Hypermethylation of the hMLH1 gene promoter is associated with microsatellite instability in early human gastric neoplasia

Fleisher, A. Steven; Esteller, Manel; Tamura, Gen; Rashid, Asma; Stine, O. Colin; Yin, Jing; Zou, Tong; Abraham, John M.; Kong, Dehe; Nishizuka, Satoshi; James, Stephen P.; Wilson, Keith T.; Herman, James G.; Meltzer, Stephen J.

doi:10.1038/sj.onc.1204104

Cited by 261 publications

(285 citation statements)

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“…In addition, APC 5' region hypermethylation has been reported in colorectal cancers (Hiltunen et al, 1997). In gastric cancers, promoter CpG island hypermethylation of p16, hMLH1, and E-cadherin has been reported (Fleisher et al, 1999;Suzuki et al, 1999;Tamura et al, 2000). Because a subset of gastric and colorectal cancers display a CpG island methylator phenotype (Toyota et al, 1999a,b), we hypothesized that APC is inactivated through promoter hypermethylation in both of these cancer types.…”

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confidence: 98%

Distinct methylation patterns of two APC gene promoters in normal and cancerous gastric epithelia

et al. 2000

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The adenomatous polyposis coli (APC) tumor suppressor gene is mutationally inactivated in both familial and sporadic forms of colorectal cancers. In addition, hypermethylation of CpG islands in the upstream portion of APC, a potential alternative mechanism of tumor suppressor gene inactivation, has been described in colorectal cancer. Because a subset of both gastric and colorectal cancers display the CpG island methylator phenotype, we hypothesized that epigenetic inactivation of APC was likely to occur in at least some gastric cancers. APC exhibits two forms of transcripts from exons 1A and 1B in the stomach. Therefore, we investigated CpG island methylation in the sequences upstream of exons 1A and 1B, i.e., promoters 1A and 1B, respectively. We evaluated DNAs from 10 gastric cancer cell lines, 40 primary gastric cancers, and 40 matching non-cancerous gastric mucosae. Methylated alleles of promoter 1A were present in 10 (100%) of 10 gastric cancer cell lines, 33 (82.5%) of 40 primary gastric cancers, and 39 (97.5%) of 40 noncancerous gastric mucosae. In contrast, promoter 1B was unmethylated in all of these same samples. APC transcripts from exon 1A were not expressed in nine of the 10 methylated gastric cancer cell lines, whereas APC transcripts were expressed from exon 1B. Thus, expression from a given promoter correlated well with its methylation status. We conclude that in contrast to the colon, methylation of promoter 1A is a normal event in the stomach; moreover, promoter 1B is protected from methylation in the stomach and thus probably does not participate in this form of epigenetic APC inactivation.

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Section: Introductionmentioning

confidence: 98%

Distinct methylation patterns of two APC gene promoters in normal and cancerous gastric epithelia

et al. 2000

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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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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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“…9,10 MSI is rarely caused by mutations of DNA-mismatch-repair genes such as hMLH1 and hMSH2, 10,11 but hypermethylation of the hMLH1 promoter region is observed in gastric cancers with MSI. 12,13 Promoter hypermethylations are known to cause silencing of genes in various human cancers. 14,15 In addition, methylation alterations of CpG islands (CGIs) outside promoter regions are associated with altered levels of gene expressions.…”

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Reduced expression of the insulin‐induced protein 1 and p41 Arp2/3 complex genes in human gastric cancers

Kaneda

Kaminishi

Nakanishi³

et al. 2002

Intl Journal of Cancer

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Aberrantly methylated DNA fragments in a human gastric cancer were searched for by a genome-scanning method, methylation-sensitive-representational difference analysis (MS-RDA). Six DNA fragments flanked by CpG islands (CGIs) and hypermethylated in the cancer were isolated. Four of the 6 fragments possessed genes in their vicinities. Quantitative RT-PCR analysis of the 4 genes showed reduced expression of 2 genes in cancers: Insulin-induced protein 1 (INSIG1/CL-6) and p41 Arp2/3 complex (p41-Arc). As for INSIG1, a DNA fragment was derived from the edge of a CGI in the promoter region. The edge was methylated in 11 of 22 primary gastric cancers, whereas the center was not methylated in any cancer. INSIG1 expression was markedly reduced in 19 cancers, including the 11 cancers with the methylation. By 5-aza-2 -deoxycytidine treatment of 5 cell lines with the methylation of the edge, partial restoration of INSIG1 expression was detected only in 2 of them. These data indicated that, although the reduced INSIG1 expression in cancers was associated with the methylation at the edge of the CGI in the promoter region, the methylation was likely to be a secondary change. As for p41-Arc, a DNA fragment was derived from a CGI overlapping exon 8, and its methylation did not correlate with its expression. However, methylation of a CGI in the promoter region with a marked reduction of its expression was observed in 1 of the 22 primary cancers. INSIG1 and p41-Arc are known to be involved in cellular differentiation and morphology, respectively, and it was suggested that their reduced expressions might be involved in gastric cancer development or progression. © 2002 Wiley-Liss, Inc. Key words: INSIG1/CL-6; p41-Arc; methylation; carcinogenesis; gastric cancerGastric cancer is one of the major causes of cancer death in many countries. 1 As underlying genetic and epigenetic alterations, mutations of p53 have been reported in 35-56% of human gastric cancers, 2-4 and silencing of p16 by its promoter hypermethylation has been reported in 42.0 -42.2%. 5,6 Mutations of K-RAS and APC genes, however, are observed only at very low frequencies, in the ranges of 0 -3.6% and 0 -1.4%, respectively. 3,7,8 As a factor that influences the accumulation of genetic alterations, microsatellite instability (MSI) is observed at high incidences, ranging from 31-67%. 9,10 MSI is rarely caused by mutations of DNA-mismatch-repair genes such as hMLH1 and hMSH2, 10,11 but hypermethylation of the hMLH1 promoter region is observed in gastric cancers with MSI. 12,13 Promoter hypermethylations are known to cause silencing of genes in various human cancers. 14,15 In addition, methylation alterations of CpG islands (CGIs) outside promoter regions are associated with altered levels of gene expressions. 16 -18 To search for genes whose expressions are altered in association with methylation alterations, we previously established a genome-scanning method for methylation alterations, methylation-sensitive-representational difference analysis (MS-RDA). 19 By this metho...

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Hypermethylation of the hMLH1 gene promoter is associated with microsatellite instability in early human gastric neoplasia

Cited by 261 publications

References 39 publications

Distinct methylation patterns of two APC gene promoters in normal and cancerous gastric epithelia

Distinct methylation patterns of two APC gene promoters in normal and cancerous gastric epithelia

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

Reduced expression of the insulin‐induced protein 1 and p41 Arp2/3 complex genes in human gastric cancers

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