Abstract
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. 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). 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). This study shows epigenetic progression in the earliest stages of glandular neoplasia of the lung and has implications for early lung cancer detection.
Highlights
According to current models of tumorigenesis, the progression of phenotypic changes culminating in overtly malignant carcinoma is driven by genetic and epigenetic alterations
Previous studies have established a causal link between promoter hypermethylation of p16, tissue inhibitor of metalloproteinase-3 (TIMP3), death-associated protein kinase (DAPK), methylguanine-DNA methyltransferase gene (MGMT), RARb, RASSF1A, and hTERT and their transcriptional silencing in lung cancer (12, 19 – 25)
We set out to determine the frequency of promoter hypermethylation for each gene in lung adenocarcinoma and to determine the timing of these events in the initiation of adenocarcinoma through examination of adenomatous hyperplasia (AAH) lesions
Summary
According to current models of tumorigenesis, the progression of phenotypic changes culminating in overtly malignant carcinoma is driven by genetic and epigenetic alterations. Using a multiplex nested methylation-specific PCR (MSP) approach, we assessed various stages of lung tumorigenesis for the frequency of promoter hypermethylation of genes regulating cancer hallmarks including cell cycle regulation (cyclin-dependent kinase inhibitor 2A or p16), DNA repair [O6-methylguanine-DNA methyltransferase gene (MGMT)], retinoic acid signaling (RARb), apoptosis [death-associated protein kinase (DAPK)], invasion [tissue inhibitor of metalloproteinase-3 (TIMP3)], Ras signaling [Ras association domain family protein 1 isoform A (RASSF1A)], and immortalization [the catalytic subunit of telomerase (hTERT)] This comprehensive analysis of early through late glandular neoplasia provides a more complete picture of the progression of human lung adenocarcinoma
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