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Promoter Hypermethylation of Hallmark Cancer Genes in Atypical Adenomatous Hyperplasia of the Lung

Authors' Affiliations: ¹ Cancer Biology Program at the Sidney Kimmel Comprehensive Cancer Center, and ² Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland

Requests for reprints: 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.

Purpose: According to current models of tumorigenesis, the progression of phenotypic changes culminating in overtly malignant carcinoma is driven by genetic and epigenetic alterations. The recognition of an early form of glandular neoplasia termed atypical adenomatous hyperplasia (AAH), a precursor lesion from which lung adenocarcinomas arise, provides an opportunity for characterizing early epigenetic alterations involved in lung tumorigenesis.

Experimental Design: We evaluated AAHs, adjacent normal lung tissue, and synchronous lung adenocarcinomas for promoter hypermethylation of genes implicated in lung tumorigenesis (p16, TIMP3, DAPK, MGMT, RARβ, RASSF1A, and hTERT).

Results: For individual genes and the number of genes methylated, we observed a significant increase in the frequency of promoter hypermethylation in the histologic progression from normal to AAH, with low-grade or high-grade atypia, and finally to adenocarcinoma (P_trend 0.01). Multifocal AAHs from individual patients had distinct patterns of promoter hypermethylation, suggesting divergent epigenetic field defects. There were statistically significant positive associations for the presence of promoter hypermethylation of individual and multiple genes with advanced histology, with odds ratios between 4.3 and 58.5. p16 conveyed the strongest individual association for promoter hypermethylation when comparing tumor or high-grade AAH to low-grade AAH or normal tissue, with an odds ratio of 45.5 (95% confidence interval, 5.8-360.5).

Conclusion: This study shows epigenetic progression in the earliest stages of glandular neoplasia of the lung and has implications for early lung cancer detection.