Global DNA hypomethylation occurs in the early stages of intestinal type gastric carcinoma.

Cravo, Marília; Pinto, Rosamaria; Fidalgo, Paula; Chaves, Paula; Glória, L; Nobre‐Leitão, Carlos; Mira, F. Costa

doi:10.1136/gut.39.3.434

Cited by 97 publications

(63 citation statements)

References 38 publications

(5 reference statements)

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“…For example, hypomethylation is common in colon, liver, stomach, esophagus, lung, breast, head and neck, as well as urothelial and metastatic prostate carcinomas, but uncommon in renal cell carcinomas, papillary carcinomas of thyroid, lymphomas and most hematological malignancies. [25][26][27][28][29] This is also corroborated in experimental models of global hypomethylation in mice. The DNA methyltransferase-1 hypomorphic mice had suppression of polyp formation and reduction in the frequency of CpG island methylation in both the normal mucosa and adenomas in Apc (Min/ þ ) mice, but developed T-cell lymphomas and liver tumors.…”

Section: Discussionmentioning

confidence: 67%

Hypomethylation of LINE-1 and Alu in well-differentiated neuroendocrine tumors (pancreatic endocrine tumors and carcinoid tumors)

et al. 2007

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Neuroendocrine tumors including carcinoid tumors and pancreatic endocrine tumors are uncommon, and the genetic alterations in these indolent tumors are not well characterized. We studied global hypomethylation by analyzing long interspersed nucleotide elements (LINE)-1 and Alu methylation using pyrosequencing in 35 neuroendocrine tumors and corresponding normal tissue. The tumor samples were less methylated than normal tissue at LINE-1 (P ¼ 0.04) and Alu (P ¼ 0.001). The mean relative tumor hypomethylation (difference in methylation between normal tissue and in tumor) was 11.5710.0 for LINE-1 and 5.876.4 for Alu, and were correlated with each other (correlation coefficient 0.6, P ¼ 0.001). Relative tumor hypomethylation of LINE-1 was higher in ileal carcinoid tumors than in non-ileal carcinoid tumors and pancreatic endocrine tumors (P ¼ 0.047), and tumors with lymph node metastasis (P ¼ 0.02), chromosome 18 loss (P ¼ 0.001) and RAS-association domain family 1, isoform A gene methylation (P ¼ 0.02). Alu methylation in tumors was inversely correlated with methylation of O 6 -methyl-guanine methyltransferase gene (P ¼ 0.02). Our study shows that hypomethylation is more common in carcinoid tumors than in pancreatic endocrine tumors and is associated with clinicopathologic features, and genetic and epigenetic alterations in these tumors, including lymph node metastasis.

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Section: Discussionmentioning

confidence: 67%

Hypomethylation of LINE-1 and Alu in well-differentiated neuroendocrine tumors (pancreatic endocrine tumors and carcinoid tumors)

et al. 2007

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“…These results suggest that hypermethylation of promoter CpG islands occurs very early in gastric carcinogenesis, in contrast to demethylation of MAGE gene promoters. Several studies have analysed MAGE gene expression Inoue et al, 1995a, b;Cravo et al, 1996;Li et al, 1996;Sadanaga et al, 2001), but none have evaluated the demethylation status of their promoters in gastric cancer. Inoue et al (1995a, b) detected MAGE expression in about 40% of primary gastric cancers, but failed to find any significant correlation between MAGE expression and clinicopathological parameters (Inoue et al, 1995a, b).…”

Section: Discussionmentioning

confidence: 99%

“…Global DNA hypomethylation has been observed in carcinomas of the breast, liver, and colon, and is considered to occur in the early stages of tumour development (Goelz et al, 1985;Cravo et al, 1996;Narayan et al, 1998;Lin et al, 2001;Bariol et al, 2003). However, little is known about promoter hypomethylation of specific genes such as oncogenes and growth-related genes, with the exception of the association between demethylation and increased expression of c-abl, c-myc, Ha-ras, and raf (Cheah et al, 1984;Weitzman et al, 1989;Sharrad et al, 1992;Counts and Goodman, 1994).…”

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confidence: 99%

Demethylation of MAGE promoters during gastric cancer progression

et al. 2004

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Melanoma antigen (MAGE)-encoding genes are expressed in various tumour types via demethylation of their promoter CpG islands, which are silent in all non-neoplastic tissues except for the testis and placenta. The clinicopathological significance of demethylation of MAGE genes in gastric carcinoma is not known. We investigated the promoter methylation status of MAGE-A1 and -A3 in 10 gastric cancer cell lines and in surgical specimens from 84 gastric cancer patients by methylation-specific PCR (MSP). Expression of MAGE-A1 and -A3 in the 10 gastric cancer cell lines was also investigated by RT -PCR. Any correlation between the methylation status of the MAGE promoters and clinicopathological characteristics of the gastric cancer patients was then assessed. Eight of the 10 gastric cancer cell lines showed demethylation of both MAGE-A1 and -A3, and the remaining two cell lines did either of MAGE-A1 or -A3. Expression of MAGE-A1 and -A3 was confirmed in seven and nine of the 10 gastric cancer cell lines, respectively. The MAGE-A1 and -A3 promoters were demethylated in 29% (25 out of 84) and 66% (56 out of 84) of the gastric tumour specimens, respectively. Demethylation of both MAGE-A1 and -A3 promoters (n ¼ 22) was found more frequently in gastric cancer patients in advanced clinical stages (P ¼ 0.0035), and these patients also exhibited a higher incidence of lymph node metastasis (P ¼ 0.0007) compared to those patients without demethylation (n ¼ 25). Furthermore, demethylation patients tended to have a worse prognosis, although this difference was not statistically significant (P ¼ 0.183). Demethylation of MAGE-A1 and -A3 occurs during progressive stages of gastric cancer, and may be associated with aggressive biological behaviour of gastric cancer.

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“…Qu et al (1999) reported a statistically signi®cant correlation between the extent of satellite 2 DNA hypomethylation in chromosomes 1 and 16 and the degree of malignancy in three types of ovarian neoplasms as well as a statistically signi®cant correlation between genome-wide hypomethylation and satellite 2 DNA hypomethylation. Global DNA hypomethylation has been frequently observed in many types of cancers and is correlated with prognostic factors in several of these Kim et al (1994); Cravo et al (1996); Soares et al (1999) and Shen et al (1998) reported that decreased levels of global DNA methylation in HCC are correlated with tumor characteristics. In our previous paper we showed that the number of altered RLGS spots in HCC compared to non-cancerous liver tissue was signi®cantly correlated with postoperative recurrence of HCC (Itano et al, 2000), and here we show that the intensity of the HTRS and CNIC spots, in other words, the degrees of demethylation in HTRS and CNIC, were signi®cantly correlated with the number of altered RLGS spots (Figure 3a,b).…”

Section: Discussionmentioning

confidence: 99%

Correlation of postoperative recurrence in hepatocellular carcinoma with demethylation of repetitive sequences

Itano

Ueda

Kikuchi³

et al. 2002

Oncogene

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Restriction landmark genomic scanning (RLGS) was utilized to identify novel genomic alterations in hepatocellular carcinoma (HCC). Thirty-one HCC samples were examined by RLGS. Two high intensity spots were common to several RLGS pro®les of di erent HCCs. Nucleotide sequencing and homology search analysis showed that these spots represented repetitive sequences, Human tandem repeat sequence (Genbank, L09552) and centromeric NotI cluster (Genbank, Y10752). These intensi®ed signals were attributable to the occurrence of demethylated areas in the recognition sequence of the NotI site of the corresponding fragments. The intensity of these spots in the RLGS pro®le re¯ects their degree of demethylation, which was signi®cantly correlated with postoperative recurrence, even in patients regarded as belonging to the good prognosis group by conventional prognostic factors. Multivariate analysis showed that the intensities of the two spots retained independent prognostic value. This is a new type of predictive factor for HCC based on epigenetic changes in hepatocarcinogenesis, and in the future it is expected to be of great value in making preoperative diagnosis and selecting postoperative therapy.

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Global DNA hypomethylation occurs in the early stages of intestinal type gastric carcinoma.

Cited by 97 publications

References 38 publications

Hypomethylation of LINE-1 and Alu in well-differentiated neuroendocrine tumors (pancreatic endocrine tumors and carcinoid tumors)

Hypomethylation of LINE-1 and Alu in well-differentiated neuroendocrine tumors (pancreatic endocrine tumors and carcinoid tumors)

Demethylation of MAGE promoters during gastric cancer progression

Correlation of postoperative recurrence in hepatocellular carcinoma with demethylation of repetitive sequences

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