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

The replication error phenotype (RER+) represents an important new form of genetic alteration characterized by widespread instability in repetitive nucleotide sequences. The aim of this study was to compare the features of RER+ gastric tumours with those of RER+ colonic tumours. RER status was determined by analysis of size alterations in the BAT-26 mononucleotide repeat microsatellite. Twelve of 121 (10 per cent) gastric carcinomas from a low-incidence region were found to be RER+. BAT-26 instability was associated with tumours showing an absence of nodal invasion ( p=0.009) and with a trend for improved prognosis. These tumours were more frequent in older, female patients. Frameshift mutations in mononucleotide repeat sequences within the transforming growth factor-beta receptor II (RII), insulin-like growth factor II receptor (IGFIIR), and BAX genes were observed in 83, 33, and 25 per cent, respectively, of RER+ tumours. Only 1/12 (8 per cent) RER+ tumours contained a p53 gene mutation compared with 29/109 (27 per cent) RER- tumours. RER+ gastric carcinomas therefore share several important features with RER+ colonic tumours, including less frequent nodal invasion, improved prognosis, a similar frequency of mutation in growth control genes containing repetitive nucleotide sequences, and a low frequency of mutation of the p53 tumour suppressor gene.
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PMID:Gastric carcinomas with microsatellite instability: clinical features and mutations to the TGF-beta type II receptor, IGFII receptor, and BAX genes. 1039 2

The recent discovery of hypermethylation of the promoter of genes is a powerful epigenetic mechanism for the inactivation of tumour suppressor genes in colorectal and other cancers. Approximately 95% of hereditary non-polyposis colorectal cancers (HNPCCs) and 15% of sporadic colorectal cancers (CRCs) are replication error positive (RER(+)). Although DNA mutations are found in mismatch repair genes in the majority of HNPCC CRC, mutations are rare in sporadic RER(+) CRCs. We have shown that the principal cause of an RER(+) phenotype is hypermethylation of the promoter of hMLH1, resulting in the absence of hMLH1 protein. In contrast to sporadic RER(+) CRCs, we found that hypermethylation of hMLH1 does not occur in HNPCC CRC, suggesting the possibility of further differences between the two types of RER(+) tumours in the adenoma to carcinoma pathway. Other known tumour suppressor genes with few or no mutations may be candidates for epigenetic changes. One such gene is E-cadherin, and we described the first mutations of this gene in CRCs. Half of all CRCs were found to be hypermethylated in the Ecadherin promoter and this correlated with reduced E-cadherin expression. Epigenetic changes occur in CRCs and arise in different frequencies in separate genes. Hypermethylation of the promoter may be reversed and gene function restored to a cell, thus partially undoing the cancer phenotype.
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PMID:Epigenetics, mismatch repair genes and colorectal cancer. 1572 Sep 1

Squamous cell carcinoma of the head and neck (SCCHN) arises as a consequence of multiple molecular events induced by the effects of various habits such as tobacco and use of alcoholic beverages, influenced by environmental factors, possibly viruses in some instances, against a background of heritable resistance or susceptibility. Oral squamous cell cancers have a similar aetiology. Genetic damage affects many chromosomes and genes, including oncogenes and tumour suppressor genes, and it is the accumulation of such genetic damage, possibly along with an impaired ability to repair this damage - an inherited trait in some cases - that appears to lead to carcinoma in some instances, sometimes via a clinically evident pre-malignant, or potentially malignant, lesion. This communication reviews the advances in the understanding of this complex and rapidly developing area of research over the past decade. Cytogenetic and molecular analyses have shown changes in several chromosomes in oral cancer, particularly in chromosomes 3, 9, 11, 13 and 17. Analyses of allelic losses has allowed for the identification of chromosomal regions harbouring tumour suppressor genes (TSGs). Impaired function of such genes or their products, or activation of oncogenes, or both, may be involved in carcinogenesis. Probably the most significant findings thus far have been in relation to TSGs with the discovery of p53 mutations on chromosome 17 as in many other tumours, indicating disturbed function of this TSG and some on chromosomes 3 and 9 (MTS-1) which may be of comparable or greater significance. Over-expression of oncogenes, especially those on chromosome 11 (PRAD-1, Int-2, hst-l, and bcl-1 in particular) has also been implicated in carcino-genesis. The analysis of microsatellite instability (MI or RER, replication error repair) in tumour specimens, which are associated with defects in DNA repair genes has provided a further method of assessing genetic damage in the genome of sporadic cancers. Microsatellite instability (MI) has been demonstrated in several carcinomas as well as SCCHN. These research findings have now reached the stage where it is becoming possible to begin to introduce them into clinical practice for the more sensitive detection of potentially malignant lesions, better diagnosis and prognostication, and hopefully, to start to develop novel therapies such as gene therapy.
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PMID:Genetic aberrations in squamous cell carcinoma of the head and neck (SCCHN), with reference to oral carcinoma (review). 2153 38