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)

Recent studies indicate that tumor suppressor genes can be epigenetically silenced through promoter hypermethylation. To further understand epigenetic alterations in cholangiocarcinoma, we have studied the methylation profiles of 12 candidate tumor suppressor genes (APC, E-cadherin/CDH1, MGMT, RASSF1A, GSTP, RAR-beta, p14ARF, p15INK4b, p16INK4a, p73, hMLH1 and DAPK) in 72 cases of cholangiocarcinoma, including equal number cases of intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma. A total of 10 cases of benign biliary epithelia were included as controls. The methylation status of tumor suppressor genes was analyzed using methylation-specific PCR. We found that 85% of all cholangiocarcinomas had methylation of at least one tumor suppressor gene. The frequency of tumor suppressor gene methylation in cholangiocarcinoma was: RASSF1A (65%), p15INK4b (50%), p16INK4a (50%), APC (46%), E-cadherin/CDH1 (43%), p14(ARF) (38%), p73 (36%), MGMT (33%), hMHL1 (25%), GSTP (14%), RAR-beta (14%) and DAPK (3%). Although single tumor suppressor gene methylation can be seen in benign biliary epithelium, methylation of multiple tumor suppressor genes is only seen in cholangiocarcinoma. About 70% (50/72) of the cholangiocarcinomas had three or more tumor suppressor genes methylated and 52% (38/72) of cases had four or more tumor suppressor genes methylated. Concerted methylation of multiple tumor suppressor genes was closely associated with methylation of RASSF1A, p16 and/or hMHL1. Methylation of RASSF1A was more common in extrahepatic cholangiocarcinoma than intrahepatic cholangiocarcinoma (83 vs 47%, P=0.003) while GSTP was more frequently seen in intrahepatic compared to extrahepatic cholangiocarcinoma (31 vs 6%, P=0.012). Our study indicates that methylation of promoter CpG islands of tumor suppressor genes is a common epigenetic event in cholangiocarcinoma. Based on distinct methylation profiles, intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma are two closely related but biologically unique neoplastic processes. Taking advantage of the unique concurrent methylation profile of multiple genes in cholangiocarcinoma may facilitate the distinction of cholangiocarcinoma from benign biliary epithelium in clinical settings.
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PMID:Promoter methylation profiles of tumor suppressor genes in intrahepatic and extrahepatic cholangiocarcinoma. 1546 12

Promoter hypermethylation represents a primary mechanism in the inactivation of tumor suppressor genes during tumorigenesis. We analyzed the promoter methylation status of eight tumor-associated genes (p14 ARF, p15 INK4B, p16 INK4A, Rb, hMLH1, hMSH2, APC, and DAPK) in 30 patients with myelofibrosis with myeloid metaplasia (MMM) by methylation specific PCR. The study showed no hypermethylation of the promoters of p16(INK4A), Rb, hMLH1, hMSH2, APC, and DAPK genes. The p14 ARF, p15 INK4B promoters were hypermethylated in only one patient each. This study indicates that, although methylation of these genes is important in other cancers, it is rare in MMM and causation of this disease should be focused elsewhere.
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PMID:Methylation analysis of the cell cycle control genes in myelofibrosis with myeloid metaplasia. 1575 3

A subset of sporadic colon cancers has been shown to have microsatellite instability caused by an epigenetic inactivation of the MLH1 gene by hypermethylation of the the CpG island in its promoter region. We report here that in colorectal cancer, inactivation of the MLH1 gene is frequently accompanied by hypermethylation of the CpG island in the promoter of the mitotic gene checkpoint with forkhead and ring finger domains (CHFR). This was first observed in the colon cancer cell lines HCT-116, DLD-1, RKO and HT29. Among the 61 primary colon cancer samples studied, hypermethylation of the MLH1 and the CHFR promoter was found in 31% of the tumors. In 68% of all primary cancers (13/19) with MLH1 promoter hypermethylation, hypermethylation of the CHFR promoter was observed as well (P-value < 0.0001, Fisher's two-sided exact). Hypermethylation of the HLTF, MGMT, RASSF1, APC, p14 and p16 promoter regions were also frequent events, being observed in 48% (28/58), 40% (26/64), 21% (14/64), 50% (31/62), 43% (26/60) and 56% (35/63), respectively. However, methylation of these genes was not associated with methylation of either MLH1 or CHFR. The observed methylation profile was unrelated to Duke's stage. The coordinated loss of both mismatch repair caused by methylation of MLH1 and loss of checkpoint control associated with methylation of CHFR suggests the potential to overcome cell cycle checkpoints, which may lead to an accumulation of mutations.
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PMID:CHFR promoter hypermethylation in colon cancer correlates with the microsatellite instability phenotype. 1576 Sep 19

Patients with Barrett's esophagus (BE) are at increased risk of developing esophageal adenocarcinoma (EAC). Clinical neoplastic progression risk factors, such as age and the length of the esophageal BE segment, have been identified. However, improved molecular biomarkers predicting increased progression risk are needed for improved risk assessment and stratification. Using real-time quantitative methylation-specific PCR, we screened 10 genes (HPP1, RUNX3, RIZ1, CRBP1, 3-OST-2, APC, TIMP3, p16, MGMT, p14) for promoter hypermethylation in 77 EAC, 93 BE, and 64 normal esophagus (NE) specimens. A subset of genes manifesting significant differences in methylation frequencies between BE and EAC was then analysed in 20 dysplastic specimens. All 10 genes except p14 were frequently methylated in EACs, with RUNX3, HPP1, CRBP1, RIZ1, and OST-2 representing novel methylation targets in EAC and/or BE. p16, RUNX3, and HPP1 displayed increasing methylation frequencies in BE vs EAC. Furthermore, these increases in methylation occurred early, at the interface between BE and low-grade dysplasia (LGD). To demonstrate the silencing effect of hypermethylation, we selected the EAC cells BIC1, in which the HPP1 promoter is natively methylated, and subjected them to 5-aza-2'-deoxycytidine (Aza-C) treatment. Real-time RT-PCR indicated increased HPP1 mRNA levels after 3 days of Aza-C treatment, as well as decreased levels of methylated HPP1 DNA. Hypermethylation of a subset of six genes (APC, TIMP3, CRBP1, p16, RUNX3, and HPP1) was then tested in a retrospective longitudinal study of 99 BE and nine LGD specimens obtained from 53 BE patients undergoing surveillance endoscopy. Only high-grade dysplasia (HGD) or EAC were defined as progression end points. Two patient groups were compared: eight progressors (P) and 45 nonprogressors (NP), using Cox proportional hazards models to determine the relative progression risks of age, BE segment length, and methylation events. Multivariate analyses revealed that only hypermethylation of p16 (odds ratio (OR) 1.74, 95% confidence interval (CI) 1.33-2.20), RUNX3 (OR 1.80, 95% CI 1.08-2.81), and HPP1 (OR 1.77, 95% CI 1.06-2.81) were independently associated with an increased risk of progression, whereas age, BE segment length, and hypermethylation of TIMP3, APC, or CRBP1 were not independent risk factors. In combined analyses, risk was detectable up to, but not earlier than, 2 years preceding neoplastic progression. Hypermethylation of p16, RUNX3, and HPP1 in BE or LGD may represent independent risk factors for the progression of BE to HGD or EAC. These findings have implications regarding risk stratification, early EAC detection, and the appropriate endoscopic surveillance interval for patients with BE.
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PMID:Inactivation of p16, RUNX3, and HPP1 occurs early in Barrett's-associated neoplastic progression and predicts progression risk. 1582 39

Methylation profile was analyzed in 10 childhood acute lymphoblastic leukemia (ALL) and nine adult ALL cases. Four genes (p15, p16, RARbeta, FHIT) had methylation in both diseases, four genes (p14, Rb, MLH1, DAPK) showed no methylation in both diseases, and the two genes (APC, RIZ) demonstrated methylation only in adult ALL. Methylation of the RARbeta was more frequent in adult ALL than that in childhood ALL (p=0.01). The number of patients with methylation of multiple genes was higher in adult ALL than that in childhood ALL (p=0.006). Moreover, overall frequency of methylation was higher in adult ALL than that in childhood ALL (p=0.01).
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PMID:Aberrant methylation in promoter-associated CpG islands of multiple genes in acute lymphoblastic leukemia. 1603 15

To evaluate the significance of alterations in DNA methylation during multistage carcinogenesis of the pancreas, tissue samples of 13 peripheral pancreatic duct epithelia showing no remarkable histological changes without inflammatory background (DE), 20 peripheral pancreatic duct epithelia showing no remarkable histological changes with inflammatory background (DEI), 40 pancreatic intraepithelial neoplasias (PanIN) and 147 areas of ductal carcinoma were microdissected from surgically resected specimens from 58 patients and were embedded into agarose beads. The embedded tissue samples were subjected to methylation-specific PCR (MSP) to evaluate the DNA methylation status of the p14, p15, p16, p73, APC, hMLH1, MGMT, BRCA1, GSTP1, TIMP-3, CDH1 and DAPK-1 genes. The prevalence of DNA methylation of at least one of the 12 genes and the average number of methylated genes were significantly higher in both DEI (60% and 0.85 +/- 0.88, P = 0.0151 and P = 0.0224, respectively) and PanIN (67.5% and 0.95 +/- 0.85, P = 0.0014 and P = 0.0028, respectively) than in DE (15.4% and 0.15 +/- 0.38), and were further increased in ductal carcinoma (98.3% and 2.50 +/- 1.35, P < 0.0001 and P < 0.0001, respectively). The BRCA1, APC, p16 and TIMP-3 genes were frequently methylated in ductal carcinoma (60.3, 58.6, 39.3 and 30.9%, respectively). Considerable heterogeneity of DNA methylation status was observed among multiple microdissected areas from individual ductal carcinomas, and the number of methylated genes per area was significantly correlated with poorer tumor differentiation (P = 0.0249). The average number of methylated genes in ductal carcinomas was significantly correlated with DNMT1 protein expression level (P = 0.0093). These data suggest that accumulation of DNA methylation of multiple tumor-related genes is involved in multistage carcinogenesis of the pancreas from early precancerous stages to malignant progression and that DNMT1 protein overexpression may be responsible for this aberrant DNA methylation.
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PMID:DNA methylation of multiple tumor-related genes in association with overexpression of DNA methyltransferase 1 (DNMT1) during multistage carcinogenesis of the pancreas. 1653 62

Small bowel adenocarcinoma (SB-AC) is a very rare tumor entity. Epigenetic alterations, including hypermethylation of DNA mismatch repair genes and tumor suppressor genes, seem to be important for carcinogenesis in tumors of the gastrointestinal tract, but have not yet been investigated in SB-AC. In the current study, the prevalence of hypermethylation in a panel of genes involved in gastrointestinal carcinogenesis (hMLH1, HPP1, p14(ARF), p16(INK4A), APC) was determined in a series of SB-AC. Paraffin-embedded tumor samples from 56 patients with SB-AC who underwent surgical resection between January 1985 and December 2003 were investigated for hypermethylation by means of methylation-specific real-time PCR, and compared with our findings in a previously investigated series of 50 gastric adenocarcinomas. In comparison with adenocarcinomas of the stomach, SB-AC revealed a significantly higher rate of hypermethylation of HPP1 (86% versus 54%, p = 0.0003), p16(INK4A) (32% versus 10%, p = 0.0006), and a significantly lower rate of hypermethylation of APC (48% versus 84%, p = 0.0001). Hypermethylation of hMLH1 and p14(ARF) was present in 23% and 9% of SB-AC, respectively. Locally advanced tumor categories (pT3/4) showed a higher rate of hypermethylation of HPP1 (90%) than did early tumor categories (pT1/2 categories, 40%; p = 0.0036). This was also reflected by the correlation between the HPP1 hypermethylation and high UICC stage (p = 0.02). No correlation was found between hypermethylation and other clinicopathologic parameters such as age, tumor grade and nodal status. Our findings suggest that hypermethylation of hMLH1, HPP1, p16(INK4A) and APC is frequent in primary adenocarcinomas of the small bowel. The differences in the hypermethylation spectrum of small bowel and stomach cancer indicate significant epigenetic differences between these tumors.
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PMID:Hypermethylation of hMLH1, HPP1, p14(ARF), p16(INK4A) and APC in primary adenocarcinomas of the small bowel. 1661 16

To clarify distinct genetic profiles of colorectal cancers based on tumor location (left- and right-sided), we evaluated the status of loss of heterozygosity (LOH), CpG islands methylation phenotype (CIMP), microsatellite instability (MSI), and mutations of p53, Ki-ras, and APC genes in 119 colorectal cancers. Statuses of LOH (at 5q, 8p, 17p, 18q, and 22q), MSI, and CIMP (MINT1, MINT2, MINT31, MLH-1, MGMT, p14, p16, and RASSF1A) were determined using microsatellite polymerase chain reaction and methylation-specific polymerase chain reaction coupled with a crypt isolation method, respectively. In addition, mutations of p53, Ki-ras, and APC genes were also examined. LOH, MSI, and CIMP status allowed us to classify samples into two groups: low or negative and high or positive. Whereas the frequency of p53 mutations in the LOH-high status was significantly higher in left-sided cancers than in right-sided cancers, CIMP-high in the LOH-high status and MSI-positive status were more frequently found in right-sided cancers compared with left-sided cancers. Finally, location-specific methylated loci were seen in colorectal cancers: type I (dominant in right-sided cancer) and type II (common in both segments of cancer). Our data confirm that distinct molecular pathways to colorectal cancer dominate in the left and right sides of the bowel.
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PMID:Analysis of molecular alterations in left- and right-sided colorectal carcinomas reveals distinct pathways of carcinogenesis: proposal for new molecular profile of colorectal carcinomas. 1664 5

The simian virus SV40 (SV40), a potent DNA oncogenic polyomavirus, has been detected in several human tumors including lymphomas, mainly in diffuse large B-cell type (DLBCL). However, a causative role for this virus has not been convincingly established. Hypermethylation in promoter regions is a frequent process of silencing tumor suppressor genes (TSGs) in cancers, which may be induced by oncogenic viruses. In this study, we investigated the relationship between the presence of SV40 DNA sequences and the methylation status of 13 TSGs in 108 DLBCLs and 60 nontumoral samples from Tunisia. SV40 DNA presence was investigated by PCR assays targeting the large T-antigen, the regulatory and the VP1 regions. Hypermethylation was carried out by methylation-specific PCR. SV40 DNA was detected in 63/108 (56%) of DLBCL and in 4/60 (6%) of nontumoral samples. Hypermethylation frequencies for the tested TSGs were 74% for DAPK, 70% for CDH1, SHP1, and GSTP1, 58% for p16, 54% for APC, 50% for p14, 39% for p15, 19% for RB1, 15% for BLU, 3% for p53, and 0% for p300 and MGMT. No hypermethylation was observed in nontumoral samples. Hypermethylation of SHP1, DAPK, CDH1, GSTP1 and p16 genes were significantly higher in SV40-positive than in SV40-negative DLBCL samples (p values ranging from 0.0006 to <0.0001). Our findings showed a high prevalence of SV40 DNA in DLBCLs in Tunisia. The significant association of promoter hypermethylation of multiple TSGs with the presence of SV40 DNA in DLBCLs supports a functional effect of the virus in those lymphomas.
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PMID:Presence of simian virus 40 DNA sequences in diffuse large B-cell lymphomas in Tunisia correlates with aberrant promoter hypermethylation of multiple tumor suppressor genes. 1772 19

We analysed chromosomal copy number aberrations (CNAs) in renal cell carcinomas by array-based comparative genomic hybridization, using a genome-wide scanning array with 2304 BAC and PAC clones covering the whole human genome at a resolution of roughly 1.3 Mb. A total of 30 samples of renal cell carcinoma were analysed, including 26 cases of clear cell carcinoma (CCC) and four cases of chromophobe renal cell carcinoma (ChCC). In CCCs, gains of chromosomes 5q33.1-qter (58%), 7q11.22-q35 (35%) and 16p12.3-p13.12 (19%), and losses of chromosomes 3p25.1-p25.3 (77%), 3p21.31-p22.3 (81%), 3p14.1-p14.2 (77%), 8p23.3 (31%), 9q21.13-qter (19%) and 14q32.32-qter (38%) were detected. On the other hand, the patterns of CNAs differed markedly between CCCs and ChCCs. Next, we examined the correlation of CNAs with expression profiles in the same tumour samples in 22/26 cases of CCC, using oligonucleotide microarray. We extracted genes that were differentially expressed between cases with and without CNAs, and found that significantly more up-regulated genes were localized on chromosomes 5 and 7, where recurrent genomic gains have been detected. Conversely, significantly more down-regulated genes were localized on chromosomes 14 and 3, where recurrent genomic losses have been detected. These results revealed that CNAs were correlated with deregulation of gene expression in CCCs. Furthermore, we compared the patterns of genomic imbalance with histopathological features, and found that loss of 14q appeared to be a specific and additional genetic abnormality in high-grade CCC. When we compared the expression profiles of low-grade CCCs with those of high-grade CCCs, differentially down-regulated genes tended to be localized on chromosomes 14 and 9. Thus, it is suggested that copy number loss at 14q in high-grade CCC may be involved in the down-regulation of genes located in this region.
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PMID:High-resolution analysis of DNA copy number alterations and gene expression in renal clear cell carcinoma. 1792 74


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