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)

Methylation profile was analyzed in eleven cases of therapy-related leukemia (t-leukemia) for p14, p15, p16, Rb, hMLH1, hMSH2, MGMT, APC, RAR beta, DAPK, RIZ1, FHIT, and SOCS-1 genes by using methylation specific polymerase chain reaction (MSP) analysis. Six (55%) of eleven cases showed methylation of at least one gene. The average time to the development of t-leukemia after the treatment of the primary tumor was significantly shorter in patients with methylation than those without methylation (49.3 months vs. 133.2 months, P=0.044). These results suggest that hypermethylation might be involved in the development of t-leukemia.
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PMID:Aberrant methylation in promoter-associated CpG islands of multiple genes in therapy-related leukemia. 1288 5

Cervical cancer is the most common gynecologic malignancy of the developing world. The oncogenic role of human papilloma virus (HPV) is well known. Attention is now focusing on the complicit genetic changes, which allow progression of these tumors. Regarding these changes, deletion of tumor suppressor genes (loss of heterozygosity [LOH]) is the preferred pathway of progression with only a subset manifesting microsatellite instability (MSI). Implicated loci include 3p14.1-22. Several studies suggest that the mutator phenotype in cervical cancer may correlate with higher grade tumors, more advanced disease stage, and poor outcome. Unlike colorectal cancer, in which an inverse relationship has been demonstrated between microsatellite instability and loss of heterozygosity, cervical cancers expressing MSI have been found to coexpress LOH at other loci. In this study we analyzed 8-microsatellite loci including p53, DCC, APC, the MMR gene hMLH1 and 2 regions of interest on chromosome 3 in a high-risk population group in which HPV infection is endemic.
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PMID:Microsatellite analysis of early stage (Ia-IIb) uterine cervical squamous carcinoma. 1461 20

The growing understanding of the epigenetic changes associated with cancer, including aberrant promoter methylation of tumor suppressor genes that afford selective growth advantages to human neoplasms, suggests that the characterization of gene methylation patterns among gastrointestinal stromal tumors (GISTs) may be useful for predicting tumor behavior. Thirty-eight c-kit-positive gastric stromal tumors were subjected to methylation-specific polymerase chain reaction (MSP) to detect promoter methylation associated with 11 candidate tumor suppressor genes (p16/INK4a, APC, MGMT, hMLH1, p73, E-cadherin, RAR-beta, RASSF1A, RB, ER, and DAPK), established to have a role in tumorigenesis of several solid human organs. Aberrant methylation of any of the 11 candidate tumor suppressor genes was detected in 84% of all GISTs. In decreasing order of frequency, the six most commonly methylated genes were: MGMT (47%), p16 (45%), RASSF1A (40%), E-cadherin (37%), hMLH1 (34%), and APC (31%). For all of the GISTs, promoter methylation was less reliable than tumor mitotic rate in predicting 5-year tumor-free survival for the GISTs; however, E-cadherin methylation was a multivariate prognostic factor for early recurrence of GISTs (50% at 2 years; P=0.030). Among the mitotically active (>5 per 50 high-power field), histologically indistinguishable GISTs, E-cadherin methylation was an independent predictor of tumor-related mortality: 5-year disease-free survival was worse for the E-cadherin methylated GISTs (19%) compared to the E-cadherin unmethylated tumors (71%; P=0.010). Detection of methylation within selected genes may afford a reliable and accurate molecular marker system for predicting neoplastic behavior among GISTs. This study supports the methylation status of E-cadherin as a prognostic marker for early GIST recurrence and survival.
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PMID:Tumor suppressor gene hypermethylation as a predictor of gastric stromal tumor behavior. 1467 10

A number of tumor suppressor and tumor-related genes exhibit promoter hypermethylation with resulting gene silencing in human cancers. In addition, several gene promoters have also been shown to become hypermethylated in non-neoplastic cells during aging. To assess the physiological consequence and clinical significance of gene promoter methylation in gastric epithelia, our laboratory has studied the methylation status of tumor suppressor and tumor-related genes, including APC, DAP-kinase, DCC, E-cadherin, GSTP1, hMLH1, p16, PTEN, RASSF1A, RUNX3 and TSLC1, in neoplastic and non-neoplastic gastric epithelia. The tumor suppressor and tumor-related genes, except APC, were generally unmethylated in non-neoplastic gastric epithelia obtained from younger individuals. The frequencies of methylation increased with age to varying degrees in various genes, although GSTP1 and PTEN methylation was completely absent in both neoplastic and non-neoplastic gastric epithelia. The methylation frequencies in each gene were found to be comparable in neoplastic and non-neoplastic gastric epithelia, except the methylation of RUNX3 and TSLC1, which was mostly cancer-specific (P<0.01). When methylation frequencies were compared between non-neoplastic gastric epithelia from cancer-bearing and non-cancer-bearing stomachs, hMLH1 and p16 methylation was more frequent in those from cancer-bearing stomachs (P<0.01). Promoter methylation in tumor suppressor and tumor-related genes initially occurs in non-neoplastic gastric epithelia, increases with age, and ultimately silences gene function to constitute a field-defect that may predispose tissues to gastric cancer evolution. In clinical applications RUNX3 and TSLC1 methylation may be utilized as molecular diagnostic markers, and hMLH1 and p16 methylation as predictors of malignancy in the stomach.
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PMID:Promoter methylation status of tumor suppressor and tumor-related genes in neoplastic and non-neoplastic gastric epithelia. 1470 90

Aberrant DNA methylation patterns may be the earliest somatic genome changes in prostate cancer. Using real-time methylation-specific PCR, we assessed the extent of hypermethylation at 16 CpG islands in DNA from seven prostate cancer cell lines (LNCaP, PC-3, DU-145, LAPC-4, CWR22Rv1, VCaP, and C42B), normal prostate epithelial cells, normal prostate stromal cells, 73 primary prostate cancers, 91 metastatic prostate cancers, and 25 noncancerous prostate tissues. We found that CpG islands at GSTP1, APC, RASSF1a, PTGS2, and MDR1 were hypermethylated in >85% of prostate cancers and cancer cell lines but not in normal prostate cells and tissues; CpG islands at EDNRB, ESR1, CDKN2a, and hMLH1 exhibited low to moderate rates of hypermethylation in prostate cancer tissues and cancer cell lines but were entirely unmethylated in normal tissues; and CpG islands at DAPK1, TIMP3, MGMT, CDKN2b, p14/ARF, and CDH1 were not abnormally hypermethylated in prostate cancers. Receiver operator characteristic curve analyses suggested that CpG island hypermethylation changes at GSTP1, APC, RASSF1a, PTGS2, and MDR1 in various combinations can distinguish primary prostate cancer from benign prostate tissues with sensitivities of 97.3-100% and specificities of 92-100%. Hypermethylation of the CpG island at EDNRB was correlated with the grade and stage of the primary prostate cancers. PTGS2 CpG island hypermethylation portended an increased risk of recurrence. Furthermore, CpG island hypermethylation patterns in prostate cancer metastases were very similar to the primary prostate cancers and tended to show greater differences between cases than between anatomical sites of metastasis.
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PMID:Hypermethylation of CpG islands in primary and metastatic human prostate cancer. 1502 33

Gastric carcinogenesis involves multiple genetic and epigenetic alterations. Epigenetic silencing of tumor-related genes due to CpG island methylation (CIM) has been recently reported in gastric cancer, but the role in precursor lesions is not well understood. We analysed the methylation status of the tumor suppressor gene p16, the DNA mismatch repair gene hMLH1, and four CpG islands (MINT1, MINT2, MINT25, and MINT31) using methylation-specific polymerase chain reaction in 35 polypoid adenomas and 46 flat dysplasias unassociated with carcinoma, 34 early adenocarcinomas (T1N0M0) and associated adenomas/dysplasias, and corresponding adjacent non-neoplastic mucosa. The extent of CIM was defined by the fraction of methylated loci (methylation index), and compared with previously characterized genetic alterations (microsatellite instability (MSI) and APC gene mutation). We found that methylation of p16 was more frequent in adenocarcinoma-associated dysplasias/adenomas (29%) and adenocarcinomas (44%) as compared to flat dysplasias (4%) and adenomas (18%) unassociated with adenocarcinoma (P=0.001). The mean methylation index increased from normal/chronic gastritis (CG) mucosa (0.09) to intestinal metaplasia (IM) (0.16), flat dysplasias (0.40) or polypoid adenomas (0.41) unassociated with carcinoma, dysplasias/adenomas associated with carcinoma (0.44), and adenocarcinomas (0.44). There was no difference in frequencies of high-level CpG island methylation (CIM-H, methylation index > or =0.5) among flat dysplasias (50%) and polypoid adenomas (51%) unassociated with carcinoma, dysplasias/adenomas associated with adenocarcinoma (47%), and adenocarcinoma (47%). CIM-H was present in 15% of IM, but not in normal/CG mucosa. There was a significant correlation between methylation of hMLH1 and high-level of microsatellite instability (MSI-H): methylation of hMLH1 was present in 71% of MSI-H tumors, but only 8% of MSI-low tumors and 13% of microsatellite-stable tumors (P=0.0001). There was no statistical difference between methylation index and APC mutation. Our results indicate that concurrent promoter methylation is an early and frequent event in gastric tumorigenesis, including both MSI-H and microsatellite-stable neoplasms. Methylation of the p16 gene may contribute to the malignant transformation of gastric precursor lesions.
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PMID:Frequent CpG island methylation in precursor lesions and early gastric adenocarcinomas. 1506 7

CpG island hypermethylation is a potential means of inactivating tumor suppressor genes, and many genes have been demonstrated to be hypermethylated and silenced in colorectal cancer. However, limited data is available upon the concurrent methylation of multiple genes in colorectal cancer and in its precursor lesion. To address changes in the methylation profiles of multiple genes during colorectal carcinogenesis, we investigated the methylation of 12 genes (APC, COX-2, DAP-kinase, E-cadherin, GSTP1, hMLH1, MGMT, p14, p16, RASSF1A, THBS1, and TIMP3) in normal colon (n=24), colon adenoma (n=95), and colorectal cancer (n=149), using methylation-specific PCR. The average number of these genes methylated per sample was 0.12, 1.8, and 3.0 in normal colon mucosa, adenoma, and carcinoma, respectively, showing a stepwise increase (P<0.001). All the genes were methylated in colorectal cancer at frequencies varying from 51 to 9.4% and colon adenoma displayed methylation for the 11 genes, except for GSTP1, at frequencies varying from 40 to 1.1%. In contrast, normal colon mucosa demonstrated methylation for APC only, at a frequency of 12.5%. The total number of methylated genes per tumor showed a continuous, nonbimodal distribution in colon adenoma or cancer. CpG island hypermethylation exhibited a proclivity toward proximal colon cancer or adenoma, and the average number of genes methylated was higher in proximal colon cancer or adenoma than in distal colon cancer or adenoma, respectively (3.5 vs 2.6, P=0.018 for cancer, and 2.5 vs 1.4, P=0.003 for adenoma). In conclusion, concurrent CpG island methylation is an early and frequent event during colorectal carcinogenesis. It appears that CpG island methylation plays a more important role in proximal colon cancer development than in distal colon cancer development.
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PMID:Aberrant CpG island hypermethylation of multiple genes in colorectal neoplasia. 1512 5

Neuroendocrine gastroenteropancreatic (GEP) tumors are rare and present with variable clinical syndromes. So far, there are no detailed studies concerning the molecular pathogenesis of sporadic GEP tumors. In our study, GEP tumors from 29 patients were assessed for microsatellite instability, aberrant promoter methylation, and LOH of various tumor suppressor genes. All tumors were microsatellite stable. One tumor showed LOH close to the APC locus, one tumor had an allelic loss near the hMLH1 gene, and one tumor showed hypermethylation of the hMLH1 promoter. Interestingly, none of the tumors was aberrantly methylated at the p16 promoter. However, 13 of 20 successfully amplified tumors (65%) were hypermethylated at the APC promoter. Of the hypermethylated tumors, none showed LOH of either the hMLH1 or the APC gene. The current study is the first report demonstrating that aberrant methylation of the APC promoter is strongly involved in the molecular tumorigenesis of neuroendocrine GEP tumors. MSI does not seem to be involved in the pathogenesis of these cancers. Further studies are required to investigate the role of hypermethylation in neuroendocrine GEP tumors and to further elucidate the role of the APC pathway in these tumors.
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PMID:Analysis of molecular pathways in neuroendocrine cancers of the gastroenteropancreatic system. 1515 37

Methylation profile was analyzed in nine cases of relapsed childhood acute lymphoblastic leukemia (ALL) for p14, p15, p16, Rb, MGMT, APC, hMLH1, RARbeta, RIZ, DAPK, and FHIT genes by using methylation specific polymerase chain reaction (MSP) analysis. Frequency of methylation in each gene was: MGMT, 56%; RARbeta, 44%; and p16, 22%, respectively. None of the p14, p15, Rb, APC, hMLH1, RIZ, DAPK, and FHIT genes were hypermethylated. Five (56%) of 9 cases showed methylation of at least one gene. All of the samples with hypermethylation in p16 and MGMT gene at relapse, had already acquired the change at the time of initial diagnosis. Interestingly, three of 4 cases with RARbeta gene methylation at relapse did not have methylation of this gene at the time of initial presentation. These results suggest that hypermethylation might be involved in the relapse of childhood ALL.
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PMID:Aberrant methylation in promoter-associated CpG islands of multiple genes in relapsed childhood acute lymphoblastic leukemia. 1520 66

The role of microsatellite instability and defects in DNA mismatch repair mechanism in the pathogenesis of gastric lymphoma of mucosa-associated lymphoid tissue (MALT) type is still controversial, as both negative and positive findings have been reported. This may be explained mainly by arbitrary selection of the tested loci, the use of various techniques of microsatellite instability analysis and by different definitions of replication error positive phenotype. The aim of our study was to evaluate the instability at selected microsatellite markers using the GeneScan Analysis Software. DNA from paraffin-embedded tissue blocks of 13 previously untreated patients with localized gastric MALT lymphoma was extracted. Five microsatellite markers, which are located in hMSH2, hMLH1, P16, APC and MLL loci, were selected from the genetic database. We found genetic instability in tumors of 9/13 patients with gastric MALT lymphoma (69%). Seven of them had replication-error-positive phenotype (54%). Microsatellite instability was found in 39% of the samples in the MLL locus, 39% in the APC, 46% in the P16, 23% in the hMLH1 and none in the hMSH2. This study demonstrates that microsatellite instability has more prominent role in pathogenesis of gastric MALT lymphoma than reported to date. We suggest that microsatellite instability should be analyzed with markers adjacent to chromosomal loci that are involved in lymphomas. Our findings support the 'Real Common Target genes' theory of high rate of microsatellite instability in specific genes, which are associated with related tumors.
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PMID:Microsatellite instability in gastric MALT lymphoma. 1527 75


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