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, RARbeta, 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.
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, RARbeta, 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.
Authors: Smruthy Sivakumar; F Anthony San Lucas; Tina L McDowell; Wenhua Lang; Li Xu; Junya Fujimoto; Jianjun Zhang; P Andrew Futreal; Junya Fukuoka; Yasushi Yatabe; Steven M Dubinett; Avrum E Spira; Jerry Fowler; Ernest T Hawk; Ignacio I Wistuba; Paul Scheet; Humam Kadara Journal: Cancer Res Date: 2017-09-26 Impact factor: 12.701
Authors: Seth A Brodie; Ge Li; Adam El-Kommos; Hyunseok Kang; Suresh S Ramalingam; Madhusmita Behera; Khanjan Gandhi; Jeanne Kowalski; Gabriel L Sica; Fadlo R Khuri; Paula M Vertino; Johann C Brandes Journal: Cancer Prev Res (Phila) Date: 2014-01-17
Authors: Uta Duppel; Matthias Woenckhaus; Christian Schulz; Johannes Merk; Wolfgang Dietmaier Journal: Oncol Lett Date: 2016-08-01 Impact factor: 2.967
Authors: Jillian de Wilde; Jan M Kooter; Renée M Overmeer; Debbie Claassen-Kramer; Chris J L M Meijer; Peter J F Snijders; Renske D M Steenbergen Journal: BMC Cancer Date: 2010-06-09 Impact factor: 4.430