Frequent p16 CpG island hypermethylation in primary remnant gastric cancer suggesting an independent carcinogenic pathway

Mino, Aya; Onoda, Naoyoshi; Yashiro, Masakazu; Aya, Makoto; Fujiwara, Ikuko; Kubo, Naoshi; Sawada, Tetsuji; Ohira, Masaichi; Kato, Yasuyuki; Hirakawa, Kosei

doi:10.3892/or.15.3.615

Cited by 9 publications

(7 citation statements)

References 28 publications

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“…However, they studied only one gene in each report which gives limited insight into DNA hypermethylation across the whole genome. Our results may contradict that of Mino et al [18] since we found that overall PGC promoter methylation is higher than in RGC. Our findings, however, are corroborated by (1) the RMVs in normal-appearing adjacent non-cancerous tissues in PGC were also significantly higher than those in RGC;+ (2) cancer tissues in RGC demonstrated significantly higher RMVs in three genes (except for TNFRSF10B) than those in normal-appearing adjacent non-cancerous tissues in RGC.…”

Section: Discussioncontrasting

confidence: 99%

“…Their study demonstrated similar results to ours in terms of higher gene methylation rates in three genes in cancer tissues compared with normal-appearing adjacent non-cancerous tissues. Mino et al [18] investigated p16 gene methylation of cancer tissues with qualitative MSP in two separate analyses for those RGCs which had newly developed after surgery performed either for benign disease or for gastric cancer. They concluded that p16 gene hypermethylation was found more frequently in RGC which developed after surgery for benign disease than in PGC or in RGC which developed after surgery for gastric cancer.…”

Section: Discussionmentioning

confidence: 99%

“…In other gastrointestinal cancers, such as Barrett's esophageal cancer, colitis-associated colon cancer and hepatitis C virus-positive hepatocellular carcinoma, chronic inflammation has been associated with carcinogenesis via aberrant DNA methylation [15]. Similarly, chronic inflammation has been reported to occur in the stomach especially during gastric carcinogenesis involving promoter gene hypermethylation [16][17][18]. However, the epigenetic events involving carcinogenesis in the remnant stomach during the development of remnant gastric cancer have been largely unexplored [19].…”

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confidence: 99%

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DNA methylation genome-wide analysis in remnant and primary gastric cancers

et al. 2019

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Background Although primary (PGC) and remnant gastric cancers (RGC) both originate from the same gastrointestinal organ, they have very distinct clinicopathological behaviors. We hypothesized that there would be distinct differences in DNA methylation patterns that would occur during carcinogenesis of RGC and PGC, and that the differences in methylation patterns may help identify the primary factor contributing to chronic inflammation in patients with RGC. Methods We investigated the genome-wide DNA methylation patterns of PGC and RGC tissues from 48 patients using the Infinium HumanMethylation450 Beadchip assay. The results were validated by quantitative methylation-specific PCR (qMSP) in separate, independent cohorts. Results We found that in our training cohort of 48 patients, the most variable genes from the gastric cancer tissues identified by the Infinium HumanMethylation450 Beadchip clustered the resultant heatmap into high and low methylation groups. On multivariate analysis, PGCs contributed significantly to the high methylation group (p = 0.004, OR 12.33), which suggested that the promoter methylation status in PGC is higher than that in RGC. Supporting this conclusion was the finding that in a separate qMSP analysis in a test cohort, the EPB41L3 gene, chosen because of its high β value on microarray analysis in the gastric cancer tissues, had significantly higher DNA promoter methylation in cancer tissues in the validation PGC tissues than in RGC. Conclusions This study demonstrated that promoter methylation status in PGC is higher than in RGC. This result may reflect the effects of the absence of Helicobacter pylori on the reduced DNA methylation in the remnant stomach.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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DNA methylation genome-wide analysis in remnant and primary gastric cancers

et al. 2019

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“…DNA methylation is a well recognized epigenetic mechanism in the regulation of gene expression (1)(2)(3)(4). Methylation inhibits gene expression directly by interfering with transcription factor binding and/or indirectly by recruiting histone deacetylases through methyl-DNA-binding proteins (5).…”

Section: Introductionmentioning

confidence: 99%

Methylation status of the long control region of HPV 16 in clinical cervical specimens

Hong¹,

Feng²,

Lü³

et al. 2008

Mol Med Report

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DNA methylation is one of the regulatory pathways that modulate human papillomavirus (HPV) gene expression. To obtain detailed methylation information on crucial areas of the long control region (LCR) of HPV 16 and to clarify the significance of methylation in clinical cervical lesions, 80 clinical samples were examined to determine the methylation status of the HPV 16 promoter and enhancer core using bisulfite modification and pyrosequencing. Seventy samples [26 of cervical carcinoma (CC), 13 of cervical intraepithelia neoplasia (CIN) III, 17 of CIN I-II and 14 of asymptomatic HPV 16 infection] were successfully examined. Analysis of the general methylation status of HPV 16 LCR in the 70 clinical specimens revealed 43 (61.4%) with methylation in the promoter and/ or enhancer core of HPV 16. The proportion of methylated samples was highest in CC specimens (84.6%), followed by asymptomatic infection (71.4%) and CIN III (46.2%), while the proportion of methylated samples was lowest in CIN I-II specimens (29.4%). The methylation status of eight CpGs in HPV 16 LCR was determined in detail. In general, the methylation of CpGs was more common in the promoter than in the enhancer core region. The methylation frequencies of the eight CpGs ranged from 14.6±7.2 to 33.7±23.0% in individual methylated CpG cases. The methylation pattern of all eight CpGs methylated in the promoter and enhancer core was more common in CC, and the pattern of scattered methylated CpGs was relatively more prevalent in asymptomatic infections. Our study demonstrates that DNA methylation is a common phenomenon in HPV 16 LCR clinical specimens, and may function as a host defense mechanism. While hypomethylation is probably associated with the initiation of neoplasia, hyper-methylation in cervical cancer may be a reflection of the host defense mechanism. In the regulation of transcription, methylation is of more importance in the HPV 16 promoter than in the enhancer core.

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“…For the CpG sites in the enhancer and promoter regions, the methylation proportion was lowest in cervical swab DNA samples from patients with normal tissue/LSIL, and highest in those with CC. Previous studies have demonstrated that methylation is able to regulate gene expression as an epigenetic mechanism (31)(32)(33). Numerous transcription factor binding sites in the HPV 16 enhancer and promoter regions contain CpG sites (19).…”

Section: Discussionmentioning

confidence: 99%

Increased methylation of human papillomavirus type 16 DNA is associated with the severity of cervical lesions in infected females from northeast China

et al. 2017

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Abstract. Hypermethylation of the cytosine-phosphate-guanine (CpG) sites located at the 3'-major capsid protein L1 (3'L1) and the long control region (LCR) of the human papillomavirus (HPV) genome may be associated with the progression of cervical cancer (CC). However, the methylation status of the LCR of HPV type 16 DNA remains to be elucidated in an infected Chinese population. The aim of the present study was to investigate the association between methylation of the HPV 16 L1 gene and LCR, and the severity of cervical lesions in infected female patients. Therefore, bisulfite modification, polymerase chain reaction amplification and sequencing were used to analyze 122 HPV 16-positive clinical cervical swabs obtained from patients in northeastern China. The proportion of methylated samples at each of the 7 CpG sites within the 3'-L1/5'-LCR and 5 CpG sites within the promoter region was significantly increased in patients with CC, compared with that observed in high-grade squamous intraepithelial lesions (HSIL) and normal tissue/low-grade intraepithelial lesions (LSIL) (χ 2 test, P<0.01). The mean methylation frequencies of the CpG sites 7,089 and 7,143 exhibited an area under the curve value of 0.822 [95% confidence interval (CI)=0.733-0.911] for distinguishing CC from other lesions, 0.787 (95% CI=0.700-0.874) for distinguishing normal/LSIL from HSIL and CC, and 0.763 (95% CI=0.652-0.874) for distinguishing CC from HSIL. These results suggest that the methylation of CpG sites within the HPV 16 3'-L1 and LCR region is correlated with the severity of cervical lesions. Quantification of HPV DNA methylation in the L1 gene and promoter region appears to provide a promising novel marker for distinguishing between normal tissue/LSIL, HSIL and CC in a Chinese population.

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Frequent p16 CpG island hypermethylation in primary remnant gastric cancer suggesting an independent carcinogenic pathway

Cited by 9 publications

References 28 publications

DNA methylation genome-wide analysis in remnant and primary gastric cancers

DNA methylation genome-wide analysis in remnant and primary gastric cancers

Methylation status of the long control region of HPV 16 in clinical cervical specimens

Increased methylation of human papillomavirus type 16 DNA is associated with the severity of cervical lesions in infected females from northeast China

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