Dataset Information

DNA methylation changes in atypical adenomatous hyperplasia, adenocarcinoma in situ, and lung adenocarcinoma.

ABSTRACT: BACKGROUND:Aberrant DNA methylation is common in lung adenocarcinoma, but its timing in the phases of tumor development is largely unknown. Delineating when abnormal DNA methylation arises may provide insight into the natural history of lung adenocarcinoma and the role that DNA methylation alterations play in tumor formation. METHODOLOGY/PRINCIPAL FINDINGS:We used MethyLight, a sensitive real-time PCR-based quantitative method, to analyze DNA methylation levels at 15 CpG islands that are frequently methylated in lung adenocarcinoma and that we had flagged as potential markers for non-invasive detection. We also used two repeat probes as indicators of global DNA hypomethylation. We examined DNA methylation in 249 tissue samples from 93 subjects, spanning the putative spectrum of peripheral lung adenocarcinoma development: histologically normal adjacent non-tumor lung, atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS, formerly known as bronchioloalveolar carcinoma), and invasive lung adenocarcinoma. Comparison of DNA methylation levels between the lesion types suggests that DNA hypermethylation of distinct loci occurs at different time points during the development of lung adenocarcinoma. DNA methylation at CDKN2A ex2 and PTPRN2 is already significantly elevated in AAH, while CpG islands at 2C35, EYA4, HOXA1, HOXA11, NEUROD1, NEUROD2 and TMEFF2 are significantly hypermethylated in AIS. In contrast, hypermethylation at CDH13, CDX2, OPCML, RASSF1, SFRP1 and TWIST1 and global DNA hypomethylation appear to be present predominantly in invasive cancer. CONCLUSIONS/SIGNIFICANCE:The gradual increase in DNA methylation seen for numerous loci in progressively more transformed lesions supports the model in which AAH and AIS are sequential stages in the development of lung adenocarcinoma. The demarcation of DNA methylation changes characteristic for AAH, AIS and adenocarcinoma begins to lay out a possible roadmap for aberrant DNA methylation events in tumor development. In addition, it identifies which DNA methylation changes might be used as molecular markers for the detection of preinvasive lesions.

SUBMITTER: Selamat SA

PROVIDER: S-EPMC3121768 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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DNA methylation changes in atypical adenomatous hyperplasia, adenocarcinoma in situ, and lung adenocarcinoma.

Selamat Suhaida A SA Galler Janice S JS Joshi Amit D AD Fyfe M Nicky MN Campan Mihaela M Siegmund Kimberly D KD Kerr Keith M KM Laird-Offringa Ite A IA

PloS one 20110623 6

<h4>Background</h4>Aberrant DNA methylation is common in lung adenocarcinoma, but its timing in the phases of tumor development is largely unknown. Delineating when abnormal DNA methylation arises may provide insight into the natural history of lung adenocarcinoma and the role that DNA methylation alterations play in tumor formation.<h4>Methodology/principal findings</h4>We used MethyLight, a sensitive real-time PCR-based quantitative method, to analyze DNA methylation levels at 15 CpG islands t ...[more]

PMID: 21731750

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Project description:Lung adenocarcinoma (LUAD) is one of the most common cancers and lethal diseases in the world. Recognition of the undetermined lung nodules at an early stage is useful for a favorable prognosis. However, there is no good method to identify the undetermined lung nodules and predict their clinical outcome. DNA methylation alteration is frequently observed in LUAD and may play important roles in carcinogenesis, diagnosis, and prediction. This study took advantage of publicly available methylation profiling resources and a machine learning method to investigate methylation differences between LUAD and adjacent non-malignant tissue. The prediction panel was first constructed using 338 tissue samples from LUAD patients including 149 non-malignant ones. This model was then validated with data from The Cancer Genome Atlas database and clinic samples. As a result, the methylation status of four CpG loci in homeobox A9 (HOXA9), keratin-associated protein 8-1 (KRTAP8-1), cyclin D1 (CCND1), and tubby-like protein 2 (TULP2) were highlighted as informative markers. A random forest classification model with an accuracy of 94.57% and kappa of 88.96% was obtained. To evaluate this panel for LUAD, the methylation levels of four CpG loci in HOXA9, KRTAP8-1, CCND1, and TULP2 of tumor samples and matched adjacent lung samples from 25 patients with LUAD were tested. In these LUAD patients, the methylation of HOXA9 was significantly upregulated, whereas the methylation of KRTAP8-1, CCND1, and TULP2 were downregulated obviously in tumor samples compared with adjacent tissues. Our study demonstrates that the methylation of HOXA9, KRTAP8-1, CCND1, and TULP2 has great potential for the early recognition of LUAD in the undetermined lung nodules. The findings also exhibit that the application of improved mathematic algorithms can yield accurate and particularly robust and widely applicable marker panels. This approach could greatly facilitate the discovery process of biomarkers in various fields.

Dataset Information

DNA methylation changes in atypical adenomatous hyperplasia, adenocarcinoma in situ, and lung adenocarcinoma.

Publications

DNA methylation changes in atypical adenomatous hyperplasia, adenocarcinoma in situ, and lung adenocarcinoma.

Similar Datasets

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