Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dissection of germline mutations in a sensitive and specific manner presents a continuing challenge. In dominantly inherited diseases, mutations occur in only one allele and are often masked by the normal allele. Here we report the development of a sensitive and specific diagnostic strategy based on somatic cell hybridization termed MAMA (monoallelic mutation analysis). We have demonstrated the utility of this strategy in two different hereditary colorectal cancer syndromes, one caused by a defective tumour suppressor gene on chromosome 5 (familial adenomatous polyposis, FAP) and the other caused by a defective mismatch repair gene on chromosome 2 (hereditary non-polyposis colorectal cancer, HNPCC).
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PMID:Monoallelic mutation analysis (MAMA) for identifying germline mutations. 755 Mar 26

The purpose of this review is to analyze the role of genetic factors in the pathogenesis of human cancer, with particular attention to tumours of the digestive organs. Human neoplasms are defined as "sporadic" when there is no evidence of cancer among relatives besides the index case; "Familial" tumours are characterized by cancer aggregation in a given family, but without verticality or other features of mendelian (autosomal) transmission. In "Hereditary" tumours there is sufficient clinical and biologic evidence to suspect that genetic factors are the main event responsible for their development. Hereditary tumours have been associated with germ-line mutations of oncogenes or, more often, of tumour suppressor genes. More recently, a new category of cancer-related genes has been defined-the mutator genes-which are involved in the mechanisms of DNA repair. Among the various hereditary cancer syndromes, Hereditary non polyposis Colorectal Cancer (HNPCC or Lynch syndrome), Familial Adenomatous Polyposis (FAP) and related syndromes, Hereditary Breast tumours, Li-Fraumeni syndrome and Von Hippel-Lindau disease have been discussed in more detail. Besides purely scientific problems, many ethical and social aspects remain to be solved in hereditary cancer syndromes, and it is likely that their solution will require-in the years to come-a close collaboration between oncologists, geneticists and basic research workers.
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PMID:Genetic basis of tumour development. 884 41

The discovery of powerful mutator phenotypes in a subset of colon cancers provides direct support for the hypothesis that destabilization of replication fidelity and repair drive the accumulation of mutations in tumour suppressor or proto-oncogenes. Nevertheless, many important questions remain. The tumour cell lines in which these mutator genes were characterized have many other mutations that may contribute to the mutator phenotype and the characteristic pattern of mutations found in these cells. Thus, mismatch repair deficiency may be necessary for the mutator phenotype, but is it sufficient? Certainly, changes in DNA replication fidelity or cell cycle checkpoint controls may contribute to the mutator phenotype. This question also has important implications for the effect of mismatch repair deficiency on tumour development. Does the mutator phenotype in HNPCC patients arise as a very early event resulting from the loss of the wild type allele or does it arise in later stages only after alterations of cell cycle controls or replication fidelity? Given that eukaryotic cells have numerous homologues of the mismatch repair genes, what are the roles of all these genes? Are these involved in the repair of very specific types of replication errors or do they have other roles in cells? Finally, what mechanisms underlie the accumulation of mutations in other types of tumours? Given the rapid progress made since the isolation of the human homologues of the E coli mismatch repair genes less than 3 years ago, we can look forward to the answers to many of these questions in the near future.
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PMID:Patterns of mutation in cancer cells. 897 27

DNA methylation plays an important part in the regulation of gene expression. Alterations in DNA methylation in tumours have been reported and have been used to generate hypotheses about mutagenesis and silencing of tumour suppressor genes. However, the underlying mechanism is still poorly understood, and conflicting data on the levels of overexpression of 5'-cytosine DNA methyltransferase in sporadic colon carcinoma have been published. We used a competitive RT-PCR assay for quantification of mRNA of 5'-cytosine DNA methyltransferase in colon biopsies obtained from patients with hereditary colon carcinoma syndromes and compared the results with those obtained in a control group. No significant difference was found between the flat mucosa of FAP patients and the mucosa of the control group. In FAP and HNPCC patients, the 5'-cytosine DNA methyltransferase mRNA levels of adenomas were significantly higher (P<0.05) than of flat mucosa in the same group, but both showed great variability from patient to patient. Our findings suggest that the mRNA levels of methyltransferase cannot be used as predictive marker for screening in families affected by hereditary colon carcinoma.
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PMID:5'-Cytosine DNA-methyltransferase mRNA levels in hereditary colon carcinoma. 1007 Dec 36

About 5% of colorectal cancer cases are due to an autosomal dominant genetic predisposition with high penetrance. In this condition, the patient is carrier of a pathogenic gene mutation present in all body cells which can be transmitted to descendants, a so-called germ line mutation. The mutation is usually present in a tumour suppressor gene. Three subgroups of hereditary colorectal cancer can be distinguished on the basis of the clinical characteristics: (a) syndromes without polyposis (mostly hereditary non-polyposis colorectal carcinoma; HNPCC), (b) syndromes with adenomatous polyposis (mostly familial adenomatous polyposis; FAP) and (c) syndromes with hamartomatous polyposis. Recently, the main gene defects which underlie these syndromes were identified. Consequently, it is possible in approximately half the families with HNPCC or FAP in patients with colorectal cancer to demonstrate the causative gene defect and subsequently, by blood testing of healthy relatives to determine who is and is not a carrier of this hereditary condition. Thus, preventive measures can be directed toward family members with a demonstrable high risk of large bowel cancer.
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PMID:[Genetics of colorectal cancer. I. Non-polyposis and polyposis forms of hereditary colorectal cancer]. 1038 34

Cancer is a genetic disease. Colorectal cancer is probably the type of cancer for which the most is known about the genes affected by cancer-causing mutations, their normal functions and their carcinogenic effects when mutated. Most cancer-causing mutations are somatic, occurring in the affected tissue during the course of carcinogenesis. However, most cancers also have a hereditary component that is caused by predisposing mutations that affect the germline, are heritable and contribute to the initiation of carcinogenesis. High-penetrance mutations confer predisposition to colorectal cancer mainly in Lynch syndrome (which involves mutations in mismatch-repair genes) and in familial adenomatous polyposis (which involves mutations in the APC tumour suppressor). Together, these conditions account for 5% or less of all cases of colorectal cancer. Low-penetrance mutations account for a high proportion of all the attributable risk of colorectal cancer, in both familial and sporadic cases. These mutations are more difficult to identify, but mainly due to the implementation of association studies, are increasingly being detected and characterized. The identification of both high- and low-penetrance mutations contributes significantly to our understanding of the molecular genetic processes occurring in cancer. This understanding facilitates the development of therapeutic drugs and preventive strategies.
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PMID:Molecular biology in colorectal cancer. 1679 Mar 91

p53 and the prostate-cancer-susceptibility gene RNASEL are tumour suppressor genes involved in apoptosis. We have previously reported that the common, functionally different variants Arg72Pro in p53 and Arg462Gln in RNASEL are associated with the age of disease onset of colorectal cancer in Lynch syndrome patients. To assess the combined effect of both variants, we screened 246 unrelated Lynch syndrome patients with a pathogenic germline mutation either in MSH2 (n=138) or in MLH1 (n=108) and colorectal cancer as first tumour, and 245 healthy controls. The global log rank test revealed significant differences in the age of disease onset for the genotypes of each variant (p=0.0176 for p53 and p=0.0358 for RNASEL) and for the combined genotypes of both variants (p=0.0174). The highest difference in median age of disease onset was seen between homozygotes for the wild-types in both genes (42years [range 22-75]) and homozygotes for the variant alleles in both genes (30years [range 26-47]). A multivariate Cox regression model indicated that only the p53 and RNASEL genotypes had a significant influence on age of disease onset (p=0.016 for p53 and p=0.014 for RNASEL) in an additive mode of inheritance, and that the effects of both variants are purely additive, which supports the notion that the p53 and RNaseL pathways do not interact. These findings may be relevant for preventive strategies in Lynch syndrome.
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PMID:The additive effect of p53 Arg72Pro and RNASEL Arg462Gln genotypes on age of disease onset in Lynch syndrome patients with pathogenic germline mutations in MSH2 or MLH1. 1722 35

HNPCC (Hereditary non-polyposis colorectal cancers) development is caused by mutation of genes included in system of mismatch repair genes. The mutation exists at 60% of patients in hMSH2 gene, 30% in hMLH1 and 10% both in hPMS1and hPMS2 genes. RER+ exists in about 90% in hereditary non-polyposis colorectal cancer and about 15-28% in sporadic cancers. The purpose of the study was to determine highly sensitive microsatellite markers which can be fast and efficient way of microsatellite screening for detection of HNPCC patients. Moreover, we have analysed the loss of heterozygosity of tumour suppressor genes which could have the diagnostic value in detection of HPNCC patients.
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PMID:Molecular analysis: microsatellity instability and loss of heterozygosity of tumor suppressor gene in hereditary non-polyposis colorectal cancers (HNPCC). 1928 89

Hereditary cancer syndromes are frequently seen in young cancer patients and patients with a positive family history. Genetic testing is important for the identification of high-risk individuals, and for the early introduction of specialized preventive care or prophylactic surgeries. High-risk tumour suppressor genes (BRCA1 and BRCA2) and DNA repair genes (MLH1, MSH2 and MSH6) are responsible for a substantial part of hereditary breast, ovarian and colorectal cancer. Other hereditary cancers are seen less frequently, but genetic testing has increased for many other site-specific cancers and complex syndromes. Genetic centres and molecular genetic laboratories are located mostly within university or regional hospitals. Some genetic centres are private. It is highly recommended (Czech Society for Medical Genetics) that all laboratories are accredited according to ISO 15,189 and that genetic testing of hereditary cancer syndromes is indicated by medical geneticists. The indication criteria and prevention strategies were published in Supplement 22 of Clinical Oncology 2009 (in Czech). Preventive care for high-risk individuals is organized by thirteen Oncology Centres, which provide most of the oncology care in the Czech Republic. Genetic testing and preventive care for high-risk individuals and mutation carriers is covered by health insurance. The molecular genetic laboratory at the MMCI provides molecular genetic testing of BRCA1, BRCA2, CHEK2 for hereditary breast/ovarian cancer, MLH1, MSH2, MSH6 for Lynch syndrome,TP53 for Li-Fraumeni syndrome, CDKN2A for familial malignant melanoma syndrome and CDH1 gene for hereditary diffuse gastric cancer. Other syndromes are tested in specialized laboratories elsewhere.The use of genetic testing is increasing because of more frequent referrals from oncologists and other specialists and the increasing variety of genes tested. However, in some patients the testing is not recommended and other family members are dying because of the late diagnosis of hereditary syndrome. Greater awareness of the importance of genetic testing in oncology is needed.
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PMID:Genetic testing and prevention of hereditary cancer at the MMCI--over 10 years of experience. 2134 12