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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In urothelial cancer, hypermethylation of specific genes and genome-wide hypomethylation, reflected in decreased methylation of LINE-1 retrotransposons, have both been reported, but were never investigated in the same specimens. We analyzed hypermethylation of six genes by methylation-specific PCR and LINE-1 hypomethylation by Southern blotting in 96 carcinoma tissues. Hypermethylation frequencies were: SFRP1 (55%), APC (45%), RASSF1A (35%), DAPK1 (29%), RARB2 (19%), and CDKN2A (2%). Three groups of cancers could be discerned, with escalating hypermethylation. Hypermethylation increased with tumor stage, particularly at the transition to invasive cancers, and RARB2 hypermethylation was indicative of lymph node involvement. A comparison to a previous study on prostate cancer using the same techniques suggests that hypermethylation in urothelial carcinoma occurs in a random rather than coordinated manner. LINE-1 hypomethylation was present in 90% of specimens, largely independent of hypermethylation. Lack of hypomethylation indicated a significantly better clinical prognosis. Bisulfite sequencing of SFRP1 demonstrated dense or patchy hypermethylation in tumor tissues that likely accounts for discrepant reported frequencies. In urothelial carcinoma cell lines, the same genes as in tissues were frequently hypermethylated. SFRP1 hypermethylation was concordant with lack of expression. 5-Aza-deoxycytidine induced its reexpression in some lines, whereas additional treatment with a histone deacetylase inhibitor was required in others. Thus, epigenetic SFRP1 inactivation occurs in a graduated manner. In conclusion, markers of genome-wide hypomethylation seem optimally suited for urothelial carcinoma detection, whereas combinations of hypermethylation and hypomethylation assays hold promise for classification.
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PMID:DNA methylation alterations in urothelial carcinoma. 1677 27

Several studies have suggested that hypermethylation and hypomethylation of CpG islands within the promoters and 5' exons of tumor-related genes are closely associated with carcinogenesis. However, large-scale analysis of candidate genes has been hampered by the lack of a high throughput approach for analyzing methylation patterns. Using methylation-specific oligonucleotide (MSO) chips, we evaluated the methylation patterns of eight samples of fresh frozen glioblastoma tissue. The MSO chip used contained DNA probes with the CpG sites of p16 (p16INK4A, CDKN2A), MGMT (O6-Methylguanine-DNA-methyltransferase), APC (adenomatous polyposis coil), RASSF1A (human RAS effect homolog), which are usually hypermethylated in cancer cells and MAGE (melanoma antigen), which is usually hypomethylated in cancer cells. We selected CpG sites for analysis; 28 CpG sites (263 bp) for p16, 26 CpG sites (249 bp) for MGMT, 16 CpG sites (195 bp) for APC, 22 CpG sites (262 bp) for RASSF1A and 18 CpG sites (235 bp) for MAGE. We then constructed primer sets not including CpG sites. Bisulfite modification of genomic DNA, methylation specific PCR, hybridization and image scan with data analysis and sequencing of the bisulfite modified DNA were carried out. Of the eight glioblastomas, hypermethylation of the 5'-CpG sites of the MGMT were found in two, RASSF1A were found in five, and p16 and APC genes were not found in any cases and hypomethylation of that of the MAGE was found in eight cases. These results obtained from the oligo DNA chip study were correlated well with the sequencing data of bisulfite modified genomic DNA except in regard to the RASSF1A and MAGE genes. The devised MSO DNA chip is a useful tool for studies on methylation.
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PMID:Oligonucleotide DNA chips are useful adjuncts in epigenetic studies of glioblastomas. 1708 Jul 17

High-risk human papillomavirus (hrHPV)-induced immortalization and malignant transformation are accompanied by DNA methylation of host genes. To determine when methylation is established during cell immortalization and whether it is hrHPV-type dependent, DNA methylation was studied in a large panel of HPVE6E7-immortalized keratinocyte cell lines. These cell lines displayed different growth behaviors, i.e., continuous growth versus crisis period prior to immortalization, reflecting differential immortalization capacities of the 7 HPV-types (16/18/31/33/45/66/70) studied. In this study, cells were monitored for hypermethylation of 14 host genes (APC, CADM1, CYGB, FAM19A4, hTERT, mir124-1, mir124-2, mir124-3, MAL, PHACTR3, PRDM14, RASSF1A, ROBO3, and SFRP2) at 4 different stages during immortalization. A significant increase in overall methylation levels was seen with progression through each stage of immortalization. At stage 1 (pre-immortalization), a significant increase in methylation of hTERT, mir124-2, and PRDM14 was already apparent, which continued over time. Methylation of ROBO3 was significantly increased at stage 2 (early immortal), followed by CYGB (stage 3) and FAM19A4, MAL, PHACTR3, and SFRP2 (stage 4). Methylation patterns were mostly growth behavior independent. Yet, hTERT methylation levels were significantly increased in cells that just escaped from crisis. Bisulfite sequencing of hTERT confirmed increased methylation in immortal cells compared to controls, with the transcription core and known repressor sites remaining largely unmethylated. In conclusion, HPV-induced immortalization is associated with a sequential and progressive increase in promoter methylation of a subset of genes, which is mostly independent of the viral immortalization capacity.
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PMID:Longitudinal assessment of DNA methylation changes during HPVE6E7-induced immortalization of primary keratinocytes. 2558 Jun 31

Aberrant DNA methylation has been observed in cervical cancer; however, most studies have used non-quantitative approaches to measure DNA methylation. The objective of this study was to quantify methylation within a select panel of genes previously identified as targets for epigenetic silencing in cervical cancer and to identify genes with elevated methylation that can distinguish cancer from normal cervical tissues. We identified 49 women with invasive squamous cell cancer of the cervix and 22 women with normal cytology specimens. Bisulfite-modified genomic DNA was amplified and quantitative pyrosequencing completed for 10 genes (APC, CCNA, CDH1, CDH13, WIF1, TIMP3, DAPK1, RARB, FHIT, and SLIT2). A Methylation Index was calculated as the mean percent methylation across all CpG sites analyzed per gene (~4-9 CpG site) per sequence. A binary cut-point was defined at >15% methylation. Sensitivity, specificity and area under ROC curve (AUC) of methylation in individual genes or a panel was examined. The median methylation index was significantly higher in cases compared to controls in 8 genes, whereas there was no difference in median methylation for 2 genes. Compared to HPV and age, the combination of DNA methylation level of DAPK1, SLIT2, WIF1 and RARB with HPV and age significantly improved the AUC from 0.79 to 0.99 (95% CI: 0.97-1.00, p-value = 0.003). Pyrosequencing analysis confirmed that several genes are common targets for aberrant methylation in cervical cancer and DNA methylation level of four genes appears to increase specificity to identify cancer compared to HPV detection alone. Alterations in DNA methylation of specific genes in cervical cancers, such as DAPK1, RARB, WIF1, and SLIT2, may also occur early in cervical carcinogenesis and should be evaluated.
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PMID:Quantitative DNA methylation analysis of candidate genes in cervical cancer. 2582 59