Concerted promoter hypermethylation of hMLH1, p16INK4A, and E‐cadherin in gastric carcinomas with microsatellite instability

Kim, Hyunki; Kim, Yun Hee; Kim, Sung Eun; Kim, Nam Gyun; Noh, Sung Hoon; Kim, Hoguen

doi:10.1002/path.1325

Cited by 68 publications

(60 citation statements)

References 34 publications

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“…The present study demonstrates no significant difference in the proportion of MSI between the differentiated type and the undifferentiated type. Although predominant intestinal-type histology in microsatellite-unstable carcinomas has been widely accepted [2,4,5,9,10,23], several reports have shown predominant poorly differentiated histology [1], or no significant association between histological morphology and MSI [6,[11][12][13]. The differences among these reports were considered to depend upon the specific groups of cases studied and the type and number of markers examined.…”

Section: Discussionmentioning

confidence: 99%

“…However, several issues remain poorly defined and are the subject of much debate because of several reports showing predominant poorly differentiated histology [1] or no significant association between histological morphology and MSI [6,[11][12][13]. Because most previous reports were not concerned with histological subtype, but rather with Lauren's classification, a relationship between the histological subtypes of gastric carcinomas and MSI remains obscure.…”

Section: Introductionmentioning

confidence: 99%

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Frequent microsatellite instability in papillary and solid-type, poorly differentiated adenocarcinomas of the stomach

et al. 2012

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Background Microsatellite instability (MSI) has been observed in 8-39 % of sporadic gastric cancers. However, despite numerous reports indicating a significant relationship between intestinal-type histology and MSI, detailed correlation between histological subtypes and MSI remains obscure. The purpose of the present study is to clarify the relationship between histological subtype and microsatellite status in gastric carcinomas. Methods Microsatellite status was examined for 464 consecutive gastric carcinomas from 420 patients as well as histological subtypes and other clinicopathological findings.Results MSI was observed in 82 carcinomas (17.7 %), and the greatest proportions were observed in solid-type, poorly differentiated adenocarcinoma (43.0 %) and papillary adenocarcinoma (32.5 %), both being significantly higher than those of other subtypes. The proportion increased with advancing age (0 % at 51-64 years, 8.5 % at 65-74 years, 18.4 % at 75-84 years, 35.3 % at 85-96 years). Compared with microsatellite-stable carcinomas, microsatellite-unstable carcinomas were significantly related with older age, female gender, antral location, and predominant papillary adenocarcinoma and solid-type, poorly differentiated adenocarcinoma. Poorly differentiated type carcinoma was significantly less frequent than differentiated type in microsatellite-unstable cancer at the early stage, whereas no significant difference existed at the advanced stage. Conclusions These results suggest that there are specific histological subtypes with highly frequent MSI and that gastric carcinoma with MSI originates from differentiatedtype carcinomas, indicating histological diversity during tumor growth.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Frequent microsatellite instability in papillary and solid-type, poorly differentiated adenocarcinomas of the stomach

et al. 2012

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“…The hypermethylation of CpG islands within the promoter and/or upstream exon regions is an important epigenetic mechanism underlying the inactivation of tumor-suppressor genes (TSGs) [3] . It was reported that quite a few TSGs, including the Ras association domain family 1A (RASSF1A) gene, are epigenetically silenced by aberrant promoter hypermethylation in gastric and colorectal cancer [4][5][6][7][8][9][10] . RASSF1A is a newly identified candidate TSG located in the 3p21.3 region [11] , and promoter hypermethylation of RASSF1A, which is its most common inactivation mechanism, has been observed in many human solid tumors, including gastric and colorectal cancers [11][12][13][14][15][16][17] .…”

Section: Introductionmentioning

confidence: 99%

Detection of RASSF1A promoter hypermethylation in serum from gastric and colorectal adenocarcinoma patients

Wang¹,

Yu²,

Liu³

et al. 2008

WJG

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AIM:To evaluate the diagnostic role of serum RASSF1Apromoter hypermethylation in gastric and colorectal adenocarcinoma. METHODS:Methylation-specific polymerase chain reaction (MSPCR) was used to examine the promoter methylation status of the serum RASSF1A gene in 47 gastric adenocarcinoma patients, 45 colorectal adenocarcinoma patients, 60 patients with benign gastrointestinal disease (30 with benign gastric disease and 30 with benign colorectal disease), and 30 healthy donor controls. A paired study of RASSF1A promoter methylation status in primary tumor, adjacent normal tissue, and postoperative serum were conducted in 25 gastric and colorectal adenocarcinoma patients who later were underwent surgical therapy. RESULTS:The frequencies of detection of serum RASSF1A promoter hypermethylation in gastric (34.0%) and colorectal (28.9%) adenocarcinoma patients were significantly higher than those in patients with benign gastric (3.3%) or colorectal (6.7%) disease or in healthy donors (0%) (P < 0.01). The methylation status of Wang YC, Yu ZH, Liu C, Xu LZ, Yu W, Lu J, Zhu RM, Li GL, Xia XY, Wei XW, Ji HZ, Lu H, Gao Y, Gao WM, Chen LB. Detection of RASSF1A promoter hypermethylation in serum from gastric and colorectal adenocarcinoma patients.

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“…17,18 The CpG island methylation phenotype (CIMP) is an epigenetic phenomenon found in a variety of cancers. 19,20 In colorectal and gastric cancers, CIMP frequently associates with MLH1 methylation, loss of MLH1 transcription, and MSI-H. 19,21,22 An association of CIMP with BRAF mutations has been found in colorectal cancer 23 but, interestingly, mutations in BRAF do not have a significant role in either CIMP-positive or -negative gastric cancers. 24 Analyses of genomic and epigenetic interrelations in human neoplasms have added largely to our understanding of tumor development and have led to a novel molecular classification of colorectal cancer.…”

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confidence: 99%

Genetics and epigenetics of small bowel adenocarcinoma: the interactions of CIN, MSI, and CIMP

et al. 2011

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Characterization of tumor genetics and epigenetics allows to stratify a tumor entity according to molecular pathways and may shed light on the interactions of different types of DNA alterations during tumorigenesis. Small intestinal adenocarcinoma is rare, and to date the interrelation of genomic instability and epigenetics has not been investigated in this tumor type. We therefore analyzed 37 primary small bowel carcinomas with known microsatellite instability and KRAS status for chromosomal instability using comparative genomic hybridization, for the presence of aberrant methylation (CpG island methylation phenotype) by methylation-specific polymerase chain reaction, and for BRAF mutations. Chromosomal instability was detected in 22 of 37 (59%) tumors (3 of 9 microsatellite instable, and 19 of 28 microsatellite stable carcinomas). Nine carcinomas (24%) were microsatellite and chromosomally stable. High-level DNA methylation was found in 16% of chromosomal instable tumors and in 44% of both microsatellite instable and microsatellite and chromosomally stable carcinomas. KRAS was mutated in 55, 0, and 10% of chromosomal instable, microsatellite instable, and microsatellite and chromosomally stable tumors, respectively whereas the frequencies of BRAF mutations were 6% for chromosomal instable and 22% for both microsatellite instable and microsatellite and chromosomally stable carcinomas. In conclusion, in this study we show that chromosomal instable carcinomas of the small intestine are distinguished from microsatellite instable and microsatellite and chromosomally stable tumors by a high frequency of KRAS mutations, low frequencies of CpG island methylation phenotype, and BRAF mutations. In microsatellite instable and microsatellite and chromosomally stable cancers, CpG island methylation phenotype and BRAF/KRAS mutations are similarly distributed, indicating common mechanisms of tumor initiation or progression in their molecular pathogenesis.

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Concerted promoter hypermethylation of hMLH1, p16^INK4A, and E‐cadherin in gastric carcinomas with microsatellite instability

Cited by 68 publications

References 34 publications

Frequent microsatellite instability in papillary and solid-type, poorly differentiated adenocarcinomas of the stomach

Frequent microsatellite instability in papillary and solid-type, poorly differentiated adenocarcinomas of the stomach

Detection of RASSF1A promoter hypermethylation in serum from gastric and colorectal adenocarcinoma patients

Genetics and epigenetics of small bowel adenocarcinoma: the interactions of CIN, MSI, and CIMP

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