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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Glioblastoma multiforme (GBM) is an incurable malignancy with inherent tendency to recur. In this study, we have comparatively analyzed the epigenetic profile of 32 paired tumor samples of relapsed GBM and their corresponding primary neoplasms with special attention to genes involved in the mitochondria-independent apoptotic pathway. The CpG island promoter hypermethylation status was assessed by methylation-specific polymerase chain reaction and selected samples were double checked by bisulfite genomic sequencing. Thirteen genes were analyzed for DNA methylation: the pro-apoptotic CASP8, CASP3, CASP9, DcR1, DR4, DR5 and TMS1; the cell adherence CDH1 and CDH13; the candidate tumor suppressor RASSF1A and BLU; the cell cycle regulator CHFR and the DNA repair MGMT. The CpG island promoter hypermethylation profile of relapsed GBM in comparison with their corresponding primary tumors was identical in 37.5% of the cases, whereas in 62.5% of patients, differences in the DNA methylation patterns of the 13 genes were observed. The most prominent distinction was the presence of previously undetected CASP8 hypermethylation in the GBM relapses (P = 0.031). This finding was also linked to the observation that an unmethylated CASP8 CpG island together with methylated BLU promoter in the primary GBM was associated with prolonged time to tumor progression (P = 0.0035). Our data strongly suggest that hypermethylation of the pro-apoptotic CASP8 is a differential feature of GBM relapses. These remarkable findings may foster the development of therapeutic approaches using DNA demethylating drugs and activators of the extrinsic apoptotic pathway to improve the dismal prognosis of GBM.
Carcinogenesis 2007 Jun
PMID:CpG island promoter hypermethylation of the pro-apoptotic gene caspase-8 is a common hallmark of relapsed glioblastoma multiforme. 1727 9

Renal cell carcinoma (RCC) is more frequently observed in patients on dialysis than in patients with normal renal function. However, the mechanism underlying carcinogenesis in RCC patients on dialysis is still unclear. We hypothesized that oxidative stress affects patients on dialysis and generates new neoplasms, and therefore analysed the correlation between the influences of various markers of oxidative stress and carcinogenesis in those patients. We evaluated the immunohistochemical expression of oxidative stress markers, such as iNOS, 8-OHdG, and COX-2 in 42 cases on dialysis and 51 cases with normal renal function as a control. The methylation status of p16INK4a, p14ARF, VHL, and RASSF1A was analysed together with clinicopathological factors. Histologically, the papillary type was observed more frequently in dialysis RCC than in sporadic RCC. Immunohistochemically, overexpression of iNOS (p < 0.0001) and COX-2 (p = 0.0002) was more frequently observed in dialysis RCC. Furthermore, the 8-OHdG labelling index was significantly higher in dialysis RCC than in sporadic RCC. Hypermethylation of p16INK4a was more frequently found in dialysis RCC (p < 0.05). However, no significant correlations between oxidative stress markers and DNA hypermethylation status were observed. The overexpression of iNOS, COX-2, and 8-OHdG in dialysis RCC suggests that patients on dialysis are affected by oxidative stress and that this effect plays an important role in the genesis of dialysis RCC.
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PMID:Oxidative stress and DNA hypermethylation status in renal cell carcinoma arising in patients on dialysis. 1745 Nov 87

Colorectal cancer (CRC) is a complex and heterogeneous disease in which genomic instability and DNA promoter methylation play important roles. The aim of this study was to investigate the relationship between chromosomal instability (CIN), microsatellite instability (MSI) and promoter methylation of CRC-associated genes. Therefore, 71 CRCs were analysed for CIN and MSI by comparative genomic hybridization and the mononucleotide marker BAT-26, respectively. Promoter methylation of the tumour suppressor and DNA repair genes hMLH1, O(6)-MGMT, APC, p14(ARF), p16(INK4A), RASSF1A, GATA-4, GATA-5 and CHFR was analysed using methylation-specific polymerase chain reaction. These integrative analyses showed that in CIN+ CRCs, promoter methylation of GATA-4 and p16(INK4A) was inversely related to chromosomal loss at 15q11-q21 and gain at 20q13, respectively (P values: 3.8 x 10(-2) and 4.5 x 10(-2), respectively). Interestingly, promoter methylation of RASSF1A, GATA-4, GATA-5 and CHFR, as well as a high methylation index (MI), was positively related to chromosomal gain at 8q23-qter (P values: 1.5 x 10(-2), 3.8 x 10(-2), 3.9 x 10(-2), 4.9 x 10(-2) and 8.2 x 10(-3), respectively). MSI was associated with BRAF mutation, promoter methylation of hMLH1, APC and p16(INK4A) and a high MI (total number of methylated genes) (P values: 2.4 x 10(-2), 2.5 x 10(-3), 1.8 x 10(-2), 4.6 x 10(-2) and 1.0 x 10(-2), respectively). Therefore, we conclude that promoter methylation of pivotal tumour suppressor and DNA repair genes is associated with specific patterns of chromosomal changes in CRC, which are different from methylation patterns in MSI tumours.
Carcinogenesis 2008 Feb
PMID:Integrated analysis of chromosomal, microsatellite and epigenetic instability in colorectal cancer identifies specific associations between promoter methylation of pivotal tumour suppressor and DNA repair genes and specific chromosomal alterations. 1804 85

In endometrial carcinomas (ECs), previous report suggested that PIK3CA mutations do not coexist with KRAS mutations, but the significant mutual exclusiveness has not been demonstrated. In this study, we examined the mutation frequency of PIK3CA in EC and its mutual exclusiveness with KRAS mutation. We performed mutational analysis of PIK3CA through a polymerase chain reaction single-strand conformation polymorphism assay in 44 cases of endometrial cancer and analyzed the correlation with loss of PTEN, KRAS mutation, and RASSF1A hypermethylation. Somatic mutations of PIK3CA were detected in 14 of 44 (31.8%) of endometrial cancers. In exon 9, seven PIK3CA mutations were located, while seven mutations were located in exon 20. The most common mutation was E545A (35.7%), followed by H1047R (28.6%). Concomitant loss of PTEN expression and PIK3CA mutation was found in four cases of endometrial cancer. KRAS mutations were mutually exclusive with PIK3CA mutations, and those mutations were inversely correlated with statistical significance (P = 0.039). Also, we found that mutations in ERBB2 were mutually exclusive with PIK3CA mutations. RASSF1A and hMLH1 methylation were not correlated with the presence of PIK3CA mutations. PIK3CA was frequently mutated in endometrial cancers. KRAS and PIK3CA mutations are inversely correlated, suggesting that genetic alterations of KRAS and PIK3CA may play equivalent roles in endometrial carcinogenesis.
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PMID:Mutual exclusiveness between PIK3CA and KRAS mutations in endometrial carcinoma. 1822 84

Epigenetic aberration is known to be important in human carcinogenesis. Promoter methylation status of RAS effector related genes, RASSF1A, RASSF2A, hDAB2IP (m2a and m2b regions) and BLU, was evaluated in 76 endometrial carcinomas and their non-neoplastic endometrial tissue by methylation specific PCR. Hypermethylation of at least one of the 5 genes was detected in 73.7% of carcinomas. There were significant correlations between methylation of hDAB2IP and RASSF1A, RASSF2A (p = 0.042, p = 0.012, respectively). Significantly, more frequent RASSF1A hypermethylation was found in Type I endometrioid carcinomas than Type II carcinomas (p = 0.049). Among endometrioid cancers, significant association between RASSF1A hypermethylation and advanced stage, as well as between methylation of hDAB2IP at m2a region with deep myometrial invasion (p < 0.05) was observed. mRNA expression of RASSF1A, RASSF2A and BLU in endometrial cancer cell lines significantly increased after treatment with the demethylating agent 5-Aza-2'-deoxycytidine supporting the repressive effect of hypermethylation on their transcription. Immunohistochemical study of DNMT1 on eight normal endometrium, 16 hyperplastic endometrium without atypia, 40 atypical complex hyperplasia and 79 endometrial carcinomas showed progressive increase in DNMT1 immunoreactivity from normal endometrium to endometrial hyperplasia and endometrioid carcinomas (p = 0.001). Among carcinomas, distinctly higher DNMT1 expression was observed in Type I endometrioid carcinomas (p < 0.001). DNMT1 immunoreactivity correlated with RASSF1A and RASSF2A methylation (p < 0.05). The data suggested that hypermethylation of RAS related genes, particularly RASSF1A, was involved in endometrial carcinogenesis with possible divergent patterns in different histological types. DNMT1 protein overexpression might contribute to such aberrant DNA hypermethylation of specific tumor suppressor genes in endometrial cancers.
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PMID:Hypermethylation of RAS effector related genes and DNA methyltransferase 1 expression in endometrial carcinogenesis. 1840 74

Alterations in the regulation of the RAS-MAPK pathway are frequent in endometrial carcinoma. RASSF1A is a tumor-suppressor gene that can regulate this pathway negatively. RASSF1A has been found to be inactivated by promoter methylation in some human tumors. The aim of the study was to assess the immunohistochemical expression of RASSF1A in normal endometrium and endometrial carcinoma, and to correlate its expression with K-RAS mutations, presence of microsatellite instability, RASSF1A promoter methylation, and clinicopathological data. RASSF1A immunostaining was evaluated in one tissue microarray constructed from 80 paraffin-embedded samples of normal endometrium, and two tissue microarrays constructed with a total of 157 endometrial carcinomas (one constructed with 95 endometrial carcinomas previously evaluated for K-RAS mutations, and microsatellite instability, and another one containing 62 endometrial carcinomas that were also subjected to RASSF1A promoter methylation analysis). RASSF1A immunostaining was correlated with cell proliferation (Ki67), Cyclin D1 expression and clinicopathological data. Promoter methylation of RASSF1A was assessed by methylation-specific PCR. RASSF1A immunostaining was variable during the menstrual cycle in normal endometrium. RASSF1A expression was significantly reduced in 48% of endometrial carcinomas, particularly in tumors exhibiting microsatellite instability. RASSF1A-promoter methylation was very frequent in endometrial carcinoma (74%), and was frequently associated with reduced expression of RASSF1A. RASSF1A-promoter hypermethylation was common in advanced-stage endometrial carcinoma. The results suggest that reduced expression of RASSF1A may play a role in endometrial carcinogenesis by controlling cell proliferation and apoptosis through the MAPK-signaling pathway.
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PMID:Promoter hypermethylation and reduced expression of RASSF1A are frequent molecular alterations of endometrial carcinoma. 1846 97

Promoter hypermethylation of genes is implicated in the pathogenesis of many cancers, including breast cancer. Herein, we analyzed the promoter methylation status of a panel of critical growth regulatory genes, RASSF1A, RARbeta2, BRCA1 and HOXA5, in 54 breast cancers and 5 distant normal breast tissues of Indian patients. The methylation data were correlated with clinicopathological characteristics and hormone receptor status to determine the impact of methylation in breast carcinogenesis. Promoter hypermethylation of RASSF1A was observed in 39/54 (72%), HOXA5 in 36/54 (67%), BRCA1 in 15/54 (28%) and RARbeta2 in 8/54 (15%) breast cancers. Our most significant findings were the association of RASSF1A methylation with nodal metastasis (p=0.05); and RARbeta2 methylation with age (all tumors in patients in the older age group were methylated, p=0.04). Further, the interactions between DNA methylation and hormone receptor biology in breast cancer cells are beginning to be clearly understood. In this context the association of HOXA5 methylation with loss of ERalpha (p=0.009) is noteworthy.
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PMID:Clinical significance of promoter hypermethylation of RASSF1A, RARbeta2, BRCA1 and HOXA5 in breast cancers of Indian patients. 1853 49

Hepatocellular carcinoma (HCC) most commonly arises from chronic inflammation due to viral infection, as a result of genetic and epigenetic abnormalities. A global picture of epigenetic changes in HCC is lacking. We used methylated CpG island amplification microarrays (MCAMs) to study 6458 CpG islands in HCC and adjacent preneoplastic tissues [chronic hepatitis (CH) or liver cirrhosis (LC)] in comparison with normal liver tissues where neither viral infection nor hepatitis has existed. MCAM identified 719 (11%) prominent genes of hypermethylation in HCCs. HCCs arising from LC had significantly more methylation than those arising from CH (1249 genes or 19% versus 444 genes or 7%, P < 0.05). There were four patterns of aberrant methylation: Type I (4%, e.g. matrix metalloproteinase 14) shows a substantially high methylation level in adjacent tissue and does not increase further in cancer. Type II (55%, e.g. RASSF1A) shows progressively increasing methylation from adjacent tissue to HCC. Type III (4%, e.g. GNA14) shows decreased methylation in adjacent tissue but either similar or increased methylation in HCC. Type IV (37%, e.g. CDKN2A) shows low levels of methylation in normal tissue and adjacent tissue but high levels in HCC. These DNA methylation changes were confirmed by quantitative pyrosequencing methylation analysis in representative 24 genes and were analyzed for correlation with clinicopathological parameters in 38 patients. Intriguingly, methylation in the Type IV genes is characteristic of moderately/poorly differentiated cancer. Our global epigenome analysis reveals distinct patterns of methylation that are probably to represent different pathophysiologic processes in HCCs.
Carcinogenesis 2008 Oct
PMID:Variable DNA methylation patterns associated with progression of disease in hepatocellular carcinomas. 1863 56

Molecular targets of known risk factors for the development of urological tumors, such as age, smoking, and adiposity, have not yet been elucidated. Hypermethylation of CpG islands in promoters can lead to silencing of gene expression and has frequently been detected in tumors. Age-dependent accumulation of methylation of gene promoters has been observed in various normal tissues and is discussed as a common risk factor for carcinogenesis.Here we describe the RASSF1A tumor suppressor gene as exhibiting an age-dependent promoter methylation in normal kidney tissue, which is additionally affected by the risk factors of anthracosis and adiposity. Furthermore, we found significantly increased methylation of the RASSF1A promoter when comparing peripheral versus central zone prostatic tissue samples.Preliminary expression analysis indicates that RASSF1A could be involved in early tumorigenesis. Our results support the hypothesis that age and other lifestyle-dependent factors may influence promoter methylation of specific genes, possibly serving as future individual tumor risk markers.
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PMID:[Methylation of the RASSF1A tumor suppressor gene promoter. Risk factor for carcinogenesis of urological tumors]. 1867 51


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