High concordance between DNA methylation of tumor suppressor loci in pancreatic cancer cell lines and their corresponding primary carcinoma

Ueki, Takashi; Toyota, Minoru; Walter, Kimberly; Jaffee, Elizabeth M.; Yeo, Charles J.; Hruban, Ralph H.; Goggins, M.

doi:10.1016/s0016-5085(00)82253-2

Cited by 18 publications

(30 citation statements)

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“…The importance of MMP12 in human lung has, however, been shown by its role in the development of emphysema caused by cigarette smoke (Hautama¨ki et al, 1997). Silencing of TIMP3 by DNA methylation has been detected in lung, gastric and pancreatic tumours (Kang et al, 2000;Ueki et al, 2000;Zochbauer-Mu¨ller et al, 2001). In our data TIMP3 was significantly less expressed among the cases, while TIMP1 was expressed at a significantly higher level among the cases.…”

Section: Up-regulated Genescontrasting

confidence: 42%

Identification of differentially expressed genes in pulmonary adenocarcinoma by using cDNA array

et al. 2002

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No clear patterns in molecular changes underlying the malignant processes in lung cancer of different histological types have been found so far. To identify critical genes in lung cancer progression we compared the expression profile of cancer related genes in 14 pulmonary adenocarcinoma patients with normal lung tissue by using the cDNA array technique. Principal component analyses (PCA) and permutation test were used to detect the differentially expressed genes. The expression profiles of 10 genes were confirmed by semiquantitative real-time RT -PCR. In tumour samples, as compared to normal lung tissue, the up-regulated genes included such known tumour markers as CCNB1, PLK, tenascin, KRT8, KRT19 and TOP2A. The downregulated genes included caveolin 1 and 2, and TIMP3. We also describe, for the first time, down-regulation of the interesting SOCS2 and 3, DOC2 and gravin. We show that silencing of SOCS2 is not caused by methylation of exon 1 of the gene. In conclusion, by using the cDNA array technique we were able to reveal marked differences in the gene expression level between normal lung and tumour tissue and find possible new tumour markers for pulmonary adenocarcinoma.

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Section: Up-regulated Genescontrasting

confidence: 42%

Identification of differentially expressed genes in pulmonary adenocarcinoma by using cDNA array

et al. 2002

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“…Methylated CpG island amplification/representational difference analysis MCA/RDA was performed as described by Toyota et al (Toyota et al, 1999b;Ueki et al, 2001) with a few modifications. Briefly, 5 mg of DNA was digested with 100 U of SmaI (New England Biolabs, Beverly, MA, USA) and then with 20 U of XmaI (New England Biolabs).…”

Section: Cell Lines and Samplesmentioning

confidence: 99%

Epigenetic inactivation of the candidate tumor suppressor gene HOXB13 in human renal cell carcinoma

Okuda¹,

Toyota

Ishida

et al. 2005

Oncogene

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Epigenetic alterations like DNA methylation and the resulting inactivation of cancer-related genes often contribute to the development of various cancers. To identify the genes that are silenced by aberrant methylation in renal cell carcinoma (RCC), we subjected two RCC lines to methylated CpG island amplification/representational difference analysis. This identified 27 CpG islands. Combined bisulfite restriction analysis of these CpG islands in primary RCC cases revealed that four were methylated in a tumor-specific manner. One of these was identified as the human homeo-box gene B13 (HOXB13) gene, but the remaining three CpG islands were not associated with known genes. The methylation frequencies of HOXB13 in primary RCC samples and lines were 30 and 73%, respectively. The methylation status of HOXB13 correlated with the loss of its expression both in RCC lines and primary tumors, and methyltransferase inhibitor treatment induced the recovery of its expression. Exogenous expression of HOXB13 in RCC cells that lacked endogenous HOXB13 expression suppressed colony formation and induced apoptotic features. Furthermore, HOXB13 methylation correlated positively with tumor grade and microvessel invasion. These results suggest that HOXB13 is a novel candidate tumor suppressor gene in RCC and that its inactivation may play an important role in both RCC tumorigenesis and progression.

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“…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). Recent data, however, suggest that there is concordant methylation of multiple genes (termed CpG-island methylation phenotype, CIMP) (Toyota et al, 1999a) in carcinomas from diverse sites including uterine cervix, colorectum, biliary tree, pancreas, bladder, nasopharynx, esophagus, and stomach (Toyota et al, 1999a, b;Eads et al, 2000Eads et al, , 2001Kang et al, 2001;Leung et al, 2001;Maruyama et al, 2001Maruyama et al, , 2002Ueki et al, 2001;Virmani et al, 2001;Lee et al, 2002a, b;Kwong et al, 2002). Concordant methylation of multiple loci has been described in 41% of gastric cancer (Toyota et al, 1999b).…”

Section: Introductionmentioning

confidence: 99%

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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High concordance between DNA methylation of tumor suppressor loci in pancreatic cancer cell lines and their corresponding primary carcinoma

Cited by 18 publications

References 0 publications

Identification of differentially expressed genes in pulmonary adenocarcinoma by using cDNA array

Identification of differentially expressed genes in pulmonary adenocarcinoma by using cDNA array

Epigenetic inactivation of the candidate tumor suppressor gene HOXB13 in human renal cell carcinoma

Frequent CpG island methylation in precursor lesions and early gastric adenocarcinomas

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