Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aflatoxin B1 (AFB1) has been postulated to be a hepatocarcinogen in humans, possibly by causing p53 mutations at codon 249. AFB1 is metabolized via the phase I and II detoxification pathways; hence, genetic variation at those loci may predict susceptibility to the effects of AFB1. To test this hypothesis, genetic variation in two AFB1 detoxification genes, epoxide hydrolase (EPHX) and glutathione S-transferase M1 (GSTM1), was contrasted with the presence of serum AFB1-albumin adducts, the presence of hepatocellular carcinoma (HCC), and with p53 codon 249 mutations. Mutant alleles at both loci were significantly overrepresented in individuals with serum AFB1-albumin adducts in a cross-sectional study. Mutant alleles of EPHX were significantly overrepresented in persons with HCC, also in a case-control study. The relationship of EPHX to HCC varied by hepatitis B surface antigen status and indicated that a synergistic effect may exist. p53 codon 249 mutations were observed only among HCC patients with one or both high-risk genotypes. These results indicate that individuals with mutant genotypes at EPHX and GSTM1 may be at greater risk of developing AFB1 adducts, p53 mutations, and HCC when exposed to AFB1. Hepatitis B carriers with the high-risk genotypes may be an even greater risk than carriers with low-risk genotypes. These findings support the existence of genetic susceptibility in humans to the environmental carcinogen AFB1 and indicate that there is a synergistic increase in risk of HCC with the combination of hepatitis B virus infection and susceptible genotype.
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PMID:Susceptibility to hepatocellular carcinoma is associated with genetic variation in the enzymatic detoxification of aflatoxin B1. 789 76

To determine whether a constitutive p53 deficiency would enhance the rate of development of chemically induced hepatocellular carcinoma, we treated groups of wild-type, p53-heterozygous (+/-), and null (-/-) male mice with a single dose of diethylnitrosamine at 12 d of age. Although the null mice had to be killed very early, at 15 wk of age because of the development of nonliver tumors, hemangiosarcoma of the liver had already developed in two of seven mice. More detailed analysis of the wild-type and heterozygous mice showed no difference in the number, size, or growth rate of early microscopic lesions or in the number or apparent malignancy of hepatocellular adenomas or carcinomas at later time points. Thus, germline p53 deficiency does not enhance the rate of development of diethylnitrosamine-induced hepatocellular adenoma or carcinoma but may instead favor development of hepatic hemangiosarcoma.
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PMID:Hepatocarcinogenesis in p53-deficient mice. 789 66

Hepatocellular carcinoma is common among Alaska Natives. The known risk factor in this population is hepatitis B viral infection; fungal toxins, including aflatoxin B1, have not been detected in foodstuffs. In this series of 14 patients (including 4 siblings and 2 second cousins), 3 patients were less than 12 years old at diagnosis of hepatocellular carcinoma, 8 patients were 13-24 years old, and 3 patients were more than 60 years old. Since p53 mutations occur in 29% of hepatocellular carcinomas worldwide, we tested the tumors for p53 mutations and serum samples for anti-p53 antibodies. Serum samples from these 14 patients did not contain detectable levels of anti-p53 antibodies. Loss of heterozygosity within the p53 locus was not detected in any of 9 informative cases. Immunohistochemical analysis for p53 protein accumulation was negative in all of 11 tumors. DNA sequence analysis of 12 tumor samples showed no evidence of p53 mutation in the highly conserved regions included in exons 5-8. These data, combined with one case from a previous report, indicate a mutation frequency of 0 of 13, which differs significantly from the worldwide frequency of 29% (chi 2 3.9; P = 0.048). These results indicate that liver carcinogenesis among Alaska Natives occurs independently of a traditional p53 pathway. The familial clustering and early onset in this population strongly suggest an inherited genetic predisposition to develop liver cancer. Germline mutations in a tumor suppressor or a cancer susceptibility gene are likely. Future studies of these samples should include investigations of candidate suppressor or susceptibility genes which map to chromosomal regions commonly deleted in liver cancers.
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PMID:p53 is not mutated in hepatocellular carcinomas from Alaska Natives. 789 27

Point mutations in ras protooncogenes and in the p53 tumor suppressor gene are common in many forms of human cancer. The identification of carcinogens which are responsible for their induction in humans is of great interest because it may suggest measures for disease prevention. Furthermore, the load of somatic mutations in cancer-related genes in premalignant tissues may become a useful parameter for risk assessment. For the measurement of such mutations, highly sensitive genotypic mutation systems are required which avoid the selection and clonal expansion of cells on the basis of a mutated phenotype. We have developed the restriction fragment length polymorphism/polymerase chain reaction method for genotypic mutation analysis and applied it to the study of the mutability of hot-spot codons in c-H-ras1 and p53 genes with human carcinogens. In particular, we studied the mutability of codons 247-250 of p53 with the mycotoxin aflatoxin B1 (AFB1) in human hepatocytes. AFB1 preferentially induced the transversion of guanosine to thymidine in the third position of codon 249, generating the same mutation which is found in a large fraction of hepatocellular carcinomas from regions of the world with AFB1-contaminated food. Our results are in support of AFB1 as an etiological factor for hepatocellular carcinoma in AFB1-contaminated areas. In an ongoing study we are comparing the load of mutations in hot-spot codon 12 of c-H-ras1 in urinary bladder carcinoma and in normal tissue, by restriction fragment length polymorphism/polymerase chain reaction. We observed moderately elevated abundances of guanosine to thymidine transversions in the middle position of codon 12 in tumor DNA. These results may reflect a mutator phenotype of the tumor tissue or they could be the consequence of the heterogeneity of the biopsies which were analyzed.
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PMID:Mutagenesis of the H-ras protooncogene and the p53 tumor suppressor gene. 790 48

Fourty-five cases of primary hepatocellular carcinoma (PHC) from areas of low aflatoxin B1 exposure but high risk of hepatitis B (HBV) were examined. Positive cases of HBV-DNA were determined in 40 of 45 cases by southern hybridization and polymerase chain reaction (PCR). Results of restriction fragment length polymorphism (RFLP) analysis showed that 1 of 33 informative cases revealed loss of heterozygosity at p53 gene locus. The point mutation of p53 exon 7 was detected by PCR and restriction enzyme digestion with RsaI, MspI and HaeIII, respectively. Only two of the 45 cases showed point mutation on codon 247 and 249, and sequence analysis showed that the changes were C-->G and G-->T, respectively. Frozen section examinations in 1 of 5 cases showed weak positive staining on nucleus by immunohistochemistry with anti-p53 monoclonal antibody (pAb1801). Our results provide evidence suggesting that HBV infection alone do not contribute to changes of p53 gene including allelic loss and point mutation. A multiple step process may exist and multiple genes may be involved in hepatocarcinogenesis.
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PMID:[Relationship between mutation of tumor suppressor gene p53 and development of hepatocellular carcinoma]. 790 44

Infection with hepadnaviruses and exposure to dietary aflatoxin are considered major risk factors in the development of hepatocellular carcinoma (HCC) both in humans and in animals. Recently, a broad range of mutations in the p53 tumor suppressor gene has been reported in human HCCs, predominantly from hepatitis B virus carriers in areas with either high or low levels of exposure to dietary aflatoxin. To determine whether p53 mutations are common to HCCs of hosts infected with related hepadnaviruses with and without treatment with aflatoxin, we studied the occurrence of mutations in the p53 gene in HCCs of ground squirrels and woodchucks with history of infection with ground squirrel hepatitis virus (GSHV) and woodchuck hepatitis virus, respectively. Sequencing of wild type p53 genes from ground squirrels and woodchucks revealed remarkable homology between the two species with only a few amino acid differences in exons 4, 8, and 9. Using direct polymerase chain reaction sequencing, we analyzed the state of the p53 gene (exons 4-9) in 20 HCCs from ground squirrels (2 uninfected, 7 with past, and 11 with ongoing infection with GSHV) and in 11 HCCs from woodchucks persistently infected with woodchuck hepatitis virus. Five GSHV carrier and two uninfected ground squirrels received i.p. administration of aflatoxin B1. We detected only one mutation in the p53 gene of the tested animals. This mutation was located in codon 176 of exon 5 in the HCC of a GSHV-positive ground squirrel treated with aflatoxin. Mutation was caused by a G to T transversion in the second position of the codon, resulting in the replacement of cysteine with phenylalanine, and was accompanied by a tumor-specific loss of heterozygosity. p53 allelic amino acid variation with sequences coding for aspartic acid or asparagine was present in codon 61 in the variable region of exon 4 in both HCCs and nonneoplastic tissues of ground squirrels. In view of the considerably lower apparent rate of mutations in comparison to human HCCs, we suggest a less important role for aflatoxin in the induction of p53 mutations in HCCs of ground squirrels. Alternatively, etiological factors other than p53 mutations may be of greater significance in the development of HCC in ground squirrels and woodchucks.
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PMID:State of the p53 gene in hepatocellular carcinomas of ground squirrels and woodchucks with past and ongoing infection with hepadnaviruses. 792 76

The recently cloned protein, p21 (WAF1/CIP1) is a downstream effector of p53, and mediates growth arrest by inhibiting the action of G1 cyclin-dependent kinases. Since cellular differentiation is frequently characterized by G1 arrest, we examined whether p21 upregulation occurs in differentiation. We show that p21 expression is triggered by multiple differentiation-inducing agents in hematopoietic and hepatoma cells through a p53-independent pathway. The dramatic rise in p21 levels occurs as an immediate early response to differentiation inducers. The induction of p21 is coupled to the expression of early differentiation markers, and is uncoupled from apoptosis. Finally, evidence is presented that p21 expression is uncoupled from G1 arrest in the presence of deregulated c-myc.
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PMID:Induction of p21 (WAF-1/CIP1) during differentiation. 793 67

In order to investigate the expression of mutant p53 protein (Mp53) and HBxAg in chronic active hepatitis (CH) and hepatocellular carcinoma (HCC), 30 specimens of HCC with surrounding liver tissues (SL), 15 biopsy specimens from CH were examined with immunohistochemical method (ABC system). The results showed, that 13 (43.3%) specimens of HCC and 15 (50%) of SL were positive for MP53 and HBxAg staining; 3 (16.7%) of HCC and 8 (26.7%) of SL were only MP53 positive, being HBxAg staining negative. On the contrary, 4 (13.3%) of HCC and 1 (3%) of SL were negative for MP53 staining and positive for HBxAg staining (P < 0.05, chi 2 test). In 15 specimens of CH, 3 cases were positive for MP53, 2 for HBxAg. The results indicate that there is a correlation between mutant p53 protein and HBxAg, suggesting that the p53 gene mutation may be closely related with HBV infection, and the mutation of p53 gene would be one of hepatocarcinogenesis mechanisms of HBV.
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PMID:[Expression of mutant p53 in chronic HBV infection and hepatocellular carcinoma]. 795 95

The p53 protein is now well established as a crucial player in regulation of cell growth. Mutations arising in the coding sequences of its gene have been demonstrated in a wide variety of human tumors, including hepatocellular carcinoma (HCC). Our previous studies have shown that codon 249 mutations, the most common mutation of the p53 gene in HCCs, did not occur in our group of patients. To examine the prevalence of p53 mutations in other areas of the p53 gene, PCR and direct sequencing were carried out on these samples covering the four highly conserved regions of the gene between exons 5 and 8. Liver samples were obtained from both HBV+ and HBV- patients in a variety of ethnic groups. Primers to the flanking regions of exon 5, 6, 7, and 8 were used in PCR to amplify these exons. Following purification, the products were sequenced in both directions by cycle sequencing. In 15 HCCs examined, no mutations in these exons of the p53 gene were found. This suggests a less important role for p53 in development of HCC in this group of patients than in patients from other areas of the world.
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PMID:p53 gene in hepatocellular carcinomas from Australia. 802 94

The p53 tumor suppressor protein plays an important role in the G1 arrest of cells treated with DNA-damaging agents. Mouse hepatoma cells with wild-type or mutated p53 genotype were gamma-irradiated and the time course of p53 expression was determined by immunocytochemical staining. In p53 wild-type cells, gamma-irradiation led to a transient accumulation of the protein in the nuclei, whereas no such accumulation occurred in p53-mutated cells. Micronuclei were induced by gamma-irradiation in both wild-type and mutated cells in a dose- and time-dependent manner, but only micronuclei from p53 wild-type cells demonstrated a strongly positive staining reaction for p53 protein. This accumulation of p53 protein in micronuclei was not associated with a block in DNA synthesis as evidenced by bromodeoxyuridine labeling experiments.
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PMID:Gamma-irradiation-induced micronuclei from mouse hepatoma cells accumulate high levels of the tumor suppressor protein p53. 803 78


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