Chromosomal Losses are Associated with Hypomethylation of the Gene-Control Regions in the Stomach with a Low Number of Active Genes

Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Journal of Korean Medical Science (Impact Factor: 1.27). 01/2009; 23(6):1068-89. DOI: 10.3346/jkms.2008.23.6.1068
Source: PubMed


Transitional-CpG methylation between unmethylated promoters and nearby methylated retroelements plays a role in the establishment of tissue-specific transcription. This study examined whether chromosomal losses reducing the active genes in cancers can change transitional-CpG methylation and the transcription activity in a cancer-type-dependent manner. The transitional-CpG sites at the CpG-island margins of nine genes and the non-island-CpG sites round the transcription start sites of six genes lacking CpG islands were examined by methylation-specific polymerase chain reaction (PCR) analysis. The number of active genes in normal and cancerous tissues of the stomach, colon, breast, and nasopharynx were analyzed using the public data in silico. The CpG-island margins and non-island CpG sites tended to be hypermethylated and hypomethylated in all cancer types, respectively. The CpG-island margins were hypermethylated and a low number of genes were active in the normal stomach compared with other normal tissues. In gastric cancers, the CpG-island margins and non-island-CpG sites were hypomethylated in association with high-level chromosomal losses, and the number of active genes increased. Colon, breast, and nasopharyngeal cancers showed no significant association between the chromosomal losses and methylation changes. These findings suggest that chromosomal losses in gastric cancers are associated with the hypomethylation of the gene-control regions and the increased number of active genes.

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Available from: Yuchae Jung, Apr 10, 2015
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    • "A comparative analysis of stomach, colon, head, neck and thyroid cancers has described an association between the level of LOH and the expression of tissue-specific genes lacking CpG-islands [11]. The LOH events are more frequent in gastric cancers along with a higher expression of stomach-specific genes lacking CpG-islands in the gastric normal mucosa, when compared with other tissue types. "
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    ABSTRACT: The level of loss of heterozygosity (LOH) that reduces a gene dose and exerts a cell-adverse effect is known to be a parameter for the genetic staging of gastric cancers. This study investigated if the cell-adverse effect induced with the gene reduction was a rate-limiting factor for the LOH events in two distinct histologic types of gastric cancers, the diffuse- and intestinal-types. The pathologic specimens obtained from 145 gastric cancer patients were examined for the level of LOH using 40 microsatellite markers on eight cancer-associated chromosomes (3p, 4p, 5q, 8p, 9p, 13q, 17p and 18q). Most of the cancer-associated chromosomes were found to belong to the gene-poor chromosomes and to contain a few stomach-specific genes that were highly expressed. A baseline-level LOH involving one or no chromosome was frequent in diffuse-type gastric cancers. The chromosome 17 containing a relatively high density of genes was commonly lost in intestinal-type cancers but not in diffuse-type cancers. A high-level LOH involving four or more chromosomes tended to be frequent in the gastric cancers with intestinal and mixed differentiation. Disease relapse was common for gastric cancers with high-level LOH through both the hematogenous (38%) and non-hematogenous (36%) routes, and for the baseline-level LOH cases through the non-hematogenous route (67%). The cell-adverse effect of gene reduction is more tolerated in intestinal-type gastric cancers than in diffuse-type cancers, and the loss of high-dose genes is associated with hematogenous metastasis.
    BMC Gastroenterology 11/2010; 10(1):138. DOI:10.1186/1471-230X-10-138 · 2.37 Impact Factor
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    • "The host genome suppresses the hazardous mutation effect of the parasitic retroelements via a DNA methylation-dependent mechanism [10]. The transitional area between the weakly methylated genes and the densely methylated retroelements, such as the CpG-island margin and the transcription start site lacking CpG-islands, is methylated to various degrees in a tissue-type-dependent manner [4,11,12]. The methylation of transitional-CpG sites changes dynamically in response to the trans-differentiation of bone marrow stromal cells and the loss-of-heterozygosity (LOH) events in gastric cancers [12-15]. "
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    ABSTRACT: The transitional-CpG sites between weakly methylated genes and densely methylated retroelements are overmethylated in the gastric mucosa infected with Helicobacter pylori (H. pylori) and they are undermethylated in the gastric cancers depending on the level of loss of heterozygosity (LOH) events. This study delineated the transitional-CpG methylation patterns of CpG-island-containing and -lacking genes in view of the retroelements. The transitional-CpG sites of eight CpG-island-containing genes and six CpG-island-lacking genes were semi-quantitatively examined by performing radioisotope-labelling methylation-specific PCR under stringent conditions. The level of LOH in the gastric cancers was estimated using the 40 microsatellite markers on eight cancer-associated chromosomes. Each gene was scored as overmethylated or undermethylated based on an intermediate level of transitional-CpG methylation common in the H. pylori-negative gastric mucosa. The eight CpG-island genes examined were overmethylated depending on the proximity to the nearest retroelement in the H. pylori-positive gastric mucosa. The six CpG-island-lacking genes were similarly methylated in the H. pylori-positive and -negative gastric mucosa. In the gastric cancers, long transitional-CpG segments of the CpG-island genes distant from the retroelements remained overmethylated, whereas the overmethylation of short transitional-CpG segments close to the retroelements was not significant. Both the CpG-island-containing and -lacking genes tended to be decreasingly methylated in a LOH-level-dependent manner. The overmethylated genes under the influence of retroelement methylation in the H. pylori-infected stomach are demethylated in the gastric cancers influenced by LOH.
    BMC Gastroenterology 11/2010; 10(1):137. DOI:10.1186/1471-230X-10-137 · 2.37 Impact Factor
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    • "Each CpG amplicon site was analyzed by cloning and sequencing the common-polymerase chain reaction (PCR) products encompassing both the unmethylated and methylated CpGs, as previously reported (7, 16, 23, 24). Standard curves were then plotted for each methylation specific PCR (MSP) primer set using a mixture containing the methylated and unmethylated DNA clones at various ratios. "
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    ABSTRACT: Recent evidence suggests that gastric mucosal injury induces adaptive changes in DNA methylation. In this study, the methylation status of the key tissue-specific genes in normal gastric mucosa of healthy individuals and cancer patients was evaluated. The methylation-variable sites of 14 genes, including ulcer-healing genes (TFF1, TFF2, CDH1, and PPARG), were chosen from the CpG-island margins or non-island CpGs near the transcription start sites. The healthy individuals as well as the normal gastric mucosa of 23 ulcer, 21 non-invasive cancer, and 53 cancer patients were examined by semiquantitative methylation-specific polymerase chain reaction (PCR) analysis. The ulcer-healing genes were concurrently methylated with other genes depending on the presence or absence of CpG-islands in the normal mucosa of healthy individuals. Both the TFF2 and PPARG genes were frequently undermethylated in ulcer patients. The over- or intermediate-methylated TFF2 and undermethylated PPARG genes was more common in stage-1 cancer patients (71%) than in healthy individuals (10%; odds ratio [OR], 21.9) and non-invasive cancer patients (21%; OR, 8.9). The TFF2-PPARG methylation pattern of cancer patients was stronger in the older-age group (> or =55 yr; OR, 43.6). These results suggest that the combined methylation pattern of ulcer-healing genes serves as a sensitive marker for predicting cancer-prone gastric mucosa.
    Journal of Korean medical science 03/2010; 25(3):405-17. DOI:10.3346/jkms.2010.25.3.405 · 1.27 Impact Factor
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