Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with esophageal squamous cell carcinoma (ESCC) frequently develop other primary cancers, such as gastric cancer and head and neck cancer. Details of carcinogenesis in patients with multiple primaries that include esophageal carcinoma with other primary carcinoma (ECOPC) remain uncertain. We examined microsatellite instability (MSI) status, frameshift mutation in target genes of MSI, mismatch repair protein expression and hypermethylation of the hMLH1 promoter region in ECOPC patients to better understand the underlying carcinogenic processes. High frequency MSI (MSI-H) was found in 15 (44.1%) of 34 patients with ECOPC, but in only 6 (14.3%) of 42 patients with esophageal cancer alone (p < 0.01). Frameshift mutations in TGFbetaRII, BAX, MSH3 and MSH6 genes respectively were present in 4, 1, 2 and 2 of 34 ECOPC patients. Immunohistochemical study showed that 12 (80.0%) of 15 MSI-H tumors showed loss of expression of either hMLH1 or hMSH2. In addition, 6 of 9 tumors (66.7%) that showed reduced hMLH1 expression also had hypermethylation of the hMLH1 promoter region. Our findings suggested that carcinogenesis in ECOPC was closely associated with the MSI pathway because of mismatch repair protein deficiency.
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PMID:Frequent microsatellite instability in primary esophageal carcinoma associated with extraesophageal primary carcinoma. 1554 Feb 18

Mutations in the PTEN gene are frequent in endometrial carcinoma. PTEN methylation is an alternative mechanism of gene inactivation. To elucidate different mechanisms of PTEN gene inactivation, we have studied a population-based series of endometrial carcinomas for PTEN mutations in relation to clinicopathologic characteristics, promoter methylation and protein expression. PTEN mutations were found in 54%, mainly in exons 5 and 8; with at least two different mutations in 21%. Presence of PTEN mutation was significantly correlated with young age, low FIGO-stage, endometrioid subtype, low grade, microsatellite instability and favourable prognosis. Previous studies of these tumours have observed PTEN methylation in 18% and low protein expression in 20%. Low expression of PTEN-antibody 6H2.1 was correlated with the presence of mutations in exon 8 among patients with 'two hits'; i.e. > or =2 mutations, or mutation(s) plus methylation (p=0.001). Number of PTEN hits was significantly associated with microsatellite instability, low hMLH1 expression and hMLH1 methylation. Thus, PTEN mutations are frequent in sporadic endometrial carcinoma and define a prognostically favourable subgroup, whereas the relationship with PTEN protein expression is complex. A pathway in endometrial carcinogenesis involving PTEN mutation and microsatellite instability is confirmed, and this study also indicates the importance of PTEN and hMLH1 methylation in this pathway.
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PMID:Significance of PTEN alterations in endometrial carcinoma: a population-based study of mutations, promoter methylation and PTEN protein expression. 1554 98

Cholangiocarcinoma is a crucial health problem in Northeast Thailand where liver fluke infection is endemic. However, molecular genetic and epigenetic mechanisms involved in carcinogenesis of this cancer remain unclear. We attempted to study genetic and epigenetic alterations of hMLH1 gene in 65 intrahepatic cholangiocarcinoma using polymerase chain reaction (PCR) based microsatellite marker D3S1611 and methylation-specific PCR, respectively. Of 65 cases, 29 (44.6%) showed hypermethylation of hMLH1 promoter. Loss of heterozygosity (LOH) of hMLH1 was detected in 12 of 51 informative cases (23.5%). Five out of 29 (17.2%) methylated cases demonstrated LOH. Aberrant methylation of hMLH1 promoter was significantly associated with poorly differentiated type (P=0.013). Our study suggests that both genetic and epigenetic mechanisms cause the inactivation of hMLH1 where epigenetic is a major event resulting in mismatch repair deficiency and contributing to carcinogenesis of liver fluke related cholangiocarcinoma. Since, gene silencing by methylation is an early event in carcinogenesis, promoter hypermethylation of hMLH1 may be a molecular targeted therapy and prevention of liver fluke related cholangiocarcinoma.
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PMID:Promoter hypermethylation is a major event of hMLH1 gene inactivation in liver fluke related cholangiocarcinoma. 1561 39

The Raf/MEK/ERK (MAPK) signal transduction cascade is an important mediator of a number of cellular fates including growth, proliferation and survival. The BRAF gene is activated by oncogenic Ras, leading to cooperative effects in cells responding to growth factor signals. Our study was performed to elucidate a possible function of BRAF in ulcerative colitis (UC)-related colorectal carcinogenesis. Mutations of BRAF and KRAS were determined in 33 UC-related colorectal cancers by direct DNA sequencing analyses after microdissection. Mismatch-repair deficiency was assessed by immunohistochemistry for major mismatch-repair proteins hMLH1, hMSH2 and hMSH6 and microsatellite analyses of the BAT25 and BAT26 loci. Hypermethylation of the hMLH1 promoter was also tested. The results obtained were correlated with histopathologic variables. Activating BRAF missense mutations were identified in 3/33 UC-related cancers (9%), 2 of which exhibited a loss of hMLH1-protein expression and hypermethylation of the hMLH1 promoter. Corresponding nondysplastic UC-mucosa of these patients did not show BRAF mutations. KRAS mutations were found in 6/33 (18%) UC cancers. All 6 UC cancers with KRAS mutations had an intact BRAF gene as the 3 cancers with BRAF mutations had an intact KRAS gene. There was no significant correlation between BRAF or KRAS status and clinicopathologic variables. Our data indicate that BRAF mutations are not an initiating event in UC-related carcinogenesis and are associated with mismatch-repair deficiency through hMLH1-promoter hypermethylation. Disruption of the Raf/MEK/ERK (MAPK) kinase pathway-either through RAS or BRAF mutation-was detected in 27% of all UC-related cancers and thus plays an important role in UC-related carcinogenesis.
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PMID:Mutations of the BRAF gene in ulcerative colitis-related colorectal carcinoma. 1570 57

A distinctive pathway of colorectal carcinogenesis termed CpG island methylator phenotype is characterized by extensive DNA methylation in colorectal carcinoma (CRC) cells but not in nonneoplastic mucosa. Many CRCs with CpG island methylator phenotype have methylation of the hMLH1 mismatch repair gene and consequently have high levels of microsatellite instability (MSI-H). MSI-H confers distinctive clinical-pathologic features, but the phenotype of microsatellite-stable CRC with methylation has not been characterized in detail. We therefore examined the clinical-pathologic features of 87 sporadic microsatellite-stable CRCs that had been characterized for methylation of p16, p14, MGMT, hMLH1, MINT1, MINT2, and MINT31. Regression analyses of each clinical-pathologic characteristic were run against the individual and aggregated methylation markers to evaluate and quantify associations. CpG island methylation was associated with right-sided carcinoma (odds ratio = 6.9, P = 0.03). Paucity of gland formation, indicating poor differentiation, was strongly associated with methylation (beta = -42.6, P = 0.0008), as were presence of cribriform glands (beta = 34.3, P = 0.02) and lack of corkscrew/serrated glandular pattern (beta = -32.5, P = 0.03). Our epigenotype-phenotype correlation study shows that microsatellite-stable CRC with CpG island methylation have a distinctive pathologic phenotype with both similarities to and differences from MSI-H tumors.
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PMID:Phenotype of microsatellite-stable colorectal carcinomas with CpG island methylation. 1576 94

Microsatellite instability (MSI) constitutes an alternative-to the chromosomal instability-pathway of carcinogenesis for certain tumour types with prognostic and therapeutic significance for the respective patients. MSI is caused by mutations in mismatch repair (MMR) genes, mainly hMLH1, hMSH2, leading to a defective MMR system. The role of MSI in basal cell carcinoma (BCC) has not been clearly delineated yet. p53 gene as a target for ultraviolet radiation-induced mutations may enhance genomic instability in BCC, with loss of its function. Our aim was to investigate the involvement of MSI and expression of hMLH1 and hMSH2 in parallel with P53 protein accumulation in the pathogenesis of BCC and its possible correlation to the clinicopathological features of the patients. The presence of MSI was investigated in 76 BCCs using mononucleotide microsatellite markers, BAT-25, BAT-26 and TGF-beta receptor type II (TGF-beta-RII). Additionally, 3 dinucleotide markers were analysed in 20 cases in which matched normal tissue was available. The expression of hMLH1, hMSH2 and P53 proteins was evaluated by immunohistochemical analysis. Alterations of the BAT-26 marker were observed in one fibroepithelioma of Pincus, one nodular and one multifocal superficial BCC. A keratotic BCC showed an altered BAT-25 locus. Two samples, a multifocal superficial and a nodular BCC, displayed MSI at two markers (BAT-25 and BAT-26; and BAT-25 and TGF-beta-RII, respectively). Three more cases, a metatypical, a multifocal superficial and a signet ring BCC exhibited frameshift mutations in the TGF-beta-RII. No sample showed length alterations at the dinucleotide markers examined. hMLH1 and hMSH2 protein immunohistochemical expression was scored positive in 46 and 49 out of 52 cases respectively. P53 accumulation was observed in 27 out of 56 samples. Correlation of the molecular and immunohistochemical findings with the clinicopathological parameters produced no statistically significant results. No correlation between MSI and hMLH1, hMSH2 or P53 protein expression was determined. MSI appears to play a minor role in the pathogenesis of BCCs being present only in a small subset of such tumours.
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PMID:Expression of mismatch repair enzymes, hMLH1 and hMSH2 is not associated with microsatellite instability and P53 protein accumulation in basal cell carcinoma. 1601 76

Hypermethylation of CpG islands near gene promoter regions is associated with transcriptional inactivation and represents an important mechanism of gene silencing in carcinogenesis. Such epigenetic phenomena can act alongside DNA mutations and deletions to disrupt tumor-suppressor gene function. The methylation status of the promoter-associated CpG islands from 11 well-characterized cancer-related genes was analyzed by methylation-specific polymerase chain reaction in 60 adult patients with acute myelogenous leukemia (AML) at diagnosis. The frequency of aberrant methylation among the patient samples was 45.0% (27/60) for suppressor of cytokine signaling-1, 31.7% (19/60) for p15, 20.0% (12/60) for retinoic acid receptor beta2, 13.3% (8/60) for p73 and E-cadherin, 5.0% (3/60) for O(6)-methylguanine DNA methyltransferase, 3.3% (2/60) for death-associated protein kinase 1 and hMLH1, 1.7% (1/60) for p16, and 0% (0/60) for the tissue inhibitor of matrix metalloproteinases-3 and Ras association domain family 1A. Aberrant DNA methylation was found in AML of all French-American-British subtypes and throughout all cytogenetic risk groups. There appeared to be a trend towards a higher methylation frequency in AML patients with an unfavorable karyotype, but this difference was not statistically significant. Our data indicate that hypermethylation of multiple genes involving fundamental cellular pathways is a common event in AML, which varies greatly in frequency among the genes examined. The accumulation of epigenetic events affecting genes which are involved in regulating cell cycle inhibition, cell adhesion, growth factor signaling, and apoptosis may contribute to the malignant AML phenotype. The growing knowledge of the role of epigenetics in the aberrant silencing of cancer-related genes provides a rationale and molecular basis for targeted therapeutic approaches with demethylating agents in AML.
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PMID:Clinical implications of aberrant DNA methylation patterns in acute myelogenous leukemia. 1623 Nov 40

The development and progression of gastric cancer involves a number of genetic and epigenetic alterations of tumor suppressor and tumor-related genes. The majority of differentiated carcinomas arise from intestinal metaplastic mucosa and exhibit structurally altered tumor suppressor genes, typified by p53, which is inactivated via the classic two-hit mechanism, i.e. loss of heterozygosity (LOH) and mutation of the remaining allele. LOH at certain chromosomal loci accumulates during tumor progression. Approximately 20% of differentiated carcinomas show evidence of mutator pathway tumorigenesis due to hMLH1 inactivation via hypermethylation of promoter CpG islands, and exhibit high-frequency microsatellite instability. In contrast, undifferentiated carcinomas rarely exhibit structurally altered tumor suppressor genes. For instance, while methylation of E-cadherin is often observed in undifferentiated carcinomas, mutation of this gene is generally associated with the progression from differentiated to undifferentiated carcinomas. Hypermethylation of tumor suppressor and tumor-related genes, including APC, CHFR, DAP-kinase, DCC, E-cadherin, GSTP1, hMLH1, p16, PTEN, RASSF1A, RUNX3, and TSLC1, can be detected in both differentiated and undifferentiated carcinomas at varying frequencies. However, the significance of the hypermethylation varies according to the analyzed genomic region, and hypermethylation of these genes can also be present in non-neoplastic gastric epithelia. Promoter demethylation of specific genes, such as MAGE and synuclein Y, can occur during the progressive stages of both histological types, and is associated with patient prognosis. Thus, while the molecular pathways of gastric carcinogenesis are dependent on histological background, specific genetic alterations can still be used for risk assessment, diagnosis, and prognosis.
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PMID:Alterations of tumor suppressor and tumor-related genes in the development and progression of gastric cancer. 1648 17

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.
Carcinogenesis 2006 Jun
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


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