Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The polycomb proteins BMI-1, EZH2, and SIRT1 are characteristic components of the PRC1, PRC2, and PRC4 repressor complexes, respectively, that modify chromatin. Moreover, EZH2 may influence DNA methylation by direct interaction with DNA methyltransferases. EZH2 expression increases during prostate cancer progression, whereas BMI-1 and SIRT1 are not well investigated. Like EZH2 expression, DNA methylation alterations escalate in higher stage prostate cancers, raising the question whether these epigenetic changes are related. Expression of EZH2, BMI-1, SIRT1, and the DNA methyltransferases DNMT1 and DNMT3B measured by qRT-PCR in 47 primary prostate cancers was compared to APC, ASC, GSTP1, RARB2, and RASSF1A hypermethylation and LINE-1 hypomethylation. SIRT1 and DNMT3B were overexpressed in cancerous over benign tissues, whereas BMI-1 was rather downregulated and DNMT1 significantly diminished. Nevertheless, cancers with higher DNMT1 and BMI-1 expression had worse clinical characteristics, as did those with elevated EZH2. In particular, above median DNMT1 expression predicted a worse prognosis. EZH2 and SIRT1 overexpression were well correlated with increased MKI67. Immunohistochemistry confirmed limited EZH2 and heterogeneous DNMT3B overexpression and explained the decrease in BMI-1 by pronounced heterogeneity among tumor cells. EZH2 overexpression, specifically among all factors investigated, was associated with more frequent hypermethylation, in particular of GSTP1 and RARB2, and also with LINE-1 hypomethylation. Our data reveal complex changes in the composition of polycomb repressor complexes in prostate cancer. Heterogeneously expressed BMI-1 and slightly increased EZH2 may characterize less malignant cancers, whereas more aggressive cases express both at higher levels. SIRT1 appears to be generally increased in prostate cancers. Intriguingly, our data suggest a direct influence of increased EZH2 on altered DNA methylation patterns in prostate cancer.
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PMID:Expression changes in EZH2, but not in BMI-1, SIRT1, DNMT1 or DNMT3B are associated with DNA methylation changes in prostate cancer. 1863 71

To investigate whether aberrant hypermethylation in plasma DNA could be used as diagnosis makers for hepatocellular carcinoma (HCC), we performed methylation-specific PCR (MSP) to check the methylation status of five tumor associated genes in 36 cases of tissue and 42 cases of plasma samples from HCC and liver cirrhosis patients, respectively. The hypermethylation frequency of GSTP1 and RASSF1A showed significant difference between HCCs and liver cirrhosis with or without HBV infection (P<0.05), but differences of the hypermethylation status of APC, E-cadherin, and P16 were not statistically significant. There were no significant differences in the hypermethylation status of five genes between the groups of cirrhosis with and without HBV infection. The significant differences of E-cadherin, GSTP1, P16, and RASSF1A in methylation between HCCs and liver cirrhosis were not observed in the plasma samples. Furthermore, the inconsistent results of MSP and real-time quantitative PCR for the paired samples of tissue and plasma suggested that plasma DNA could not fully stand for tissue DNA. In conclusion, hypermethylation of some specific, but not all, tumor associated genes may be involved in hepatocarcinogenesis; examination of the methylation status of E-cadherin, GSTP1, P16, and RASSF1A in the plasma samples might have limited usage for HCC diagnosis.
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PMID:Methylation of tumor associated genes in tissue and plasma samples from liver disease patients. 1869 70

Transcriptional deregulation in cancer has been shown to be associated with epigenetic alterations, in particular to tumor-suppressor- gene (TSG) promoters. In contrast, DNA methylation of TSGs is not considered to be present in normal differentiated cells. Nevertheless, we previously showed that the promoter of the tumor-suppressor gene APC is methylated, for one allele only, in normal gastric cells. Recently, RASSF1A has been shown to be imprinted in normal human placenta. To clarify putative TSG methylation in the placenta, 23 normal placental tissues from the first trimester, both decidua and villi, and four normal non-gestational endometrium were screened for DNA methylation by methylation-sensitive single-strand conformation analysis (MS-SSCA) and sequencing after bisulfite modification, on a panel of 12 genes known to be implicated in carcinogenesis. In all placental villi, four TSG promoters-APC, SFRP2, RASSF1A and WIF1-were hypermethylated, whereas all decidua and normal endometrium did not show any methylation. Allele-specific methylation analysis revealed that this methylation was monoallelic. Furthermore, comparison with maternal DNA indicated that APC and WIF1 were methylated on the maternal allele, whereas SFRP2 was methylated on the paternal allele. Sequence analysis of WIF1 mRNA revealed that only the unmethylated paternal allele was transcribed. The imprinting status of these TSGs is conserved during pregnancy. These results indicate that TSG imprinting is pre-existent in normal human placenta and should not be confused with carcinogenesis or pathology-induced methylation.
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PMID:Imprinting of tumor-suppressor genes in human placenta. 1910 45

The current study was conducted to identify robust methylation markers and their combinations that may prove useful for the diagnosis of early hepatocellular carcinoma (HCC). To achieve this, we performed in silico CpG mapping, direct sequencing and pyrosequencing after bisulfite treatment, and quantitative methylation-specific PCR (MSP) in HCC and non-HCC liver tissues. In the filtering group (25 HCCs), our direct sequencing analysis showed that, among the 12 methylation genes listed by in silico CpG mapping, 7 genes (RASSF1A, CCND2, SPINT2, RUNX3, GSTP1, APC and CFTR) were aberrantly methylated in stages I and II HCCs. In the validation group (20 pairs of HCCs and the corresponding non-tumor liver tissues), pyrosequencing analysis confirmed that the 7 genes were aberrantly and strongly methylated in early HCCs, but not in any of the corresponding non- tumor liver tissues (p < 0.00001). The results obtained using our novel quantitative MSP assay correlated well with those observed using the pyrosequencing analysis. Notably, in MSP assay, RASSF1A showed the most robust performance for the discrimination of HCC and non-HCC liver tissues. Furthermore, a combination of RASSF1A, CCND2 and SPINT2 showed 89-95% sensitivity, 91-100% specificity and 89-97% accuracy in discriminating between HCC and non-HCC tissues, and correctly diagnosed all early HCCs. These results indicate that the combination of these 3 genes may aid in the accurate diagnosis of early HCC.
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PMID:Methylation of multiple genes as molecular markers for diagnosis of a small, well-differentiated hepatocellular carcinoma. 1938 46

Renal cell carcinoma (RCC) is the most common malignancy of the kidney. Since RCC is curable when it is confined to the renal capsule, early diagnosis is extremely important. Promoter hypermethylation is the most common mechanism for the inactivation of the tumor suppressor genes (TSG) in the development of human cancer. This study aimed to investigate the methylation profiles of 7 TSG (RASSF1A, ECAD, TIMP3, APC, MGMT, p16 and RARbeta2) in 3 different tissue samples (normal, premalign, malign) of patients with RCC. Twenty-one patients diagnosed with RCC were included in the study. Methylation-specific polymerase chain reaction was performed to detect the methylation patterns of the 7 TSG. High methylation rates for the genes RASSF1A (76%), p16 (80%), ECAD (42%), TIMP3 (33%) and MGMT (33%) were observed in the patients with RCC. The APC (14%) and RARbeta2 (19%) genes showed low methylation rates. In conclusion, 5 TSG (RASSF1A, ECAD, TIMP3, MGMT and p16) showed high methylation rates in RCC patients. A methylation-based gene test including these genes may be useful in the early detection of RCC.
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PMID:Multigene methylation analysis of conventional renal cell carcinoma. 1964 69

Biliary intraepithelial neoplasia (BilIN) is the premalignant lesion of extrahepatic cholangiocarcinoma (EHC), and there are no published data regarding epigenetic changes throughout disease progression from normal biliary epithelia to BilIN to EHC. The objective of this study was to identify the occurrence of CpG island hypermethylation and repetitive DNA hypomethylation in BilIN. A total of 50 EHCs, 31 BilINs, and 31 normal cystic duct samples were analyzed for their methylation status in seven genes and two repetitive DNA elements. The number of methylated genes increased with disease progression (normal bile duct, 0.6; BilIN, 2.0; EHC, 3.6; P < 0.001). The methylation level of examined genes was significantly higher in BilIN than in normal samples (TMEFF2, HOXA1, NEUROG1, and RUNX3, P < 0.05) and in EHC than in BilIN samples (TMEFF2, HOXA1, NEUROG1, RUNX3, RASSF1A, and APC, P < 0.05). Long interspersed nucleotide element-1 (LINE-1) and juxtacentromeric satellite 2 (SAT2) methylation levels were markedly lower in EHC than in normal duct and BilIN samples, and BilIN samples showed a decrease of SAT2 methylation levels but no decrease of LINE-1 methylation levels compared to normal samples. These findings suggest that most of cancer-specific CpG island hypermethylation occur in the stage of BilIN and that CpG island hypermethylation seems to occur earlier than repetitive DNA element hypomethylation.
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PMID:CpG island hypermethylation and repetitive DNA hypomethylation in premalignant lesion of extrahepatic cholangiocarcinoma. 1976 13

In this study, a comparative quantitative methylation profiling of inflammatory breast cancer (IBC) and non-IBC was set up for the identification of tumor-specific methylation patterns. Methylation ratios of six genes (DAPK, TWIST, HIN-1, RASSF1A, RARbeta2 and APC) were measured in benign breast tissues (n = 9) and in tumor samples from non-IBC (n = 81) and IBC (n = 19) patients using quantitative methylation-specific PCR. Median methylation ratios observed in breast cancer (n = 100) were significantly higher than those observed in benign breast tissues for five of six genes (TWIST, HIN-1, RASSF1A, RARbeta2 and APC). Only one of the individual genes studied, RARbeta2, showed differential methylation ratios in IBC and non-IBC (p = 0.016). Using the maximal methylation ratio observed in benign breast tissue as a threshold, the methylation frequency of two genes, RARbeta2 and APC, was significantly increased in IBC (n = 19) when compared to non-IBC (n = 81): 53 vs. 23% for RARbeta2 (p = 0.012) and 84 vs. 54% for APC (p = 0.017). Using hierarchical clustering, methylation patterns could not classify breast cancers according to their phenotype. The finding of differential frequencies of methylation in IBC and non-IBC for two out of six genes suggests that gene-specific patterns of methylation could provide a basis for molecular classification of IBC. Testing for additional genes could help to define the IBC phenotype based on patterns of aberrant gene promoter methylation.
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PMID:Quantitative assessment of DNA hypermethylation in the inflammatory and non-inflammatory breast cancer phenotypes. 1990 21

Hepatoblastoma comprises only 1% of all cancers in childhood. Because of its low frequency, a small number of prognostic factors are described in hepatoblastoma and most of them are related to resectability. Microarray studies showed a large number of underexpressed genes in hepatoblastoma. Because aberrant DNA methylation has been recognized as an alternative mechanism for tumor suppressor gene inactivation, this could be involved with gene downregulation in these tumors. Despite the rarity of hepatoblastoma, this study evaluated the methylation pattern of 25 genes in 20 paraffin-embedded tumor specimens and five non-neoplastic liver samples (normal control) by quantitative methylation-specific PCR (QMSP). The examination of the methylation profile of hepatoblastoma samples and normal liver specimens revealed a high tumor-specific DNA hypermethylation in the promoter regions of five genes (APC, CDH1, MT1G, RASSF1A, and SOCS1). Furthermore, MT1G hypermethylation showed a significant correlation with poor prognosis of patients with hepatoblastoma. This study represents the first quantitative evaluation of promoter hypermethylation in hepatoblastoma and demonstrated that aberrant methylation is a frequent event in this malignancy. Furthermore, our data provide evidence that MT1G hypermethylation may be useful as prognostic indicator for this disease and suggest that patients with hepatoblastoma may benefit from demethylating drug treatments.
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PMID:MT1G hypermethylation: a potential prognostic marker for hepatoblastoma. 2003 11

CpG island methylator phenotype (CIMP) involves methylation targeted toward the promoters of multiple genes. We determined a methylation profile of tumor-related genes in serum of sporadic breast cancer (SBC). The multigene methylation was examined by methylation-specific polymerase chain reaction assay in serum of 50 SBCs and 50 paired nontumors, and CIMP+ was defined as having three genes that are concordantly methylated. The methylation frequency of ten genes in serum of 50 SBCs varied from 10% in FHIT to 74% in RASSF1A. The methylation status of RASSF1A, BRCA1, p16, CDH1, ER, RARbeta2, APC, and DAPK was significantly correlated with SBC and nontumor serum (P < 0.05). Methylation of at least one gene was found in 92% SBC; CIMP was more frequent in SBC than nontumor serum (P < 0.001). There was a significant association between CIMP and methylation of RASSF1A, BRCA1, p16, CDH1, ER, RARbeta2, APC, and DAPK (P < 0.05); the methylation link profile of CDH1, RASSF1A, BRCA1, and RARbeta2 as breast cancer marker may contribute high sensitivity (90%) and specificity (88%). ER and RARbeta2 methylation was associated with elevated serum CA153 levels in 39 SBC samples with CIMP+ (P < 0.05). Multivariate analysis showed that living area of patients was found to provide independent prognostic information associated with a relative risk of tumor recurrence of 5.3. Multigene-specific methylation profile in serum was association with the recurrence risk of rural SBC, and positive correlation of CIMP can serve as a promising molecular marker of SBC.
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PMID:CpG island methylator phenotype of multigene in serum of sporadic breast carcinoma. 2049 Sep 64

Previously, we have shown that methylation-specific PCR (MSP) analysis of a key panel of genes may be useful as an ancillary tool for diagnosing squamous cell carcinomas (SCC) and high-grade squamous intraepithelial lesions (HSIL) in cervical scrapings. Because quantitative MSP (QMSP) is more suitable as a screening tool than conventional MSP, we investigated the diagnostic role of QMSP for the detection of SCC and HSIL in cervical scrapings. A quantitative multiplex-MSP approach was used to examine promoter methylation of five genes (APC, HIN-1, RAR-beta, RASSF1A, and Twist) in biopsy-confirmed SCC (n = 63), HSIL (n = 45), low-grade SIL (LSIL, n = 26), and negative (n = 28) liquid-based cytology samples. For four genes (HIN-1, RAR-beta, RASSF1A, and Twist), the methylation levels among four groups were significantly different (p < 0.001 for each). Methylation levels of HIN-1, RAR-beta, RASSF1A, and Twist were increased in HSIL and SCC samples, compared with either negative or LSIL samples. However, methylation levels were not significantly different between SCC and HSIL, with the exception of RASSF1A. Receiver-operating characteristic analysis demonstrated that HIN-1, RAR-beta, RASSF1A, and Twist had the ability to distinguish HSIL/SCC from LSIL/negative samples. The two-gene combination (RASSF1A/Twist) showed the best performance in distinguishing HSIL/SCC from LSIL/negative samples. The estimated specificity of this two-gene panel for detecting HSIL/SCC was 90.7%, and its sensitivity was 74.1%. These results suggest that quantitative detection of aberrant DNA methylation in cervical scrapings may be a promising high-throughput approach for the diagnosis of HSIL/SCC.
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PMID:Quantitative assessment of DNA methylation for the detection of cervical neoplasia in liquid-based cytology specimens. 2049 80


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