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)

Hereditary nonpolyposis colorectal cancer (HNPCC) is a common autosomal dominant cancer susceptibility condition. Inherited mutations in at least four DNA mismatch repair genes, hMSH2, hMLH1, hPMS1, and hPMS2, are known to cause HNPCC. In this study we used denaturing gradient gel electrophoresis (DGGE) to screen for hMLH1 mutations in 34 unrelated HNPCC families (30 Dutch, 3 Italian, and 1 Danish). Ten novel pathogenic germ-line mutations (seven affecting splice sites, two frameshifts, and one in-frame deletion of a single amino acid) have been identified in 12 (35%) of these families. In a previous study, hMSH2 mutations were found in 21% of the same families. While the spectrum of mutations at the hMSH2 gene among HNPCC patients appears heterogeneous, a cluster of hMLH1 mutations has been found in the region encompassing exons 15 and 16, which accounts for 50% of all the independent hMLH1 mutations described to date and for > 20% of the unrelated HNPCC kindreds here analyzed. This unexpected finding has a great practical value in the clinical scenario of genetic services.
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PMID:Majority of hMLH1 mutations responsible for hereditary nonpolyposis colorectal cancer cluster at the exonic region 15-16. 857 56

Hereditary nonpolyposis colorectal cancer (HNPCC) is a major cancer susceptibility syndrome known to be caused by the inheritance of mutations in DNA mismatch repair genes, such as hMSH2, hMLH1, hPMS1 and hPMS2. To investigate the role of genetic alterations of hMSH2 in HNPCC tumorigenesis, we analyzed 36 Japanese HNPCC kindreds as to hMSH2 germline mutations. Moreover, we also examined somatic mutations of hMSH2 or loss of heterozygosity at or near the hMSH2 locus in the tumors from the hMSH2-related kindreds. Germline mutations were detected in five HNPCC kindreds (5/36, 14%). Among them, three were nonsense mutations, one was a frameshift mutation and the other was a mutation in an intron where the mutation affected splicing. Loss of heterozygosity in four and somatic mutations in one were detected among the eight tumors with hMSH2 germline mutations. All these alterations were only detected in genomic instability(+) tumors, i.e., not in genomic instability(-) ones, indicating that mutations of hMSH2 were responsible for at least some of the tumors with genomic instability. These data establish a basis for the presymptomatic diagnosis of HNPCC patients, and constitute further evidence that both DNA mismatch repair genes and tumor suppressor genes may share the same requirement, i.e., two hits are necessary to inactivate the gene function.
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PMID:Loss or somatic mutations of hMSH2 occur in hereditary nonpolyposis colorectal cancers with hMSH2 germline mutations. 861 31

The p53 tumor suppressor gene is often mutated in various human cancers and a common polymorphism is known at codon 72 of exon 4, with two alleles encoding either arginine (CGC) or proline (CCC). Association of this polymorphism with any human cancer susceptibility has yet to be clarified. We have conducted a case-control study in Japan on the distribution of the three genotypes with 191 lung cancer patients, 152 control patients with non-cancerous pulmonary diseases and 115 colorectal cancer patients. The genotypes were examined by PCR using DNA samples from peripheral blood lymphocytes. Frequency distributions of the three genotypes were quite comparable with each other among groups, with allelic frequencies of approximately 60% for arginine and 40% for proline. The genotypic frequencies in lung cancer patients, however, were largely different between smokers and non-smokers (chi 2 = 13.5, df = 2, P < 0.001). Compared with the control and colorectal cancer patients a significant difference in genotypic frequency was observed only in non-smoker lung cancers (chi 2 = 10.9, df = 2, P < 0.01), with an excess of Arg/Arg homozygotes and a deficit of Arg/Pro heterozygotes. Our present data suggest that the p53 polymorphism affects the risk of lung cancer unrelated to smoking.
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PMID:Analysis of a germ line polymorphism of the p53 gene in lung cancer patients; discrete results with smoking history. 862 47

Starting from a survey of the studies on familial aggregation of colorectal cancer, we introduce the aims of genetic epidemiology. One of its main goals is to assess population frequency of cancer susceptibility genes and to determine the age-specific risks for carriers with respect to non-carriers. In section two, segregation analysis investigations are reviewed, and inferences on the relevance of genetic components of susceptibility to colorectal cancer are drawn. In section three, the HNPCC paradigm is discussed in the light of the Knudson model of tumorigenesis and recent advances of molecular research. In the last section we show an example of genotype/environment interaction in the etiology of a particular cancer and present a conceptual framework for studies on cancer genetic epidemiology in terms of attributable and relative risk.
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PMID:Genetic epidemiology of colorectal cancer. 864 71

Genetic counseling is a medical process aimed at providing information about disease risks for hereditary conditions. For adult-onset diseases, such as cancer, the main purpose consists in formulating probability estimates of disease appearance, along with details on preventive or follow-up measures. The process of genetic counseling has been substantially modified by the availability of molecular tests to identify mutant gene carriers. So far, 16 autosomal dominant genes associated with cancer susceptibility have been cloned. Four of these, which encode for components of the DNA mismatch repair machinery, have been implicated in hereditary non-polyposis colorectal cancer, one of the most common hereditary cancer syndromes. Genetic counseling and testing in hereditary non-polyposis colorectal cancer is associated with several problems that are common to other hereditary conditions (psychologic consequences, confidentiality, genetic "discrimination", testing of minors, prenatal diagnosis) and peculiar to the specific condition (incomplete penetrance, genotypic and phenotypic heterogeneity, limits of currently available tests). For such reasons, genetic testing should be performed in qualified research laboratories and restricted to highly selected families. In this way, pilot studies, involving both clinicians and researchers, can be undertaken with the aim of providing comprehensive results, potentially applicable to other cancer-predisposing conditions.
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PMID:Genetic counseling in hereditary non-polyposis colorectal cancer. 864 75

A new mechanism leading to cancer has been delineated in the last two years when genes whose mutations cause susceptibility to hereditary nonpolyposis colorectal cancer, HNPCC, have been mapped, cloned, and characterized. The genes involved belong to a family of DNA mismatch repair genes, and the homozygous effects of their mutations lead to a so-called mutator or replication error phenotype characterized by genome-wide mutations most readily detectable as lengthening or shortening of microsatellite repeats in tumor tissue as compared to normal tissue from the same individual. Germline mutations are inherited in a dominant Mendelian fashion causing the multiorgan cancer susceptibility syndrome misnamed HNPCC. Clinically, the molecular characterization of these mutations in affected individuals now allows genotype-phenotype correlations, and a new view of the natural history of the disease may arise. In at risk individuals, it allows predictive testing for cancer susceptibility, enhanced clinical surveillance with the aim of early cancer detection and cure, and preventive measures.
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PMID:Genetics of hereditary colon cancer. 882 78

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal, dominantly inherited disease leading to a marked increase in cancer susceptibility, notably colorectal cancer, affecting up to one in 400 individuals in the Western world. Four genes responsible for the majority of cases have been identified. Colorectal cancer in affected people tends to be right sided, occur at an earlier age, and there is a propensity for synchronous or metachronous lesions. Extra-colonic tumours may occur with an elevated frequency, most importantly cancer of the endometrium, but also stomach, hepatobiliary system, small bowel, proximal ureter and renal pelvis, and ovary. On account of these features, management guidelines for members of HNPCC kindreds require modification from those generally advised for patients with sporadic tumours. The cardinal feature for the identification of affected families is the family history. All clinicians have a duty to identify such patients under their care as appropriate screening and surgery should lead to an improved prognosis for such patients and their families.
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PMID:[Hereditary nonpolyposis colorectal cancers]. 884 75

Carcinogen-DNA adducts are generally regarded as relevant biomarkers of carcinogen exposure and their levels in target tissues have often been predictive of tumor incidence in experimental animals. Thus, human risk assessment procedures have utilized dose-response models that assume proportional relationships between carcinogen exposure and cancer susceptibility, even though wide inter-individual variations in human metabolic activating enzymes have now been clearly established. To evaluate these approaches, we have examined the relationship between carcinogen exposure, DNA adduct levels, metabolic activation phenotypes, and cancers of the larynx, urinary bladder, and colon. Cigarette smoking is a strong risk factor for cancers of the larynx and urinary bladder. In the larynx, the DNA adducts appear to be derived predominantly from polycyclic aromatic hydrocarbons (PAHs) and are evident only in tissue from smokers. However, adduct levels appear to be determined primarily by expression of cytochrome P450 (CYP) 2C9/10, which varies > 10-fold in different individuals. This CYP catalyzes the metabolic activation of benzo (alpha) pyrene (BP) to a 9-hydroxy-BP-DNA adduct that accounts for up to 25% of the putative PAH adducts formed in vivo. For the urinary bladder, putative aromatic amine (AA)-DNA adducts are predominant and are significantly elevated in current smokers. Rapid CYP1A2 and slow acetyltransferase (NAT2) phenotypes have been previously implicated in the activation (N-oxidation) and detoxification (N-acetylation) of AAs for human bladder carcinogenesis. Data now indicate that NAT1, which is expressed in human urothelium and catalyzes the O-acetylation of N-hydroxy arylamines, is significantly correlated with DNA adduct levels and is bimodally distributed in this tissue. Colo-rectal cancer risk, which has been associated with exposure to heterocyclic amines (HAs) in cooked foods, is strongly elevated in individuals with the combined rapid phenotypes for CYP1A2 and NAT2. These enzymes are uniquely responsible for HA N-oxidation and subsequent O-acetylation, forming DNA adducts that are found in human colon. These studies indicate that cancer risk assessment procedures should be redesigned to include biomarkers of susceptibility, especially those involved in carcinogen bioactivation.
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PMID:Cytochrome P-450 and acetyltransferase expression as biomarkers of carcinogen-DNA adduct levels and human cancer susceptibility. 889 86

Hereditary nonpolyposis colorectal cancer (HNPCC) is a major cancer susceptibility syndrome known to be caused by the inheritance of mutations in DNA mismatch repair genes, such as hMSH2, hMLH1, hPMS1 and hPMS2. Germline mutations in the hMSH2 and hMLH1 genes were detected in 9 and 11 Japanese or Korean HNPCC kindreds, respectively. These data establish a basis for the presymptomatic diagnosis of HNPCC patients. To determine the relation between the mutation of the TGF-beta type II receptor gene and genomic instability in the tumorigenesis of HNPCC, we screened genomic DNA of tumors from HNPCC patients. Seventeen of the 24 (71%) genomic instability-positive HNPCC tumors carried one or two A deletions in the (A)10 repeat, while none of the 14 genomic instability-negative tumors did. These deletions inactivate the receptor through a frameshift mutation and the resultant protein truncation. These data suggest that the TGF-beta type II receptor gene is a major target of genomic instability in HNPCC tumorigenesis.
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PMID:[Human mismatch repair genes and HNPCC]. 892 Jun 63

Hereditary nonpolyposis colorectal cancer is a cancer susceptibility syndrome that has been found to be caused by mutations in any of several genes involved in DNA mismatch repair, including hMSH2, hMLH1, or hPMS2. Recent reports have suggested that hMSH2 and hMLH1 have a role in the regulation of the cell cycle. To determine if these genes are cell cycle regulated, we examined their mRNA and protein levels throughout the cell cycle in IMR-90 normal human lung fibroblasts. We demonstrate that the levels of hMSH2 mRNA and protein do not change appreciably throughout the cell cycle. Although hMLH1 mRNA levels remained constant, there was a modest (approximately 50%) increase in its protein levels during late G1 and S phase. The levels of hPMS2 mRNA fluctuated (decreasing 50% in G1 and increasing 50% in S phase), whereas hPMS2 protein levels increased 50% in late G1 and S phase. Our data indicate that, at least in normal cells, the machinery responsible for the detection and repair of mismatched DNA bases is present throughout the cell cycle.
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PMID:Cell cycle regulation of the human DNA mismatch repair genes hMSH2, hMLH1, and hPMS2. 900 May 55


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