Carcinogenesis, Vol. 24, No. 2, 193-198,
February 2003
© 2003 Oxford University Press
CANCER BIOLOGY |
Molecular progression of promoter methylation in intraductal papillary mucinous neoplasms (IPMN) of the pancreas
1 Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, MD, USA,
2 Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA and
3 Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA
To understand the role of gene promoter methylation in neoplastic evolution and progression, the methylation changes associated with 15 candidate tumor suppressor genes were studied throughout stages of tumor progression involving intraductal papillary mucinous neoplasms (IPMN) of the pancreas. Genomic DNA from 28 pancreatic IPMN tissue samples, categorized histologically as non-invasive intraductal IPMN (n = 3), IPMN with carcinoma in situ (n = 7), IPMN with microinvasion <1 mm (n = 4), and infiltrative IPMN with associated adenocarcinoma (n = 14), was modified by bisulfite treatment and analyzed with methylation-specific PCR (MSP). Promoter methylation of at least one tumor suppressor gene was present in 26/28 (92%) of the IPMNs. The cell cycle control genes, p16 and p73, were methylated frequently (>50%) in both non-invasive and invasive tumors. APC methylation was discovered in <10% of the non-invasive IPMNs versus 45% of the IPMNs associated with infiltrative adenocarcinoma, P = 0.040. Mismatch repair genes, hMLH1 and MGMT, were frequently methylated in the invasive IPMNs compared with the non-invasive tumors (38 versus 10% and 45 versus 20%, respectively) as was E-cadherin (38 versus 10%), P = 0.11. Multiple gene methylation at greater than three loci was present in 55% of the invasive tumors compared with 20% of the non-invasive tumors, P = 0.075. Lymph node status did not predict multi-gene methylation among tumors associated with invasive cancer. Compared with non-invasive IPMNs of the pancreas, IPMNs associated with adenocarcinoma demonstrate higher rates of aberrant tumor suppressor gene methylation. The sequential acquisition of hypermethylation at multiple gene promoter sites may explain tumor progression in IPMNs and other malignancies. Detection of methylation within selected genes may afford an accurate diagnostic molecular marker and predictor of neoplastic behavior.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  N Katabi and D S Klimstra Intraductal papillary mucinous neoplasms of the pancreas: clinical and pathological features and diagnostic approach J. Clin. Pathol., December 1, 2008; 61(12): 1303 - 1313. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D.F. Licchesi, W. H. Westra, C. M. Hooker, E. O. Machida, S. B. Baylin, and J. G. Herman Epigenetic alteration of Wnt pathway antagonists in progressive glandular neoplasia of the lung Carcinogenesis, May 1, 2008; 29(5): 895 - 904. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Ghaneh and J. Neoptolemos A new approach to managing intraductal papillary mucinous pancreatic neoplasms Gut, August 1, 2007; 56(8): 1041 - 1044. [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Miyasaka, E. Nagai, H. Yamaguchi, K. Fujii, T. Inoue, K. Ohuchida, T. Yamada, K. Mizumoto, M. Tanaka, and M. Tsuneyoshi The Role of the DNA Damage Checkpoint Pathway in Intraductal Papillary Mucinous Neoplasms of the Pancreas Clin. Cancer Res., August 1, 2007; 13(15): 4371 - 4377. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. K. Jung, P. Arora, J. S. Pagano, and K. L. Jang Expression of DNA Methyltransferase 1 Is Activated by Hepatitis B Virus X Protein via a Regulatory Circuit Involving the p16INK4a-Cyclin D1-CDK 4/6-pRb-E2F1 Pathway Cancer Res., June 15, 2007; 67(12): 5771 - 5778. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Yuan, J. Wang, J. Li, L. Wang, M. Li, Z. Yang, C. Zhang, and J. L. Dai Frequent Epigenetic Inactivation of Spleen Tyrosine Kinase Gene in Human Hepatocellular Carcinoma. Clin. Cancer Res., November 15, 2006; 12(22): 6687 - 6695. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ohuchida, K. Mizumoto, S. Ohhashi, H. Yamaguchi, H. Konomi, E. Nagai, K. Yamaguchi, M. Tsuneyoshi, and M. Tanaka S100A11, A Putative Tumor Suppressor Gene, Is Overexpressed in Pancreatic Carcinogenesis. Clin. Cancer Res., September 15, 2006; 12(18): 5417 - 5422. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Guo, J. Ren, M. G. House, Y. Qi, M. V. Brock, and J. G. Herman Accumulation of Promoter Methylation Suggests Epigenetic Progression in Squamous Cell Carcinoma of the Esophagus Clin. Cancer Res., August 1, 2006; 12(15): 4515 - 4522. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. D. Gore, S. Baylin, E. Sugar, H. Carraway, C. B. Miller, M. Carducci, M. Grever, O. Galm, T. Dauses, J. E. Karp, et al. Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res., June 15, 2006; 66(12): 6361 - 6369. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Schonleben, W. Qiu, N. T. Ciau, D. J. Ho, X. Li, J. D. Allendorf, H. E. Remotti, and G. H. Su PIK3CA Mutations in Intraductal Papillary Mucinous Neoplasm/Carcinoma of the Pancreas. Clin. Cancer Res., June 15, 2006; 12(12): 3851 - 3855. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D.-F. Peng, Y. Kanai, M. Sawada, S. Ushijima, N. Hiraoka, S. Kitazawa, and S. Hirohashi DNA methylation of multiple tumor-related genes in association with overexpression of DNA methyltransferase 1 (DNMT1) during multistage carcinogenesis of the pancreas Carcinogenesis, June 1, 2006; 27(6): 1160 - 1168. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Zhang, C. R. Martins, Z. B. Fansler, K. L. Roemer, E. A. Kincaid, K. S. Gustafson, D. F. Heitjan, and D. P. Clark DNA Methylation in Anal Intraepithelial Lesions and Anal Squamous Cell Carcinoma Clin. Cancer Res., September 15, 2005; 11(18): 6544 - 6549. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Sato, H. Matsubayashi, T. Abe, N. Fukushima, and M. Goggins Epigenetic Down-Regulation of CDKN1C/p57KIP2 in Pancreatic Ductal Neoplasms Identified by Gene Expression Profiling Clin. Cancer Res., July 1, 2005; 11(13): 4681 - 4688. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Brandes, M. van Engeland, K. A.D. Wouters, M. P. Weijenberg, and J. G. Herman CHFR promoter hypermethylation in colon cancer correlates with the microsatellite instability phenotype Carcinogenesis, June 1, 2005; 26(6): 1152 - 1156. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Zuo, L. Ai, P. Ratliff, J. Y. Suen, E. Hanna, T. P. Brent, and C.-Y. Fan O6-Methylguanine-DNA Methyltransferase Gene: Epigenetic Silencing and Prognostic Value in Head and Neck Squamous Cell Carcinoma Cancer Epidemiol. Biomarkers Prev., June 1, 2004; 13(6): 967 - 975. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Sato, N. Fukushima, A. Maitra, C. A. Iacobuzio-Donahue, N. T. van Heek, J. L. Cameron, C. J. Yeo, R. H. Hruban, and M. Goggins Gene Expression Profiling Identifies Genes Associated with Invasive Intraductal Papillary Mucinous Neoplasms of the Pancreas Am. J. Pathol., March 1, 2004; 164(3): 903 - 914. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. G. House, I. I. Wistuba, P. Argani, M. Guo, R. D. Schulick, R. H. Hruban, J. G. Herman, and A. Maitra Progression of Gene Hypermethylation in Gallstone Disease Leading to Gallbladder Cancer Ann. Surg. Oncol., October 1, 2003; 10(8): 882 - 889. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Yang, M. Guo, J. G. Herman, and D. P. Clark Aberrant Promoter Methylation Profiles of Tumor Suppressor Genes in Hepatocellular Carcinoma Am. J. Pathol., September 1, 2003; 163(3): 1101 - 1107. [Abstract] [Full Text] [PDF]
|
|