DNA methylation of multiple tumor-related genes in association with overexpression of DNA methyltransferase 1 (DNMT1) during multistage carcinogenesis of the pancreas

Dun Fa Peng, Yae Kanai, Morio Sawada, Saori Ushijima, Nobuyoshi Hiraoka, Sohei Kitazawa, Setsuo Hirohashi

Research output: Contribution to journalArticle

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Abstract

To evaluate the significance of alterations in DNA methylation during multistage carcinogenesis of the pancreas, tissue samples of 13 peripheral pancreatic duct epithelia showing no remarkable histological changes without inflammatory background (DE), 20 peripheral pancreatic duct epithelia showing no remarkable histological changes with inflammatory background (DEI), 40 pancreatic intraepithelial neoplasias (PanIN) and 147 areas of ductal carcinoma were microdissected from surgically resected specimens from 58 patients and were embedded into agarose beads. The embedded tissue samples were subjected to methylation-specific PCR (MSP) to evaluate the DNA methylation status of the p14, p15, p16, p73, APC, hMLH1, MGMT, BRCA1, GSTP1, TIMP-3, CDH1 and DAPK-1 genes. The prevalence of DNA methylation of at least one of the 12 genes and the average number of methylated genes were significantly higher in both DEI (60% and 0.85 ± 0.88, P = 0.0151 and P = 0.0224, respectively) and PanIN (67.5% and 0.95 ± 0.85, P = 0.0014 and P = 0.0028, respectively) than in DE (15.4% and 0.15 ± 0.38), and were further increased in ductal carcinoma (98.3% and 2.50 ± 1.35, P < 0.0001 and P < 0.0001, respectively). The BRCA1, APC, p16 and TIMP-3 genes were frequently methylated in ductal carcinoma (60.3, 58.6, 39.3 and 30.9%, respectively). Considerable heterogeneity of DNA methylation status was observed among multiple microdissected areas from individual ductal carcinomas, and the number of methylated genes per area was significantly correlated with poorer tumor differentiation (P = 0.0249). The average number of methylated genes in ductal carcinomas was significantly correlated with DNMT1 protein expression level (P = 0.0093). These data suggest that accumulation of DNA methylation of multiple tumor-related genes is involved in multistage carcinogenesis of the pancreas from early precancerous stages to malignant progression and that DNMT1 protein overexpression may be responsible for this aberrant DNA methylation.

Original languageEnglish
Pages (from-to)1160-1168
Number of pages9
JournalCarcinogenesis
Volume27
Issue number6
DOIs
Publication statusPublished - 2006 Jun
Externally publishedYes

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Methyltransferases
DNA Methylation
Ductal Carcinoma
Pancreas
Carcinogenesis
DNA
Genes
Protein Methyltransferases
Neoplasms
Tissue Inhibitor of Metalloproteinase-3
Pancreatic Ducts
Epithelium
Sepharose
Methylation
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Cancer Research

Cite this

DNA methylation of multiple tumor-related genes in association with overexpression of DNA methyltransferase 1 (DNMT1) during multistage carcinogenesis of the pancreas. / Peng, Dun Fa; Kanai, Yae; Sawada, Morio; Ushijima, Saori; Hiraoka, Nobuyoshi; Kitazawa, Sohei; Hirohashi, Setsuo.

In: Carcinogenesis, Vol. 27, No. 6, 06.2006, p. 1160-1168.

Research output: Contribution to journalArticle

Peng, Dun Fa ; Kanai, Yae ; Sawada, Morio ; Ushijima, Saori ; Hiraoka, Nobuyoshi ; Kitazawa, Sohei ; Hirohashi, Setsuo. / DNA methylation of multiple tumor-related genes in association with overexpression of DNA methyltransferase 1 (DNMT1) during multistage carcinogenesis of the pancreas. In: Carcinogenesis. 2006 ; Vol. 27, No. 6. pp. 1160-1168.
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abstract = "To evaluate the significance of alterations in DNA methylation during multistage carcinogenesis of the pancreas, tissue samples of 13 peripheral pancreatic duct epithelia showing no remarkable histological changes without inflammatory background (DE), 20 peripheral pancreatic duct epithelia showing no remarkable histological changes with inflammatory background (DEI), 40 pancreatic intraepithelial neoplasias (PanIN) and 147 areas of ductal carcinoma were microdissected from surgically resected specimens from 58 patients and were embedded into agarose beads. The embedded tissue samples were subjected to methylation-specific PCR (MSP) to evaluate the DNA methylation status of the p14, p15, p16, p73, APC, hMLH1, MGMT, BRCA1, GSTP1, TIMP-3, CDH1 and DAPK-1 genes. The prevalence of DNA methylation of at least one of the 12 genes and the average number of methylated genes were significantly higher in both DEI (60{\%} and 0.85 ± 0.88, P = 0.0151 and P = 0.0224, respectively) and PanIN (67.5{\%} and 0.95 ± 0.85, P = 0.0014 and P = 0.0028, respectively) than in DE (15.4{\%} and 0.15 ± 0.38), and were further increased in ductal carcinoma (98.3{\%} and 2.50 ± 1.35, P < 0.0001 and P < 0.0001, respectively). The BRCA1, APC, p16 and TIMP-3 genes were frequently methylated in ductal carcinoma (60.3, 58.6, 39.3 and 30.9{\%}, respectively). Considerable heterogeneity of DNA methylation status was observed among multiple microdissected areas from individual ductal carcinomas, and the number of methylated genes per area was significantly correlated with poorer tumor differentiation (P = 0.0249). The average number of methylated genes in ductal carcinomas was significantly correlated with DNMT1 protein expression level (P = 0.0093). These data suggest that accumulation of DNA methylation of multiple tumor-related genes is involved in multistage carcinogenesis of the pancreas from early precancerous stages to malignant progression and that DNMT1 protein overexpression may be responsible for this aberrant DNA methylation.",
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