Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Spectra of spontaneous mutations at the hypoxanthine-guanine phosphoribosyltransferase (hprt) locus in colon carcinoma cell lines HCT116 and HCT-15 deficient in mismatch repair and displaying mutator phenotypes were determined. HCT116 and HCT-15 cells, respectively, harbour a mutation in the mismatch repair gene hMLH1 and GTBP. The mutation frequency at the hprt locus in both cell lines was elevated by about two orders, but the microsatellite instability in HCT116 cells was one order higher than in HCT-15 cells. Except for one mutant of HCT-15, all the mutations (114/115) were point mutations; base substitutions of various types and frameshifts (deletions/insertions of less than a few bases, predominantly of +/-1 bp). Base substitutions (57%) and frameshifts (43%) occurred at a comparable rate in HCT116, whereas base substitutions (92%) were the major mutational events in HCT-15. Most frameshifts in HCT116 occurred at sites of monotonous or short tandem repeating sequences, and two of these sites, where there was a run of six Gs and four As, were hot spots. Three hot spot sites of base substitutions were found in HCT-15; two of them at splice acceptor sites, the other at the CpG site shared with HCT116. The distinct mutation spectra of the HCT116 and HCT-15 cell lines may reflect functional differences in the hMLH1 and GTBP gene products in mismatch repair. The gene product GTBP may be involved in the preferential repair of base mismatches, and MLH1 in the repair of both base mismatches and deletions/insertions of less than a few bases. These results suggest that mismatch repair deficiency affects the microsatellite stability as widely reported in colorectal tumour cells, but that it may not severely affect chromosome integrity as the karyotypes of these tumour cells are, unlike other tumour cells, relatively stable.
Carcinogenesis 1997 Jun
PMID:Spectra of spontaneous mutations at the hprt locus in colorectal carcinoma cell lines defective in mismatch repair. 921 93

Aberrant DNA methylation is a common phenomenon in human cancer, but its patterns, causes, and consequences are poorly defined. Promoter methylation of the DNA mismatch repair gene MutL homologue (MLH1) has been implicated in the subset of colorectal cancers that shows microsatellite instability (MSI). The present analysis of four MspI/HpaII sites at the MLH1 promoter region in a series of 89 sporadic colorectal cancers revealed two main methylation patterns that closely correlated with the MSI status of the tumors. These sites were hypermethylated in tumor tissue relative to normal mucosa in most MSI(+) cases (31/51, 61%). By contrast, in the majority of MSI(-) cases (20/38, 53%) the same sites showed methylation in normal mucosa and hypomethylation in tumor tissue. Hypermethylation displayed a direct correlation with increasing age and proximal location in the bowel and was accompanied by immunohistochemically documented loss of MLH1 protein both in tumors and in normal tissue. Similar patterns of methylation were observed in the promoter region of the calcitonin gene that does not have a known functional role in tumorigenesis. We propose a model of carcinogenesis where different epigenetic phenotypes distinguish the colonic mucosa in individuals who develop MSI(+) and MSI(-) tumors. These phenotypes may underlie the different developmental pathways that are known to occur in these tumors.
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PMID:Epigenetic phenotypes distinguish microsatellite-stable and -unstable colorectal cancers. 1053 79

Mice with mutations in both alleles of the Mgmt and the Mlh1 gene, the former encoding a DNA repair methyltransferase and the latter a protein functioning at an early step of mismatch repair, are as resistant to the killing action of alkylating agents as are wild-type mice. These mice yielded a large number of tumors when exposed to alkylating carcinogens, but this characteristic was subdued since they also showed a relatively high level of spontaneous tumorigenicity, as a consequence of the defect in mismatch repair. This complexity is now resolved by introducing the Mlh1(+/-) mutation, instead of Mlh1(-/-), in these methyltransferase-deficient mice. Mgmt(-/-) Mlh1(+/-) mice, with about half the amount of MLH1 protein as Mgmt(-/-) Mlh1(+/+) mice, were resistant to the killing action of N-methyl-N-nitrosourea (MNU), up to the level of 30 mg/kg body wt. Eight weeks after exposure to this dose of MNU, 40% of MNU-treated Mgmt(-/-) Mlh1(+/-) mice had thymic lymphomas and there were no tumors in those mice not given the treatment. It seems that the cellular content of MLH1 protein is a critical factor for determining if damaged cells enter into either one of the two pathways leading to mutation induction or to apototic cell death. Loss of Mlh1 expression was frequently observed in tumors of Mgmt(-/-) Mlh1(+/-) mice and this might be related to progression of the tumors.
Carcinogenesis 2000 Feb
PMID:A defect in a single allele of the Mlh1 gene causes dissociation of the killing and tumorigenic actions of an alkylating carcinogen in methyltransferase-deficient mice. 1065 72

A subset of sporadic gastric cancers (GC) exhibits microsatellite instability (MSI). To define the precise role of MSI in GC, a total of 100 patients with sporadic GC were classified into three groups, i.e., high-frequency MSI (MSI-H), low-frequency MSI (MSI-L), and microsatellite stable (MSS), based on 10 microsatellite markers. Mutational analyses of TGFbetaRII, IGFIIR, BAX, MSH3, MSH6, E2F4, MSH2, MLH1, and TP53 genes, and methylation and protein expression of MLH1 and MSH2 were performed and correlated. Twenty-seven percent of GC showed MSI at least in one locus and could be further graded as MSI-H (14%) and MSI-L (13%). No clinicopathologic difference was noted between GC with MSI-L and MSS. Compared with GC with MSI-L or MSS, GC with MSI-H had a significantly higher frequency of antral location, intestinal subtype, H. pylori seropositivity, but a lower incidence of lymph node metastasis, and displayed a higher frequency of frameshift mutations of TGFbetaRII, IGFIIR, BAX, MSH3, and E2F4 genes but a lower incidence of TP53 mutations. Furthermore, hypermethylation of the MLH1 promoter was responsible for the loss of protein function in 13 of 14 MSI-H tumors. It was concluded that a specific phenotype and a distinct profile of genetic alterations exist in MSI-H GC. We speculate that epigenetic inactivation of MLH1 by methylation plays a crucial role in initiating such a pathway of carcinogenesis. In contrast, GCs with MSS and MSI-L exhibit clinicopathologic features that are distinct from MSI-H tumors and have a higher frequency of TP53 mutations, suggesting that they may evolve through an entirely different pathway.
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PMID:Distinct clinicopathologic and genetic profiles in sporadic gastric cancer with different mutator phenotypes. 1071 71

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

There are two well-defined pathways for colorectal carcinogenesis, the suppressor and the mutator pathways. The latter is characteristic of hereditary non-polyposis colorectal cancer (HNPCC), but can also be found in a subset of sporadic colorectal cancer (SCC) possessing distinctive clinical and pathological features, namely early age of onset, location in the right colon, poor differentiation, and a predominant mucinous component. This mutator pathway results from inactivation of mismatch repair (MMR) genes, namely MSH2 and MLH1. The aim of this study was to ascertain if abnormal MMR protein gene expression is a good indicator for identifying tumours from the mutator pathway. Seventy-six cases of SCC were studied by immunohistochemistry using two monoclonal mouse antibodies that react against MSH2 and MLH1 protein gene products. Immunoexpression was assessed both in tumour and in non-neoplastic, adjacent and distant mucosa. Microsatellite instability (MSI) was detected by evaluating the length of poly(CA) repeated sequences at seven loci, or by the detection of small unstable alleles in a poly(A) repeat - BAT-26. Except for BAT-26, in which only tumour DNA was used, MSI analysis was performed in both tumour and normal mucosal DNA. MSI was classified as high (MSI-H), low (MSI-L) or stable (MSS). Abnormal protein expression was found in 9/76 (12%) tumours. Immunohistochemistry for hmlh1 and hmsh2 detected 75% of MSI-H. There was also a highly significant correlation between the observed immunoexpression and several clinical and pathological characteristics described as the phenotypic profile of the mutator pathway, such as right-sided location (p=0.003), mucin production (p=0.008), and a peritumoural lymphoid infiltrate (p=0.009). Non-neoplastic adjacent mucosa showed normal hMSH2 expression in all cases, but in ten cases there was no hMLH1 expression in this transitional mucosa, which is known to display an alterated mucin pattern and a high proliferative rate. These results demonstrated a good correlation between hMLH1 and hMSH2 gene immunoexpression and the clinico-pathological features characteristic of the mutator phenotype and support the use of this method as a rapid and efficient way to detect tumours arising from this pathway.
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PMID:Immunohistochemical detection of mismatch repair gene proteins as a useful tool for the identification of colorectal carcinoma with the mutator phenotype. 1091 9

Lynch syndrome is the most common hereditary form of colorectal cancer (CRC). Its natural history has been investigated extensively, so that highly targeted surveillance and management strategies, melded to its natural history, have proven effective in cancer control. Most important is the early age of onset of cancer (approximately 44 years), involving CRC and the several extracolonic cancers that are integral to the syndrome. With respect to CRC, approximately 70% of cases occur proximal to the splenic flexure. Synchronous and metachronous CRCs are extremely common. Full colonoscopy should be initiated when the patient is between the ages of 20 and 25, and because of the accelerated carcinogenesis of CRC, it should be performed every 1 to 2 years. The presence of initial CRC requires subtotal colectomy, given the mentioned increased frequency of metachronous cancer. Options available for germ-line mutation carriers, in addition to cancer screening, include prophylactic colectomy as well as prophylactic total abdominal hysterectomy and bilateral salpingo-oophorectomy. The discovery of mismatch repair germ-line mutations (most commonly MSH2 or MLH1) has added significantly to the recognition of this disease as well as to the search for high-risk individuals throughout families who, with genetic counseling, may become candidates for germ-line mutation testing. Clearly, hereditary nonpolyposis colorectal cancer provides an excellent opportunity for learning about the etio-pathogenesis of cancer at the molecular and clinical levels and how this knowledge might ultimately be exploited for cancer control. A search for chemoprevention agents, such as cyclo-oxygenase 2 inhibitors, as well as for putative environmental effects and how they may interact with the genetic component in CRC etiology should abet this entire cancer control process.
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PMID:Lynch syndrome: genetics, natural history, genetic counseling, and prevention. 1106 Mar 21

Variation in gene coding sequence represents a significant factor in predisposition to disease, including cancer. Variants of some DNA repair genes (e.g. MLH1, MSH2 and MSH6) are known to predispose to cancer. We identified single nucleotide polymorphisms (SNPs) in five DNA repair genes in 142 healthy individuals using a DNA sequencing protocol optimized for the direct detection of single nucleotide polymorphisms. This approach, called the heterozygote sequencing protocol (HSP), enables moderate-scale population surveys of SNPs. HSP uses fluorescently tagged primers and exploits the large dynamic range and low background of automated fluorescent sequencing. HSP may be used for any sequence that can be amplified by PCR. A total of 12 SNP variants in MGMT, ERCC1, CDK7, CCNH and XRCC4 were identified, 11 at polymorphic frequencies, with an average frequency of 0.22 (95% confidence interval 0.20-0.24). Among the 82 individuals for whom complete SNP profiles were available, no one person carried the GenBank reference sequence for all five genes. The extensive heterogeneity observed in these five genes is intriguing. All variants are in Hardy-Weinberg equilibrium, although the meaning of this equilibrium is unclear. Using this approach, possible associations of sequence variation, and hence of variation in DNA repair, with disease risk can be assessed.
Carcinogenesis 2000 Nov
PMID:Identification of single nucleotide polymorphisms in human DNA repair genes. 1106 57

Molecular analysis of hereditary nonpolyposis colorectal carcinomas (HNPCC) has identified DNA mismatch repair deficiencies with resulting microsatellite instability (MSI) as a pathway of carcinogenesis that appears to be relevant for prognosis, treatment, and possibly prevention. In this study, expression of cell cycle proteins and other known prognostic markers is correlated with the microsatellite status of colorectal cancers (CRC). One hundred consecutive cases from the CRC Registry at Thomas Jefferson University were analyzed for MSI. Immunohistochemistry was performed for the mismatch repair proteins hMLH1 and hMSH2, tumor suppressor p53, apoptosis inhibitor bcl-2, cell cycle proteins p21(WAF1/CIP1), and p27 and the proliferation markers Ki-67 and topoisomerase II. High MSI (MSI-H) is significantly correlated with loss of either hMLH1 or hMSH2, presence of bcl-2, and absence of p53. p21(WAF1/CIP1) is positive in all tumors with MSI-H. Previous findings of a lower proliferation rate were confirmed with a topoisomerase II stain. Microsatellite stable (MSS) tumors generally express both MSH2 and MLH1. Other highly significant differences are positive p53 in 56% of MSS cases and negative bcl-2 in 98% of MSS cases. p27 expression is found in approximately 50% of all CRCs irrespective of the microsatellite status. MSI-H tumors follow the mutator pathway, with loss of expression of one mismatch repair protein, wild-type p53, lower proliferation, and positivity for p21(WAF1/CIP1). MSS tumors follow the suppressor pathway, characterized by p53 overexpression, higher proliferation, and absence of bcl-2 expression; p21(WAF1/CIP1) expression can be variable. These data provide a molecular basis for the clinical observation that patients with HNPCC appear to have a more favorable prognosis. HUM PATHOL 31:1506-1514.
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PMID:Colorectal carcinomas with high microsatellite instability: defining a distinct immunologic and molecular entity with respect to prognostic markers. 1115 Mar 76

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


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