double primary cancers of the colorectum and endometrium carry germline MSH2 or MLH1 mutations and, thus, belong to HNPCC families. In this study, we have investigated the specific contribution of MSH6 defects to such double primary patients. By sequence analysis of the entire coding region of MSH6, three putative missense mutations were identified in patients with atypical family histories that do not meet HNPCC criteria. Moreover, one of these mutations, a novel substitution Arg901 His, was found in a patient previously shown to carry a truncating germline MLH1 mutation. Thus, MSH6 mutations are likely to contribute to the etiology of double primary cancers of the colorectum and endometrium.
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PMID:Do MSH6 mutations contribute to double primary cancers of the colorectum and endometrium? 1115 17

Muir-Torre syndrome is an autosomal-dominant inherited disorder predisposing to both sebaceous skin tumors and internal neoplasms. In a significant proportion of Muir-Torre syndrome patients skin tumors exhibit microsatellite instability as a hallmark of hereditary nonpolyposis colorectal cancer. Most individuals predisposed to hereditary nonpolyposis colorectal cancer harbor a germline mutation in the DNA mismatch repair genes MSH2 or MLH1. In Muir-Torre syndrome the vast majority of germline mutations have been identified in MSH2. Microsatellite instability in tumor tissue develops after somatic inactivation of the corresponding second mismatch repair allele ("second hit"). So far, the mechanisms of somatic inactivation of the second allele in microsatellite instability positive tumors from patients with known mismatch repair germline mutations are not well understood. We examined whether allele loss (loss of heterozygosity) is a frequent mechanism for inactivation of the second MSH2 allele in a sample of nine microsatellite instability positive skin tumors from eight unrelated Muir-Torre patients with known MSH2 germline mutations. Loss of heterozygosity was determined using microsatellite markers or heteroduplex analysis, respectively. Only one of the nine skin tumors exhibited loss of heterozygosity at the MSH2 locus. Thus, we could show in a sample of sebaceous tumors from patients with genetically proven Muir-Torre syndrome that loss of heterozygosity most probably is not the preferred mode of somatic inactivation of the second MSH2 allele.
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PMID:"Second hit" in sebaceous tumors from Muir-Torre patients with germline mutations in MSH2: allele loss is not the preferred mode of inactivation. 1123 23

The genetic alterations in colorectal cancer progression are determined by one of two separate and distinct underlying pathways of genomic instability. The first pathway, chromosomal instability, is characterized by allelic losses and aneuploidy. The second pathway, microsatellite instability, is characterized by an abundance of subtle DNA mutations and diploidy. Although the genes causing chromosomal instability remain unknown, microsatellite instability is caused by inactivation of a DNA mismatch repair gene (predominantly MLH1 or MSH2). Microsatellite instability is present in 15% of colorectal cancers, and is diagnosed by analysis of tumor DNA from paraffin blocks and by demonstration of loss of mismatch repair protein expression in cancers. In addition to the unique profile of genetic alterations, colorectal cancers with microsatellite instability have distinct pathologic features and improved survival. Finally, cancers from most patients with hereditary non-polyposis colorectal cancer (or Lynch syndrome) have microsatellite instability due to germline mutations in the DNA mismatch repair genes. Identification of the microsatellite instability pathway has enormous implications for the clinical investigation and management of colorectal cancer patients.
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PMID:Carcinogenesis in the GI tract: from morphology to genetics and back again. 1126 32

The predictive value of MLH1 or MSH2 protein expression for the presence of truncating germline mutations was examined in benign and (pre)malignant endometrial samples from 3 patient groups: (I) 10 endometrial cancer patients from hereditary non-polyposis colorectal cancer (HNPCC) families with (n = 6) or without (n = 4) a known germline mutation; (II) 15 women from HNPCC families with (n = 7) or without (n = 8) a known germline mutation, who underwent endometrial sampling for non-malignant reasons; (III) 38 endometrial cancer patients <50 years of age, without HNPCC family history. Immunostaining for MLH1 and MSH2 was performed on paraffin-embedded sections. In group III, tumor DNA was examined for microsatellite instability (MSI) and MLH1, MSH2 and MSH6 mutation analysis was carried out. In 6/6 MLH1/MSH2 mutation carriers with endometrial cancer (group I), concordance was found between protein loss in the tumor and the corresponding mutation. In 3 MLH1 mutation carriers, MLH1 protein loss was also observed in concurrent endometrial hyperplasia. In group II, no protein loss was detected in normal endometrial tissue samples; in 3/4 patients with endometrial hyperplasia, MLH1/MSH2 protein loss was observed. In group III, protein loss was detected in 12/38 patients (9 MLH1, 3 MSH2), while in 3/11 patients with concurrent endometrial hyperplasia protein loss was also observed in the hyperplasia. MSI analysis in group III revealed 26 MSI-low and 12 MSI-high tumors. Mutation analysis in 28/38 patients showed only 1 missense MSH6 and no MLH1 or MSH2 germline mutations. In group III, loss of MLH1/MSH2 protein expression was not related to the presence of MSI or MLH1/MSH2 germline mutations. In conclusion, MLH1 or MSH2 protein loss in HNPCC-related endometrial neoplasia is strongly related to corresponding germline mutations. This relation was not clearly present in young sporadic endometrial cancer patients. Immunohistochemical pre-screening of the MLH1 and MSH2 proteins in endometrial hyperplasia or cancer can thus be helpful in HNPCC families. Frequent loss of MLH1 or MSH2 protein in endometrial hyperplasia indicates that this loss is an early event in endometrial carcinogenesis.
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PMID:MLH1 and MSH2 protein expression as a pre-screening marker in hereditary and non-hereditary endometrial hyperplasia and cancer. 1129 Oct 77

Hereditary nonpolyposis colorectal cancer syndrome is associated with an inherited predisposition to primarily colorectal cancer (CRC) and endometrial cancer (EC); however, the biological basis of the organ involvement remains unknown. As an attempt to explore whether the expression levels of MLH1, MSH2, and MSH6 may play a role, we used immunohistochemistry to study 42 ECs and 35 CRCs from patients carrying the same predisposing mutations. Among MSH2 mutation carriers, MLH1 was expressed in both tumor types, whereas MSH2 and, in many cases, also MSH6, were absent. Remarkably, among MLH1 mutation carriers, 54% of ECs (21 of 39), but none of the CRCs (0 of 32), lacked the MSH2 and/or MSH6 protein in addition to lacking MLH1 protein expression. These results demonstrate a marked difference between hereditary nonpolyposis colorectal cancer-related CRCs and ECs and suggest that the development of the latter tumors is selectively associated with the MSH2/MSH6 protein complex deficiency.
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PMID:Lack of MSH2 and MSH6 characterizes endometrial but not colon carcinomas in hereditary nonpolyposis colorectal cancer. 1130 49

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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