© 1999 Oxford University Press
Article |
Aberrant methylation of p16INK4a and deletion of p15INK4b are frequent events in human esophageal cancer in Linxian, China
Laboratory for Cancer Research, College of Pharmacy, Rutgers University, Piscataway, NJ 08854 8020, USA and
1 Henan Medical University, Zhengzhou, China
p16INK4a and p15INK4b genes, which encode two functionally related CDK inhibitors, recently emerged as candidate tumor suppressor genes since they were both localized to 9p21, which frequently undergoes hemizygous and homozygous deletion in a variety of tumor types. To determine the mode of inactivation of these two genes in human esophageal squamous cell carcinoma (ESCC), we performed multiple molecular analyses in 60 ESCC specimens from Linxian, China using DNA methylation assay, LOH analysis, deletion screening and SSCP-sequencing. We observed that p16INK4a inactivation was predominantly associated with aberrant methylation in the CpG island of its promoter region, whereas p15INK4b frequently had homozygous deletions. Compared with aberrant methylation, which occurred in 17 of 34 cases, homozygous deletion of p16INK4a and LOH at its nearby D9S942 microsatellite marker were observed at a much lower frequency (17%). Intragenic mutation in p16INK4a gene was rare. In contrast, homozygous deletion in p15INK4b and LOH at the nearby D9S171 marker were observed at frequencies of 35 and 47%, respectively, and the two events were significantly associated with each other. On the other hand, aberrant methylation of p15INK4b was relatively infrequent (6/34) and occurred concomitantly with p16INK4a methylation. Among the 60 cases, only four contained a continuous homozygous deletion spanning both p15INK4b and p16INK4a. Six cases were exclusively deleted at p16INK4a and 17 exclusively deleted at p15INK4b. LOH at D9S942 and D9S171 was also found to be mutually exclusive. Our results suggest that the alteration mode at 9p21 was not uniform, and the two genes were inactivated by distinct mechanisms. Altogether, 68% of the samples harbor at least one type of alteration in p16INK4a gene and 50% of the samples were altered in p15INK4b gene, indicating that they are the frequent inactivating targets during ESCC development.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. Wang, A. J. Sasco, C. Fu, H. Xue, G. Guo, Z. Hua, Q. Zhou, Q. Jiang, and B. Xu Aberrant DNA Methylation of P16, MGMT, and hMLH1 Genes in Combination with MTHFR C677T Genetic Polymorphism in Esophageal Squamous Cell Carcinoma Cancer Epidemiol. Biomarkers Prev., January 1, 2008; 17(1): 118 - 125. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-Z. Deng, P.-P. Chen, Y. Wang, D. Yin, H. P. Koeffler, B. Li, X.-J. Tong, and D. Xie Connective Tissue Growth Factor Is Overexpressed in Esophageal Squamous Cell Carcinoma and Promotes Tumorigenicity through -Catenin-T-cell Factor/Lef Signaling J. Biol. Chem., December 14, 2007; 282(50): 36571 - 36581. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Fang, D. Chen, and C. S. Yang Dietary Polyphenols May Affect DNA Methylation J. Nutr., January 1, 2007; 137(1): 223S - 228S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Z. Fang, D. Chen, Y. Sun, Z. Jin, J. K. Christman, and C. S. Yang Reversal of Hypermethylation and Reactivation of p16INK4a, RAR{beta}, and MGMT Genes by Genistein and Other Isoflavones from Soy Clin. Cancer Res., October 1, 2005; 11(19): 7033 - 7041. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Z. Fang, C. Liu, Y. Song, G.-Y. Yang, Y. Nie, J. Liao, X. Zhao, Y. Shimada, L.-D. Wang, and C. S. Yang Over-expression of gastrin-releasing peptide in human esophageal squamous cell carcinomas Carcinogenesis, June 1, 2004; 25(6): 865 - 871. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Wang, M. Z. Fang, J. Liao, G.-Y. Yang, Y. Nie, Y. Song, C. So, X. Xu, L.-D. Wang, and C. S. Yang Hypermethylation-Associated Inactivation of Retinoic Acid Receptor {beta} in Human Esophageal Squamous Cell Carcinoma Clin. Cancer Res., November 1, 2003; 9(14): 5257 - 5263. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Nie, J. Liao, X. Zhao, Y. Song, G.-y. Yang, L.-D. Wang, and C. S. Yang Detection of multiple gene hypermethylation in the development of esophageal squamous cell carcinoma Carcinogenesis, October 1, 2002; 23(10): 1713 - 1720. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. D. Stoner and A. Gupta Etiology and chemoprevention of esophageal squamous cell carcinoma Carcinogenesis, November 1, 2001; 22(11): 1737 - 1746. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Nie, G.-y. Yang, Y. Song, X. Zhao, C. So, J. Liao, L.-D. Wang, and C. S. Yang DNA hypermethylation is a mechanism for loss of expression of the HLA class I genes in human esophageal squamous cell carcinomas Carcinogenesis, October 1, 2001; 22(10): 1615 - 1623. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Y. Y. Fong, V. T. Nguyen, J. L. Farber, K. Huebner, and P. N. Magee Early Deregulation of the p16ink4a-Cyclin D1/Cyclin-dependent Kinase 4-Retinoblastoma Pathway in Cell Proliferation-driven Esophageal Tumorigenesis in Zinc-deficient Rats Cancer Res., August 1, 2000; 60(16): 4589 - 4595. [Abstract] [Full Text]
|
|
|
|
|
|
T. J.King, L. H.Fukushima, T. A.Donlon, A.D. Hieber, K. A.Shimabukuro, and J. S.Bertram Correlation between growth control, neoplastic potential and endogenous connexin43 expression in HeLa cell lines: implications for tumor progression Carcinogenesis, February 1, 2000; 21(2): 311 - 315. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. P. Xing, Y. Nie, Y. Song, G.-Y. Yang, Y. C. Cai, L.-D. Wang, and C. S. Yang Mechanisms of Inactivation of p14ARF, p15INK4b, and p16INK4a Genes in Human Esophageal Squamous Cell Carcinoma Clin. Cancer Res., October 1, 1999; 5(10): 2704 - 2713. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. P. Xing, G.-Y. Yang, L.-D. Wang, S. T. Shi, and C. S. Yang Loss of Heterozygosity of the Rb Gene Correlates with pRb Protein Expression and Associates with p53 Alteration in Human Esophageal Cancer Clin. Cancer Res., May 1, 1999; 5(5): 1231 - 1240. [Abstract] [Full Text] [PDF]
|
|