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)

One of the major debates in hepatocellular carcinogenesis at present is whether the hepatitis-B and -C viruses are directly carcinogenic or exert their effect indirectly by causing chronic necro-inflammatory hepatic disease, which in turn is responsible for malignant transformation of hepatocytes. This debate has been fueled by the observation that hepatitis C virus is a single-stranded RNA virus with no precedent for inducing cancer but with a marked propensity to cause chronic necro-inflammatory hepatic disease and by the findings in Chisari's transgenic mouse model, which suggest that severe and prolonged hepatocellular injury per se induces a proliferative response that progresses to tumour formation. Recent reports of a guanine to thymine mutation of the third base of codon 249 of the tumour suppressor gene, p53, in 50% of patients with hepatocellular carcinoma in regions of high aflatoxin exposure, and mutagenic experiments showing that aflatoxin B1 binds particularly to guanine residues in G-C-rich domains and that codon 249 is a preferred target have suggested a mechanism whereby aflatoxin might induce malignant transformation.
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PMID:Tumours of the liver. 133 85

Mutations of the p53 gene are found in hepatocellular carcinoma (HCC), the most common form of primary liver cancer. Specific mutations might reflect exposure to specific carcinogens and we have screened HCC samples from patients in 14 different countries to determine the frequency of a hotspot mutation at codon 249 of the tumour suppressor p53 gene. We detected mutations in 17% of tumours (12/72) from four countries in south Africa and the southeast coast of Asia. There was no codon 249 mutation in 95 specimens of HCC from other geographical locations including North America, Europe, Middle East, and Japan. Worldwide, the presence of the codon 249 mutation in HCCs correlated with high risk of exposure to aflatoxins and the hepatitis B virus (HBV). Further studies were completed in two groups of HBV-infected patients at different risks of exposure to aflatoxins. 53% of patients (8/15) from Mozambique at high risk of aflatoxin exposure had a tumour with a codon 249 mutation, in contrast with 8% of patients from Transkei (1/12) who were at low risk. HCC is an endemic disease in Mozambique and accounts for up to two thirds of all tumours in men. A codon 249 mutation of the p53 gene identifies an endemic form of HCC strongly associated with dietary aflatoxin intake.
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PMID:p53 mutation in hepatocellular carcinoma after aflatoxin exposure. 168 37

Suppressor gene loci involved in the development of hepatocellular carcinoma (HCC) have not been fully identified. The aim of this study was to look for consistent allele loss, or loss of heterozygosity (LOH), in HCC which might represent such gene loci. We have prepared DNA from tumour and non-tumour material from 16 patients with HCC (nine with and seven without liver cirrhosis). Tumour DNA was compared with non-tumour DNA by Southern analysis performed with a panel of 22 probes recognising restriction fragment length polymorphisms assigned to chromosomes 1, 4, 5, 7, 9, 11, 12, 13, 14, 16, 17, 18 and 20. Non-tumour DNA from five of the seven patients with HCC without cirrhosis was heterozygous with the probe Lambda MS8 (5q35-qter), and in all five there was LOH in tumour DNA. Probes for other regions of chromosome 5 have as yet shown no LOH in this group of patients. Cirrhotic HCC patients exhibited LOH on chromosomes 1q and 5p but not in the region 5q35-qter. Both groups of HCC showed LOH on chromosome 17p13. Screening with other probes has not shown any consistent LOH in either group as yet. A comparison of LOH on chromosome 5 in seven patients with colorectal metastasis in the liver showed a different pattern, which suggests that the proposed tumour suppressor gene locus for HCC without cirrhosis on chromosome 5 appears to be distinct from the familial adenomatous polyposis coli gene.
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PMID:Loss of constitutional heterozygosity on chromosome 5q in hepatocellular carcinoma without cirrhosis. 168 7

Liver cancer is one of the most prevalent forms of cancer in the world. Hepatitis B virus (HBV) is considered to be a major aetiological factor. Evidence from epidemiological studies has also indicated that environmental contaminants such as mycotoxins may, either in combination with HBV or independently, be important aetiological factors in the pathogenesis of primary hepatocellular carcinoma (PHC). Laboratory data also suggest an interplay between viral and chemical factors in the multifactorial aetiology of PHC. Aflatoxin B1, the chemical carcinogen most frequently implicated in the aetiology of hepatocellular carcinoma is a procarcinogen that must be activated by mixed-function oxidases to an electrophilic metabolite before it can exert its carcinogenic effects. Interindividual differences (greater than 10-fold) in the metabolic activation of aflatoxin B1 are observed. These differences may play a part in an individual's oncogenic susceptibility to aflatoxin B1. Chemical carcinogens and integrated HBV may activate cellular oncogenes, eg N-ras, and inactivate tumour suppressor genes. Recently developed methods that allow monitoring of aflatoxin B1 and HBV exposures and also genetic damage caused by these agents in individuals should help in biochemical and molecular epidemiological studies concerning the aetiology of hepatocellular carcinoma. We identify areas of uncertainties and of future experimentation and propose a hypothesis of liver carcinogenesis.
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PMID:Interactive effects of chemical carcinogens and hepatitis B virus in the pathogenesis of hepatocellular carcinoma. 304 Feb 43

The present study describes mutations of the tumour suppressor gene p53 in a local collection of colorectal and hepatocellular carcinomas (HCCs). Tumour DNA was extracted from both fresh and paraffin-embedded tissues and exons 5-8 of the p53 gene were amplified by polymerase chain reaction (PCR). Mutations were detected by single-strand conformation polymorphism (SSCP) analysis followed by direct DNA sequencing. Of the 38 colorectal carcinomas and 42 HCCs examined, 15 (39%) and 13 (31%), respectively, showed p53 mutations. Two-thirds (10/15) of the mutations in colorectal carcinomas were base transitions with a predominance at CpG dinucleotide sites--a pattern characteristic to an endogenous process in cancer development. Three mutational hotspots at codons 175, 248 and 282 were also identified. Mutations did not correlate with histological grade, Dukes stage, or metastasis. However, tumours at the distal site of the colorectum showed a higher proportion of mutations than the proximal site. In the case of HCCs, majority (9/13) of the mutations were base transitions and no mutations were observed at codon 249. This is in contrast to results from other high-incidence areas such as Africa and China, where aflatoxin is believed to be a major aetiologic factor for liver cancers. The results therefore suggest that other risk factors, rather than dietary exposure to aflatoxin, may contribute to the high HCC incidence in Singapore.
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PMID:Mutations of the tumour suppressor gene p53 in colorectal and hepatocellular carcinomas. 765 61

To examine the significance of mutation of the p53 tumour suppressor gene in the development of human hepatocellular carcinoma in a high-prevalence area for hepatitis B viral infection but a low-exposure area for aflatoxin B1, the spectrum of p53 gene mutations was examined in 21 tumour samples from Hong Kong Chinese patients, all of whom were HBsAg positive. DNA sequencing covering exons 5 to 9 of the p53 gene and Hae III restriction enzyme digestion for preliminary assessment of mutation at codon 249 were performed. Immunohistochemical staining with anti-p53 monoclonal antibodies was done on both tumour and nontumour liver tissues. Six tumours (28.6%) showed a p53 mutation and all were point mutations. Of the six point mutations, two (9.5%) were at codon 249 and both were G to T transversions (AGG-->ATG and AGG-->AGT transversions). The remaining point mutations were transversions scattered at codon 172 (exon 5), 214 (exon 6), 273 (exon 8) and 330 (exon 9). Mutated p53 protein was detected in five of these six cases with demonstrable point mutations by DNA sequencing, in contrast to none detected in all of the 15 cases without demonstrable point mutations. The presence of p53 mutations, including those at codon 249, did not show a significant association with tumour size, sex, age, tumour invasiveness in terms of liver invasion, microsatellites and venous permeation, cirrhosis and encapsulation, but tumours with low cellular differentiation tended to have a higher incidence (71%) of point mutations than those with high cellular differentiation (8%). In conclusion, both the overall p53 mutation rate and that a codon 249 in HCC in Hong Kong Chinese are lower than those reported in tumours from China and sub-Saharan Africa. The low mutation rate at codon 249 is compatible with a low aflatoxin exposure. A special type of p53 mutation has not been found to be associated with hepatitis B viral infection. Mutations of p53 gene tends to occur in tumours with low cellular differentiation, suggesting a late occurrence in the event of tumour progression.
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PMID:p53 gene mutation spectrum in hepatocellular carcinomas in Hong Kong Chinese. 810 45

Mutations of the p53 detected in human hepatocellular carcinomas suggest that its inactivation is a critical step in hepatocellular carcinogenesis. In order to test whether the expression of p53 is compatible with the transformed phenotype of hepatoma cells, we transfected Hep 3B cell line with p53 expression vectors. This cell line, which contains integrated hepatitis B virus sequences, is a good model to study whether the wild-type p53 can function as a tumour suppressor gene in virus-related hepatocellular carcinoma. Wild-type and mutant p53 (Ala143)-expression vectors containing a neoR gene were used. The number of antibiotic-resistant colonies was six times lower after transfection with wild-type p53 vector as compared to the mutant vector. As measured by a specific radioimmunoassay, six of eight (75%) colonies randomly selected after mutant p53 transfections expressed the transfected mutant p53 protein. In contrast, out of eight colonies from wild-type p53-transfections, none expressed detectable p53 protein. The absence of p53 protein was due to the selective deletion of transfected wild-type p53 cDNA sequences. These studies demonstrate that the growth of hepatocellular carcinoma cells is not compatible with the expression of wild-type p53. Therefore, p53 should be considered as a tumour suppressor gene in hepatocytes.
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PMID:p53 as a growth suppressor gene in HBV-related hepatocellular carcinoma cells. 838 Dec 23

A 51-year-old female underwent resection of two synchronous liver tumours, a hepatocellular carcinoma and an adenoma. DNA analysis revealed allele loss on chromosome 17 (17p13, near the locus of p53 tumour suppressor gene) in the hepatocellular carcinoma but not in the adenoma. This finding may support the view that loss of p53 tumour suppressor gene is associated with tumour progression.
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PMID:Chromosome 17 allele loss in hepatocellular carcinoma but not in synchronous liver adenoma. 838 35

It has been established that loss of tumour suppressor genes is crucial in carcinogenesis. There has been no reported study on searching for tumour suppressor genes in cholangiocarcinomas as yet. In order to investigate the loss of heterozygosity (LOH), which may represent such gene loss, in cholangiocarcinoma, we studied 14 patients with this tumour using restriction fragment length polymorphism analysis. Twenty-two probes assigned to chromosomes 1, 5, 7, 9, 11, 12, 13, 14, 16, 17 and 18 were used. Allelic losses were found in chromosomal regions 5q35-qter and 17p13. Loss of genetic material in these regions in cholangiocarcinoma was shared with hepatocellular carcinoma. Probes for other chromosomes have as yet shown no consistent LOH. In conclusion, this study for the first time showed LOH on chromosomes 5 and 17 in cholangiocarcinoma.
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PMID:Loss of constitutional heterozygosity on chromosomes 5 and 17 in cholangiocarcinoma. 838 28

Aberrations of the p53 and Rb tumour suppressor genes were examined in 12 human hepatocellular carcinoma (HCC)-derived cell lines from different geographic areas and 9 local HCCs by restriction fragment length polymorphisms (RFLP), polymerase chain reaction-single-strand conformation polymorphisms (PCR-SSCP) and DNA sequencing. The relationships between genetic changes and hepatitis B virus (HBV) DNA integration in samples were compared. None of the cell lines and tumours showed structural changes in the Rb gene, while 6 cell lines and 2 tumours had mutation or deletion in exons 5 to 8 of p53. Mutations include an AGG --> AGT (Arg --> Ser) transversion at codon 249 in PLC/PRF/5 and Mahlavu, an AAT --> AAA (Asn --> Cys) transversion at codon 200 in TONG/HCC, an AAG --> GAG (Lys --> Glu) transition at codon 139 in HCC-T, a CAT --> CGT (His --> Arg) transition at codon 214 in SC4, and a CCC --> CTC (Pro --> Leu) transition at codon 250 in SC8. In Huh4, an 18-bp deletion from codon 264 to 270 resulted in loss of Leu-Gly-Arg-Asn-Ser-Phe from the amino acid sequences 265 to 270, whereas Hep3B had a 7-kb deletion after exon 7 of p53. Our data indicate that whereas Rb may not have pleiotropic effects on HCC, p53 aberrations are frequently involved in hepatocarcinogenesis. Further, HBV infection appears to be unrelated to the micro-genetic changes of p53. The G to T codon-249-mutation is consistent with HCCs arising from areas at high risk for both aflatoxin B1 (AFB1) exposure and HBV infection.
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PMID:Tumour suppressor p53 and Rb genes in human hepatocellular carcinoma. 877 41


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