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Carcinogenesis Advance Access published online on March 14, 2006
Carcinogenesis, doi:10.1093/carcin/bgi361
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received October 3, 2005
Revised January 27, 2006
Accepted January 31, 2006

CANCER BIOLOGY

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 1, Yae Kanai 1 *, Morio Sawada 1, Saori Ushijima 1, Nobuyoshi Hiraoka 1, Sohei Kitazawa 2, and Setsuo Hirohashi 1

1 Pathology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
2 Division of Molecular Pathology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan

* To whom correspondence should be addressed.
Yae Kanai, E-mail: ykanai{at}ncc.go.jp


  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 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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