p16INK4a Promoter hypermethylation of non-tumorous tissue adjacent to gastric cancer is correlated with glandular atrophy and chronic inflammation

Jang, Tae Jung; Kim, Dae In; Shin, Yeon Myung; Chang, Hee Kyung; Yang, Chang Heon

doi:10.1002/ijc.1394

Cited by 47 publications

(43 citation statements)

References 19 publications

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“…Thus, methylation of p16 may play a role in the malignant transformation of gastric precursor lesions. The frequency of p16 methylation in adenocarcinoma in our study is similar to that reported in invasive gastric adenocarcinomas (Toyota et al, 1999b;Jang et al, 2001;Kang et al, 2001Kang et al, , 2003.…”

Section: Discussionsupporting

confidence: 91%

“…In the present study, however, we show that p16 gene methylation is present only in 7% of IM, but not in normal/CG mucosa, as has been reported previously (Jang et al, 2001;Kang et al, 2001).…”

Section: Discussionsupporting

confidence: 81%

“…Methylation of p16 gene, a cyclin-dependent kinase inhibitor, and CpG islands that are methylated in tumors (MINT) has also been found to be altered in gastric tumors (Toyota et al, 1999b;Jang et al, 2001;Waki et al, 2002). To date, most of the methylation studies in gastric neoplasms have focused on aberrant methylation of a single gene in carcinomas (Kanai et al, 1998;Iida et al, 2002;Fujimoto et al, 2000;Tsuchiya et al, 2000;Kang et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Frequent CpG island methylation in precursor lesions and early gastric adenocarcinomas

et al. 2004

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Gastric carcinogenesis involves multiple genetic and epigenetic alterations. Epigenetic silencing of tumorrelated genes due to CpG island methylation (CIM) has been recently reported in gastric cancer, but the role in precursor lesions is not well understood. We analysed the methylation status of the tumor suppressor gene p16, the DNA mismatch repair gene hMLH1, and four CpG islands (MINT1, MINT2, MINT25, and MINT31) using methylation-specific polymerase chain reaction in 35 polypoid adenomas and 46 flat dysplasias unassociated with carcinoma, 34 early adenocarcinomas (T1N0M0) and associated adenomas/dysplasias, and corresponding adjacent non-neoplastic mucosa. The extent of CIM was defined by the fraction of methylated loci (methylation index), and compared with previously characterized genetic alterations (microsatellite instability (MSI) and APC gene mutation). We found that methylation of p16 was more frequent in adenocarcinoma-associated dysplasias/adenomas (29%) and adenocarcinomas (44%) as compared to flat dysplasias (4%) and adenomas (18%) unassociated with adenocarcinoma (P ¼ 0.001). The mean methylation index increased from normal/chronic gastritis (CG) mucosa (0.09) to intestinal metaplasia (IM) (0.16), flat dysplasias (0.40) or polypoid adenomas (0.41) unassociated with carcinoma, dysplasias/adenomas associated with carcinoma (0.44), and adenocarcinomas (0.44). There was no difference in frequencies of highlevel CpG island methylation (CIM-H, methylation index X0.5) among flat dysplasias (50%) and polypoid adenomas (51%) unassociated with carcinoma, dysplasias/adenomas associated with adenocarcinoma (47%), and adenocarcinoma (47%). CIM-H was present in 15% of IM, but not in normal/CG mucosa. There was a significant correlation between methylation of hMLH1 and high-level of microsatellite instability (MSI-H): methylation of hMLH1 was present in 71% of MSI-H tumors, but only 8% of MSI-low tumors and 13% of microsatellite-stable tumors (P ¼ 0.0001). There was no statistical difference between methylation index and APC mutation. Our results indicate that concurrent promoter methylation is an early and frequent event in gastric tumorigenesis, including both MSI-H and microsatellitestable neoplasms. Methylation of the p16 gene may contribute to the malignant transformation of gastric precursor lesions.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

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Frequent CpG island methylation in precursor lesions and early gastric adenocarcinomas

et al. 2004

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“…The role of the pRb pathway in gastric carcinogenesis is the subject of many papers. In distal gastric cancers it may be that disruption of p16 is an early event [11] and a recent immunohistochemical study [12] has shown a progressive decrease in expression from gastritis to atrophy and dysplasia. Less information is available on the role of pRb expression.…”

Section: Introductionmentioning

confidence: 99%

Differences in proximal (cardia) versus distal (antral) gastric carcinogenesis via retinoblastoma pathway

Gulmann¹,

Hegarty²,

Grace³

et al. 2004

WJG

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AIM: Disruption of cell cycle regulation is a critical event in carcinogenesis, and alteration of the retinoblastoma (pRb) tumour suppressor pathway is frequent. The aim of this study was to compare alterations in this pathway in proximal and distal gastric carcinogenesis in an effort to explain the observed striking epidemiological differences. METHODS:Immunohistochemistry was performed to investigate expression of p16 and pRb in the following groups of both proximal (cardia) and distal (antral) tissue samples: (a) biopsies showing normal mucosa, (b) biopsies showing intestinal metaplasia and, (c) gastric cancer resection specimens including uninvolved mucosa and tumour.

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“…[5][6][7] Aberrant methylation of p16 was reported to occur frequently in a variety of human cancers. 8 In GC, the frequency of p16 inactivation by methylation ranged from 32% to 67%, [9][10][11][12] whereas the frequencies by homozygous deletion and point mutation were both lower than 10%, [13][14][15] suggesting that methylation is a major mechanism for p16 inactivation in GC. Although p16 methylation in gastric precancerous lesions was reported, [16][17][18][19][20] however, the prevalence of aberrant p16 methylation in various gastric lesions was not reported on population-based study yet.…”

mentioning

confidence: 99%

Promoter methylation of p16 associated with Helicobacter pylori infection in precancerous gastric lesions: A population‐based study

Dong

Deng

Pan

et al. 2008

Intl Journal of Cancer

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To investigate the relationship between p16 methylation and Helicobacter pylori infection in precancerous gastric lesions, a population-based study was conducted in Linqu County, a high-risk area of gastric cancer in China. Methylation status of p16 was evaluated by methylation-specific polymerase chain reaction in 920 subjects with precancerous gastric lesions. H. pylori status was determined by 13 C-urea breath test and the density of H. pylori in biopsy specimens used for detecting methylation status was assessed by the modified Giemsa stain. The frequency of p16 methylation was significantly higher in subjects with H. pylori positive than those with H. pylori negative in each category of gastric lesion (p < 0.001, respectively). Compared with H. pylori negative, the odds ratios (ORs) of p16 methylation were markedly elevated in subjects with H. pylori positive for superficial gastritis (OR, 9.45; 95% confidence interval [CI]: 2.94-30.41), chronic atrophic gastritis (OR, 15.92; 95%CI: 7.60-33.36), intestinal metaplasia (OR, 4.46; 95%CI: 2.44-8.13), indefinite dysplasia (OR, 3.67; 95%CI: 1.90-7.10), and dysplasia (OR, 2.48; 95%CI: 1.02-5.99). Moreover, the frequencies of p16 methylation increased steadily with the severity of H. pylori density in gastric mucosa. Compared with H. pylori negative, the OR of p16 methylation was 1.02-16.13 times higher in subjects with mild H. pylori infection, and 2.69-38.73 times higher in those with moderate/severe infection, respectively. Our findings indicate that p16 methylation was significantly associated with H. pylori infection in precancerous gastric lesions, suggesting that H. pylori infection could potently induce methylation of p16 CpG island.

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p16INK4a Promoter hypermethylation of non-tumorous tissue adjacent to gastric cancer is correlated with glandular atrophy and chronic inflammation

Cited by 47 publications

References 19 publications

Frequent CpG island methylation in precursor lesions and early gastric adenocarcinomas

Frequent CpG island methylation in precursor lesions and early gastric adenocarcinomas

Differences in proximal (cardia) versus distal (antral) gastric carcinogenesis via retinoblastoma pathway

Promoter methylation of p16 associated with Helicobacter pylori infection in precancerous gastric lesions: A population‐based study

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