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)

Loss of heterozygosity (allele loss, LOH) occurs frequently on the long arm of chromosome 11 in several types of cancer. We analysed 32 melanomas (almost all metastatic lesions) for allele loss at eight loci along the length of chromosome 11 (ptel-D11S922-D11S899-D11S1324-D11S1313-++ +D11S901-NCAM-D11S29-D11S968-qtel). The highest frequency of loss (38%) was at D11S29 (11q23.3). Of 13 melanomas which had lost an allele at one or more loci, all but one showed LOH at either D11S29 or NCAM (11q22). The region between these two loci is the most likely location of any tumour suppressor gene. Low frequencies of LOH occurred on 11p and there was little evidence for tumour suppressor loci outside the 11cen-q23.3 region. Unusually for melanomas, widespread microsatellite instability, with slippage of several repeat units, was observed in two of 32 tumours studied (and four other tumours showed new microsatellite alleles that differed by just one repeat unit from their normal counterparts). However, no mutations of the mismatch repair genes hMSH2 and hMLH1 were detected in these two tumours, and the observed replication errors may result from mutations in other genes involved in mismatch repair or DNA replication. LOH on 11q and replication errors appear to comprise part of the genetic pathways of several tumour types, including melanomas.
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PMID:Allele loss on chromosome 11q and microsatellite instability in malignant melanoma. 898 92

The interpretation of cancer as a somatic evolutionary process involving genetic mutation followed by selection, traces its origins to the early years this century. The dramatic developments in molecular genetics have substantiated these early ideas. Through the application of positional cloning and genomic analysis, many mutations in particular genes, both dominant oncogenes and tumour suppressor genes have now been found in a wide variety of tumours. Other genetic events such as non-disjunction leading to haploid expression of a gene and so reduced gene dosage, or epigenetic changes following, for example, changes in methylation patterns leading to reduced or increased gene expression, may also play critical roles in the progression of a cancer. The analysis of mutations at different stages of colorectal cancer provides a good model for following the initiation and progression of a cancer. Mutations in the APC gene, which explain familial adenomatous polyposis, occur in a high proportion of sporadic colorectal carcinomas and appear to be the earliest known changes. Patterns of mutation in the gene suggest dominant negative or gain of function effects, and also reveal important low penetrance subpolymorphic missense mutations that nevertheless may have a very significant impact on the genetic contribution to colorectal cancer susceptibility. Mutations are also found in related genes in the APC pathway, such as beta-catenin and E-cadherin. Mutations in mismatch repair genes (hMLH1 and hMSH2) have also been shown to occur, as well as reduced expression due to methylation changes, in 10% to 20% of sporadic colorectal carcinomas. In addition, mutations in the well known oncogenes p53 and ras are commonly found. The growth of a cancer is a balance between the rate of cell division and the rate of cell death or apoptosis. Thus, genetic changes which reduce the probability of apoptosis, such as p53 and probably hMLH1, are as important a feature of the evolution of a cancer as those which enhance the independence (APC) and rate of cell division (growth factors). Simple models for the evolution of a cancer that take into account these two processes, show that cancers evolve initially by a series of finite increases in cell population size, following which there may be long periods of cell turnover during which there is an opportunity for further mutation and selection. This explains the long lag periods between the initiation and subsequent progression of most cancers. Our rapidly developing understanding of cancers at the fundamental genetic level provides new opportunities for developing targeted treatments, as well as novel approaches to prevention and early detection.
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PMID:1998 Runme Shaw Memorial Lecture: somatic evolution of cancer. 1057 14

Immunohistochemistry (IHC) is a rapid morphological method that allows the detection of proteins involved in different mechanisms of cancer development. It is therefore a useful tool in the study of cancerogenesis. The best known example is the product of the p53 gene, a tumour suppressor gene which is altered in 50% of all human tumors. In fact, these p53 gene mutations lead to cell protein accumulation whereas the p53 product is not detectable in normal cells. This method also enables the detection of fusion proteins which result from chimeric transcript like WT1 in desmoplastic small round cell tumors, ALK in anaplastic large-cell lymphomas and FLI-1 in Ewing's sarcomas. On the contrary, gene inactivation can induce loss of immunostaining. hMLH1 and hMSH2, which are committed in DNA mismatch repair, can be altered in familial digestive carcinomas, such as hereditary non polyposis colorectal cancer. Thus IHC, which allows us to focus on the altered gene by loss of its product in tumoral cells, represents a good alternative to molecular analysis. IHC is also useful to detect the product of oncogene overexpression such as HER-2 in some breast carcinomas, which allows appropriate therapeutic protocols. Finally, IHC can be used in diagnostic, prognostic and therapeutic ends. Nevertheless, difficulties can be en- countered in the interpretation of the results. Therefore, IHC must be performed in quality control trials.
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PMID:[Immunohistochemistry and genotype analysis of tumors. First part: Which future for the immunochemical diagnosis of cancer?]. 1212 91

Defective DNA mismatch repair results from genetic or epigenetic alterations that most frequently inactivate the genes hMLH1 and hMSH2. This is thought to promote tumourigenesis by accumulation of mutations in oncogenes and tumour suppressor genes. This pathway, first reported in colon cancer, has been recently demonstrated in a subgroup of sporadic pancreatic adenocarcinomas. Intraductal papillary-mucinous neoplasms of the pancreas are a special type of pancreatic tumours, characterised by a spectrum of morphological changes from mild to moderate and to non-invasive, and they may associate with adenocarcinoma. An immunohistochemical study of hmlh1 and hmsh2 protein expression was performed on 26 intraductal papillary-mucinous neoplasms. All tumours showed nuclear expression of hmlh1 and hmsh2 proteins. There were two distinctive patterns of protein expression on the basis of the location of cells expressing these markers: the "normal" pattern, observed mainly in adenoma and rarely in intraductal papillary-mucinous neoplasms with moderate dysplasia and the "dysplastic" pattern, frequently encountered in moderate dysplasia neoplasms, non-invasive and invasive carcinomas. These findings suggest that defective DNA mismatch repair, due to inactivation of hMLH1 and hMSH2, does not play a significant role in the pathogenesis of intraductal papillary-mucinous neoplasms of the pancreas. Two patterns of protein expression were observed and were correlated with the progression of dysplasia in intraductal papillary mucinous neoplasms.
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PMID:Correlation between patterns of DNA mismatch repair hmlh1 and hmsh2 protein expression and progression of dysplasia in intraductal papillary mucinous neoplasms of the pancreas. 1476 May 34

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominantly inherited cancer syndrome associated with germline mutations in DNA mismatch repair (MMR) genes. Recently a polymorphism at codon 72 (R72P) in the tumour suppressor gene TP53 has been implicated in the age of disease onset in HNPCC. In this report we have studied a large cohort of HNPCC patients to assess the impact of this polymorphism on disease expression and age of diagnosis of colorectal cancer (CRC). DNA samples from 218 HNPCC mutation positive patients from Australia and Poland were genotyped for the arginine to proline change at codon 72 in the TP53 gene. The association between the polymorphism and disease characteristics (mutation status, disease expression and age of diagnosis of CRC) was tested using Pearson's Chi-square and Kaplan-Meier survival analysis. Our study of Australian and Polish HNPCC patients does not provide evidence for an association between the Arg/Pro (GC) genotype of the R72P polymorphism and age of diagnosis of CRC. The R72P polymorphism was examined in HNPCC patients and found to be not associated with disease development in either the Australian or Polish populations. When gene mutation status (hMLH1 or hMSH2) was included in the analysis some evidence of an affect was observed. The genotyping revealed in the Australian population that the R72P polymorphism was under-represented in the hMSH2 group whereas it was over-represented in the Polish hMSH2 group. A similar trend was observed for hMLH1 in both groups but was not significant. Age of diagnosis of CRC in HNPCC patients is therefore more complex than that predicted by the R72P TP53 polymorphism alone, suggesting an inter-relationship with other genetic and/or environmental factors.
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PMID:Age of diagnosis of colorectal cancer in HNPCC patients is more complex than that predicted by R72P polymorphism in TP53. 1723 May 3

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

Colorectal cancer (CCR) is one of the most frequent cancers in developed countries. It poses a major public health problem and there is renewed interest in understanding the basic principles of the molecular biology of colorectal cancer. It has been established that sporadic CCRs can arise from at least two different carcinogenic pathways. The traditional pathway, also called the suppressor or chromosomal instability pathway, follows the Fearon and Vogelstein model and shows mutation in classical oncogenes and tumour suppressor genes, such as K-ras, adenomatous polyposis coli, deleted in colorectal cancer, or p53. Alterations in the Wnt pathway are also very common in this type of tumour. The second main colorectal carcinogenesis pathway is the mutator pathway. This pathway is present in nearly 15% of all cases of sporadic colorectal cancer. It is characterized by the presence of mutations in the microsatellite sequences caused by a defect in the DNA mismatch repair genes, mostly in hMLH1 or hMSH2. These two pathways have clear molecular differences, which will be reviewed in this article, but they also present distinct histopathological features. More strikingly, their clinical behaviours are completely different, having the "mutator" tumours a better outcome than the "suppressor" tumours.
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PMID:Differential colorectal carcinogenesis: Molecular basis and clinical relevance. 2116 Aug 23