Carcinogenesis Advance Access first published online on February 28, 2008
This version published online on February 28, 2008
Carcinogenesis, doi:10.1093/carcin/bgn017
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Epigenetic alteration of Wnt pathway antagonists in progressive glandular neoplasia of the lung
1 Cancer Biology Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
2 Department of Pathology, the Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA
* Requests for reprints: Dr. James G. Herman, The Sidney Kimmel Comprehensive, Cancer Center at Johns Hopkins, 1650 Orleans Street, Baltimore, MD 21231, Phone: 410-955-8506; Fax: 410-614-9884, E-mail: hermanji{at}jhmi.edu
Background: Atypical adenomatous hyperplasia (AAH) is now recognized as a precursor lesion from which lung adenocarcinomas arise and thus represents an ideal target for studying the early genetic and epigenetic alterations associated with lung tumorigenesis such as alterations of the Wnt pathway.
Methods: We assessed the level of Wnt signaling activity in lung cancer cell lines by determining the level of active β-catenin and determined the level of expression of Wnt antagonists APC, DKK1, DKK3, LKB1, SFRP 1, 2, 4, 5, WIF1, and RUNX3 using RT-PCR. Using multiplex nested-methylation specific PCR, we analyzed promoter region methylation of these genes in resected lung tissue in the histopathologic sequence of glandular neoplasia (normal lung parenchyma, low grade and high grade AAH, adenocarcinoma).
Results: The majority of NSCLC cell lines (11 of 16, 69%) have evidence of active Wnt signaling and silencing of Wnt antagonists correlated with promoter hypermethylation. Promoter region methylation of Wnt antagonists was common in primary lung adenocarcinoma and there was a significant increase in the frequency of methylation for Wnt antagonist genes and the number of genes methylated with each stage of tumorigenesis (Test for rend p
0.01). Additionally, odds ratios for promoter hypermethylation of individual or multiple Wnt antagonist genes and adenocarcinomas were statistically significantly elevated and ranged between 3.64 and 48.17.
Conclusion: These results show that gene silencing of Wnt antagonists by promoter hypermethylation occurs during the earliest stages of glandular neoplasia of the lung and accumulates with progression towards malignancy
Key Words: precursor lesions • atypical adenomatous hyperplasia • promoter hypermethylation • Wnt signaling • lung adenocarcinoma
Received October 9, 2007; revised December 18, 2007; accepted January 4, 2008.
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