Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatocellular carcinoma (HCC) is a common malignancy worldwide and highly associated with chronic virus-B or -C infection and cirrhosis. Molecular studies have shown high frequency of loss of heterozygosity (LOH) in some specific chromosome regions, but LOH on chromosome 9 in HCC has not been thoroughly investigated. In our investigation of chromosome 9 with 19 polymerase-chain-reaction (PCR)-based polymorphic microsatellite markers, 30 of 48 HCC tissue samples (63%) had LOH, and a distinct common deletion region and a region of loss were identified. The first region was located at the 9p21 region and the minimal deletion region was located between loci D9S1747 and D9S1748. This is a region of approximately 200 kb which includes the p16 tumor-suppressor gene. A region of loss was located on 9p13 to 9q33. The putative tumor-suppressor gene for nevoid-basal-cell-carcinoma syndrome (NBCCS) at 9q22.3 resides within this region. In addition to LOH, 4 HCC cases showed possible homozygous deletions at 9p21 with markers D9S1748, D9S1752 and D9S171 by multiplex PCR analysis. In 3 cases, the minimal region of possible homozygous deletion was approximately 300 kb and was defined between markers D9S1747 and D9S1752. Since this deletion region includes both the p15 and the p16 tumor-suppressor genes, these genes were possibly inactivated by homozygous deletion in HCC. In addition, a second region of possible homozygous deletion was present on the centromeric side of 9p21. However, these changes are not associated with age, gender, size or tumor-cell differentiation. Our data also suggest that inactivation of the p16 and the p15 genes and the possibility of other unknown tumor-suppressor genes located on these defined deleted regions of chromosome 9 may be involved in the pathogenesis of HCC.
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PMID:Frequent allelic loss on chromosome 9 in hepatocellular carcinoma. 1020 42

To investigate the role p15 gene plays in the pathogenesis of human primary hepatocarcinoma, 35 human hepatocarcinomas, 35 cases of adjacent non-cancerous liver cirrhosis and the blood cells of 10 normal human were analyzed for somatic mutation in p15 gene with PCR-SSCP. One case of adjacent non-cancerous liver cirrhosis showed abnormal migration single strand. In the hepatocarcinomas and in the other cases of adjacent non-cancerous liver cirrhosis, no mutation was found. Cloning and sequencing of the amplified abnormal migration single strand DNA revealed that it contained a wild type exon 2 of p15 gene in 345 bp length. The results indicate that the inaction of p15 gene by point mutation is a very uncommon event in human hepatocarcinoma.
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PMID:[Mutation analysis of the p15 gene exon 2 in human primary hepatocarcinoma]. 1074 27

We prospectively analyzed p15 methylation patterns in 25 surgically resected tumors and 130 plasma, serum, and buffy coat samples from hepatocellular carcinoma (HCC) patients, controls with chronic hepatitis/cirrhosis, and healthy subjects. Using methylation-specific PCR, we demonstrated for the first time p15 promoter methylation in 64% of tumors and 25% (4 of 16) of patients' plasma and serum samples. Concurrent p15 and p16 methylation was shown in 48% of tumors, and p15/p16 methylation was detected in the plasma/serum of 92% (11 of 12) of patients. Of note, 75% of 12 patients with concurrent tumor methylation developed clinical metastasis/recurrence (P = 0.027). In buffy coat samples, p15 methylation was detected in all eight patients with tumor p15 methylation, suggesting the presence of circulating tumor cells. None of the control samples were methylation positive. Our data underscore the important role(s) of p15 and p16 methylation in hepatocarcinogenesis and tumor progression. Among 92% (23 of 25) of patients with tumor p15/p16 methylation, circulating tumor DNA and HCC cells were detected in the peripheral blood of 87% (20 of 23) of patients. The combination of these epigenetic markers may prove valuable for noninvasive HCC diagnosis and disease monitoring.
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PMID:Frequent p15 promoter methylation in tumor and peripheral blood from hepatocellular carcinoma patients. 1099 38

One of the main regulatory pathways reported to be altered in hepatocellular carcinoma (HCC) is that of cell cycle control involving RB1 gene-related cell inhibitors. We investigated p14(ARF), p15(INK4B), p16(INK4A), p18(INK4C), and RB1 genes in a series of HCCs and associated cirrhosis with the goal of ascertaining their pattern of inactivation by gene methylation. Thirty-three HCCs, adjacent nonneoplastic cirrhotic tissues, and 6 HCC cell lines were studied. Cirrhoses (25 of 33, 76%), HCCs (31 of 33, 94%), and 3 of 6 (50%) cell lines showed 1 or more methylated genes. Cirrhoses (17 of 33, 51%) had more frequently than HCCs (11 of 33, 33%, P =.01) only 1 methylated gene. With the exception of p18(INK4C) the genes under study showed promoter methylation with frequency ranging from 82% (p16(INK4A) in HCC) to 33% and 39% (p15(INK4B) and p16(INK4A) in cirrhoses). In cases with only 1 methylated gene, p15(INK4B) in cirrhosis (8 of 17, 47%) and p16(INK4A) in HCC (10 of 11, 91%) were the more frequently altered. An optimal correlation was found between p15 and p16 gene methylation and complete protein loss in HCC detected by immunocytochemistry, whereas a partial loss of the same proteins was a feature of methylated cirrhoses. Inactivation by DNA methylation of several genes of the RB1 pathway is common to cirrhosis and HCC. An early pattern of methylatory events (1 methylated gene) is a feature of cirrhosis rather than HCC, whereas an advanced one (> or = 3 methylated genes) is characteristic of malignancy. Early methylation changes seem to involve p15(INK4B) and p16(INK4A) in cirrhosis and p16(INK4A) in HCC. In conclusion, a stepwise progression of methylating events is a feature of the sequence cirrhosis-HCC and contributes to the process of hepatic carcinogenesis with potential clinical implications.
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PMID:Methylation framework of cell cycle gene inhibitors in cirrhosis and associated hepatocellular carcinoma. 1214 52

Major etiologic factors associated with human hepatocellular carcinomas (HCCs) include infection with hepatitis C (HCV) and hepatitis B virus (HBV), excess alcohol intake and aflatoxin B(1) exposure. While the G-->T p53 mutation at codon 249 has been identified as a genetic hallmark of HCC caused by aflatoxin B(1), the genetic profile associated with other etiologic factors appears to be less distinctive. In our study, we screened HCCs resulting from HCV infection (51 cases), HBV infection (26 cases) or excess alcohol intake (23 cases) for alterations in genes involved in the RB1 pathway (p16(INK4a), p15(INK4b), RB1, CDK4 and cyclin D1), the p53 pathway (p53, p14(ARF) and MDM2) and the Wnt pathway (beta-catenin, APC). Alterations of the RB1 pathway, mainly p16(INK4a) methylation, loss of RB1 expression and cyclin D1 amplification, were most common (69-100% of cases). There was a significant correlation between loss of RB1 expression and RB1 methylation. All 24 HCCs with RB1 promoter methylation lacked RB1 expression, while none of the 67 cases with RB1 expression exhibited RB1 methylation (p < 0.0001), suggesting that promoter methylation is a major mechanism of loss of RB1 expression in HCCs. Alterations of the p53 pathway consisted mostly of p53 mutations or p14(ARF) promoter methylation (20-48%). Mutations of the p53 gene were found at a similar frequency (13-15%) in all etiologic groups, without any consistent base change or hot spot. Mutations of beta-catenin were found in 13-31% of cases, while no APC mutations were detected in any of the HCCs analyzed. With the exception of only 3 of 39 cases (8%), cyclin D1 amplification and beta-catenin mutations were mutually exclusive, supporting the view that cyclin D1 is a target of the Wnt signaling pathway. Overall, the RB1, p53 and Wnt pathways were commonly affected in HCCs of different etiology, probably reflecting common pathogenetic mechanisms, i.e., chronic liver injury and cirrhosis, but tumors associated with alcoholism had more frequent alterations in the RB1 and p53 pathways than those caused by HCV infection.
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PMID:Alterations of RB1, p53 and Wnt pathways in hepatocellular carcinomas associated with hepatitis C, hepatitis B and alcoholic liver cirrhosis. 1284 70

Hepatocellular carcinoma (HCC) is one of the most fatal human malignancies, but the molecular mechanisms of hepatocarcinogenesis remain unclear. Although p53 mutations are frequently observed in Asian HCC, it is not a common event in Western HCC. Recent studies suggest that tumor suppressor genes (TSGs) can also be silenced through epigenetic disruption, such as promoter CpG island methylation, during carcinogenesis. To further understand the molecular mechanism of hepatocarcinogenesis, we have investigated the promoter methylation status of nine TSGs (SOCS-1, GSTP, APC, E-cadherin, RAR-beta, p14, p15, p16, and p73) in 51 cases of HCC using methylation-specific polymerase chain reaction. We found that 82% of HCCs had methylation of at least one TSG promoter. The most frequently methylated TSGs in HCC were: SOCS-1 (65%), GSTP (54%), APC (53%), E-cadherin (49%), and p15 (49%). Methylation of SOCS-1, GSTP, APC, E-cadherin, and p15 was more frequent in HCC than in nontumor liver (P < 0.05). Methylation of SOCS-1, GSTP, and p15 was also significantly more frequent in HCC than cirrhotic liver (P < 0.05). Although methylation of one or two genes could be seen in both nontumor and cirrhotic livers, 53% of the HCC cases had three or more TSG promoters methylated, in comparison to 0% in nontumor liver and 13% in cirrhosis (P = 0.001). Methylation of SOCS-1, APC, and p15 was more frequently seen in hepatitis C virus-positive HCC than hepatitis C virus/hepatitis B virus-negative HCC. Our data suggest that promoter hypermethylation of TSGs is a common event in HCC and may play an important role in hepatocarcinogenesis.
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PMID:Aberrant promoter methylation profiles of tumor suppressor genes in hepatocellular carcinoma. 1293 51

Hepatocellular carcinoma (HCC) is associated with multiple risk factors and is believed to arise from pre-neoplastic lesions, usually in the background of cirrhosis. However, the genetic and epigenetic events of hepatocarcinogenesis are relatively poorly understood. HCC display gross genomic alterations, including chromosomal instability (CIN), CpG island methylation, DNA rearrangements associated with hepatitis B virus (HBV) DNA integration, DNA hypomethylation and, to a lesser degree, microsatellite instability. Various studies have reported CIN at chromosomal regions, 1p, 4q, 5q, 6q, 8p, 10q, 11p, 16p, 16q, 17p and 22q. Frequent promoter hypermethylation and subsequent loss of protein expression has also been demonstrated in HCC at tumor suppressor gene (TSG), p16, p14, p15, SOCS1, RIZ1, E-cadherin and 14-3-3 sigma. An interesting observation emerging from these studies is the presence of a methylator phenotype in hepatocarcinogenesis, although it does not seem advantageous to have high levels of microsatellite instability. Methylation also appears to be an early event, suggesting that this may precede cirrhosis. However, these genes have been studied in isolation and global studies of methylator phenotype are required to assess the significance of epigenetic silencing in hepatocarcinogenesis. Based on previous data there are obvious fundamental differences in the mechanisms of hepatic carcinogenesis, with at least two distinct mechanisms of malignant transformation in the liver, related to CIN and CpG island methylation. The reason for these differences and the relative importance of these mechanisms are not clear but likely relate to the etiopathogenesis of HCC. Defining these broad mechanisms is a necessary prelude to determine the timing of events in malignant transformation of the liver and to investigate the role of known risk factors for HCC.
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PMID:Review of genetic and epigenetic alterations in hepatocarcinogenesis. 1670 6

Aberrant DNA methylation on CpG islands is one of the most consistent epigenetic changes in human cancers, and the methylation process is catalyzed by DNA methyltransferase (DNMT). We evaluated i) the mRNA levels of three DNMTs; DNMT1, DNMT3a and DNMT3b, in 25 hepatocellular carcinomas (HCCs), in their corresponding non-cancerous liver tissues and in 7 normal livers by using real-time reverse transcriptase-polymerase chain reaction; ii) nuclear expression of DNMT1 and DNMT3a proteins in the HCCs by immunohistochemistry, iii) the methylation status of 5 genes; p16, p15, E-cadherin, HIC-1 and RASSF1A in the same tissues, and iv) the relationships between the above results and the clinicopathological characteristics, including prognosis. The differences in mRNA expression levels for DNMT1, DNMT3a and DNMT3b were statistically significant between HCC and normal livers (p<0.001), HCC and chronic hepatitis (p<0.001) and HCC and cirrhosis (p<0.001). An increase in mRNA expression levels of >4-fold for DNMT3b in HCCs was significantly associated with a poorer overall survival (p=0.027) and shorter metastasis-free survival (p=0.0299). A poorer recurrence-free survival was noted in HCCs with a >4-fold increase in DNMT3a mRNA (p=0.0120). The average numbers of methylated genes were 0, 1.27, 1.38 and 2.72 for normal livers, chronic hepatitis, cirrhosis and HCCs, respectively, and this progressive increase from normal livers to chronic hepatitis/cirrhosis through HCC may suggest that tumor suppressor gene methylation is an early event in hepatocarcinogenesis. These results first suggest that hepatocarcinogenesis involves an increased expression of DNMT1, DNMT3a and DNMT3b mRNA and a progressive increase in the number of methylated genes from normal liver, chronic hepatitis/cirrhosis to HCC and secondly that an increase in the DNMT3a and DNMT3b mRNA levels in HCCs relative to their non-cancerous tissues may be a predictor of poor survival.
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PMID:DNA methyltransferase expression and DNA methylation in human hepatocellular carcinoma and their clinicopathological correlation. 1754 90