Microsatellite instability of papillary subtype of human gastric adenocarcinoma and <i>hMLH1</i> promoter hypermethylation in the surrounding mucosa

Guo, Rong–Jun; Arai, Hajime; Kitayama, Yasuhiko; Igarashi, Hisaki; Hemmi, Hiromichi; Arai, Tomio; Hanai, Hiroyuki; Sugimura, Haruhiko

doi:10.1046/j.1440-1827.2001.01197.x

Cited by 32 publications

(35 citation statements)

References 23 publications

(62 reference statements)

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“…In our present study, however, methylation of the hMLH1 promoter was detected in non-cancerous mucosa adjacent to both solitary (6 out of 12, 50%) and multiple (5 out of 8, 63%) gastric tumours with MSI-H. Similarly to our present results, Guo et al (2001) has recently reported a high frequency (40%; 4 out of 10) of hMLH1 methylation in non-cancerous mucosa adjacent to gastric cancer showing MSI-H. The exact cause of these discrepancies among reports remains uncertain.…”

Section: Molecular and Cellular Pathologysupporting

confidence: 90%

Hypermethylation of the hMLH1 gene promoter in solitary and multiple gastric cancers with microsatellite instability

et al. 2002

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Human cancers with a high frequency microsatellite instability phenotype develop due to defects in DNA mismatch repair genes. Silencing of a DNA mismatch repair gene, hMLH1 gene, by promoter hypermethylation is a frequent cause of the microsatellite instability-H phenotype. Using methylation specific PCR we investigated the methylation status of the hMLH1 gene promoter in 17 solitary gastric cancers (12 microsatellite instability-H and five microsatellite stable tumours from 17 patients), and 13 multiple gastric cancers (eight microsatellite instability-H, one low frequency microsatellite instability-L and four microsatellite stable tumours from five patients) and also examined non-cancerous gastric mucosa both adjacent to and distant from each tumour. Expression of hMLH1 protein was evaluated by immunohistochemistry. All microsatellite instability-H tumours (20 out of 20) had evidence of methylation of hMLH1 promoter, whereas only one out of 10 microsatellite instability-L and microsatellite stable tumours did (P50.0000005), and the methylation status correlated with hMLH1 protein expression (P50.000003). Furthermore, methylation of the hMLH1 promoter was detected in 50% (6 out of 12) and 63% (5 out of 8) of non-cancerous gastric mucosa samples adjacent to, and in 33% (4 out of 12) and 40% (2 out of 5) of those obtained from distant portion of, solitary and multiple cancers with microsatellite instability-H. Thus both solitary and multiple gastric cancers with microsatellite instability-H have evidence of similar high levels of hMLH1 promoter hypermethylation in the surrounding non-cancerous tissue. Hypermethylation of the hMLH1 promoter occurs in non-cancerous gastric mucosa of microsatellite instability-H tumours and may increase the risk of subsequent neoplasia. British Journal of Cancer (2002) Microsatellite instability (MSI) due to defects in mismatch repair genes such as hMLH1 and hMSH2 is now widely recognized as an important mechanism in tumorigenesis (Aaltonen et al, 1993;Ionov et al, 1993;Thibodeau et al, 1996;Fleisher et al, 1999;Kang et al, 1999;Leung et al, 1999;Suzuki et al, 1999;Toyota et al, 1999a). MSI is reportedly present in 15 -33% of solitary gastric cancers, although mutations of the hMLH1 or hMSH2 genes are rare in sporadic gastric cancers (Chong et al, 1994;Mironov et al, 1994;Strickler et al, 1994;Tamura et al, 1996). Hypermethylation of promoter region CpG islands is a common mechanism by which tumour suppressor or tumour-related genes, and DNA mismatch repair genes are inactivated (Herman et al, 1995Kane et al, 1997;Baylin et al, 1998;Jones and Laird, 1999). Aberrant DNA methylation of promoter region CpG islands of several genes, including retinoblastoma (Rb), von Hippel-Lindau (VHL), p16, p15, APC, E-cadherin and hMLH1 has been reported in human cancers, and silencing of hMLH1 by promoter hypermethylation is the major causative event in the development of human cancers with MSI phenotype, including gastric cancers (Graff et al, 1997;Kane et al, 1997;Herman et al, 1998;Fleisher et a...

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Section: Molecular and Cellular Pathologysupporting

confidence: 90%

Hypermethylation of the hMLH1 gene promoter in solitary and multiple gastric cancers with microsatellite instability

et al. 2002

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“…Medullary-type colorectal carcinoma shows hypermethylation of the hMLH1 promoter with loss of hMLH1 expression [26]. As already mentioned, papillary adenocarcinoma of the stomach has the same features [8]. Therefore, this evidence suggests that gastrointestinal carcinomas with MSI predominantly occur at a specific site within each organ in elderly women.…”

Section: Discussionmentioning

confidence: 55%

“…More than one third of papillary and solid-type, poorly differentiated adenocarcinomas showed MSI in elderly patients with gastric carcinomas. High proportions (26-40 %) of MSI have been reported in papillary carcinoma [8,24]. Papillary or papillotubular adenocarcinoma is proposed to be a distinct morphological type with a molecular pathway of MSI because microsatellite-unstable papillary carcinoma has been found to exhibit preferential hypermethylation of the hMLH1 promoter, with absence of hMLH1 expression, and frequent mutations in genes such as BAX, TGFbRII, MSH3, and MSH6 [8].…”

Section: Discussionmentioning

confidence: 99%

“…Microsatellite-unstable gastric carcinomas have the following clinicopathological features: older age, expanding growth pattern, antral location, intestinal-type histology, a lower incidence of lymph node metastasis, and favorable prognosis. Regarding molecular mechanism, age-related hypermethylation in the hMLH1 promoter is closely associated with the development of sporadic gastric carcinomas with MSI [7,8].…”

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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“…Dr. Arai and his colleagues took advantage of a particular series of surgical cases at a single institute, which mainly treats the elderly, and they clearly characterized MSI-positive tumors, which tended to occur in older patients and exhibited a female preponderance and particular histological features. As previously reported, MSI in earlystage adenocarcinoma with papillary features (papillary subtype of well-differentiated adenocarcinoma) is often caused by MLH1 promoter methylation [5], and the concept of field cancerization arising from epigenetic changes has now been extended to and established for other cancers and genes [6]. Arai further showed that a solid subtype of poorly differentiated adenocarcinoma that usually appears as a component in a progressive stage also gains MSI during tumor growth.…”

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confidence: 75%

Editorial: an obsession with subtyping gastric cancer

Sugimura

2013

Gastric Cancer

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Microsatellite instability of papillary subtype of human gastric adenocarcinoma and hMLH1 promoter hypermethylation in the surrounding mucosa

Cited by 32 publications

References 23 publications

Hypermethylation of the hMLH1 gene promoter in solitary and multiple gastric cancers with microsatellite instability

Hypermethylation of the hMLH1 gene promoter in solitary and multiple gastric cancers with microsatellite instability

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

Editorial: an obsession with subtyping gastric cancer

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