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Epigenomic analysis of lung adenocarcinoma reveals novel DNA methylation patterns associated with smoking.

Tan Q, Wang G, Huang J, Ding Z, Luo Q, Mok T, Tao Q, Lu S - Onco Targets Ther (2013)

Bottom Line: Interestingly, we discovered that two genes in the mitogen-activated protein kinase signaling pathway (RPS6KA3 and ARAF) were hypomethylated in smokers but not in nonsmokers.In addition, we found that the smoking-induced lung cancer-specific DNA methylations were mostly enriched in nuclear activities, including regulation of gene expression and chromatin remodeling.Moreover, the smoking-induced hypermethylation could only be seen in lung adenocarcinoma tissue but not in adjacent normal lung tissue.

View Article: PubMed Central - PubMed

Affiliation: Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China.

ABSTRACT
The importance of epigenetic regulation has been increasingly recognized in the development of cancer. In this study, we investigated the impact of smoking, a major risk factor of lung cancer, on DNA methylation by comparing the genome-wide DNA methylation patterns between lung adenocarcinoma samples from six smokers and six nonsmokers. We identified that smoking-induced DNA methylations were enriched in the calcium signaling and neuroactive ligand receptor signaling pathways, which are closely related to smoking-induced lung cancers. Interestingly, we discovered that two genes in the mitogen-activated protein kinase signaling pathway (RPS6KA3 and ARAF) were hypomethylated in smokers but not in nonsmokers. In addition, we found that the smoking-induced lung cancer-specific DNA methylations were mostly enriched in nuclear activities, including regulation of gene expression and chromatin remodeling. Moreover, the smoking-induced hypermethylation could only be seen in lung adenocarcinoma tissue but not in adjacent normal lung tissue. We also used differentially methylated DNA loci to construct a diagnostic model to distinguish smoking-associated lung cancer from nonsmoking lung cancer with a sensitivity of 88.9% and specificity of 83.2%. Our results provided novel evidence to support that smoking can cause dramatic changes in the DNA methylation landscape of lung cancer, suggesting that epigenetic regulation of specific oncogenic signaling pathways plays an important role in the development of lung cancer.

No MeSH data available.


Related in: MedlinePlus

Hypothesized model of smoking-induced lung cancer based on our data.
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f2-ott-6-1471: Hypothesized model of smoking-induced lung cancer based on our data.

Mentions: To gain a functional insight from our data, we performed a Gene Ontology analysis of all candidate genes. As a result, we found that the 90 smoking-induced DMRs in the normal lung tissues of smokers were enriched in pathways including energy metabolism, phosphorylase kinase activity, and ubiquitin thiolesterase activity (Table 1). The 110 smoking-induced DMRs specific to lung cancer were mostly enriched in biological processes associated with transcription factor activity, chromatin remodeling, and neural signal processing (Table 2). Using the data we obtained from this study, we proposed a model to depict the developmental progress of smoking-induced lung cancer from an epigenetic point of view (Figure 2).


Epigenomic analysis of lung adenocarcinoma reveals novel DNA methylation patterns associated with smoking.

Tan Q, Wang G, Huang J, Ding Z, Luo Q, Mok T, Tao Q, Lu S - Onco Targets Ther (2013)

Hypothesized model of smoking-induced lung cancer based on our data.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3818101&req=5

f2-ott-6-1471: Hypothesized model of smoking-induced lung cancer based on our data.
Mentions: To gain a functional insight from our data, we performed a Gene Ontology analysis of all candidate genes. As a result, we found that the 90 smoking-induced DMRs in the normal lung tissues of smokers were enriched in pathways including energy metabolism, phosphorylase kinase activity, and ubiquitin thiolesterase activity (Table 1). The 110 smoking-induced DMRs specific to lung cancer were mostly enriched in biological processes associated with transcription factor activity, chromatin remodeling, and neural signal processing (Table 2). Using the data we obtained from this study, we proposed a model to depict the developmental progress of smoking-induced lung cancer from an epigenetic point of view (Figure 2).

Bottom Line: Interestingly, we discovered that two genes in the mitogen-activated protein kinase signaling pathway (RPS6KA3 and ARAF) were hypomethylated in smokers but not in nonsmokers.In addition, we found that the smoking-induced lung cancer-specific DNA methylations were mostly enriched in nuclear activities, including regulation of gene expression and chromatin remodeling.Moreover, the smoking-induced hypermethylation could only be seen in lung adenocarcinoma tissue but not in adjacent normal lung tissue.

View Article: PubMed Central - PubMed

Affiliation: Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China.

ABSTRACT
The importance of epigenetic regulation has been increasingly recognized in the development of cancer. In this study, we investigated the impact of smoking, a major risk factor of lung cancer, on DNA methylation by comparing the genome-wide DNA methylation patterns between lung adenocarcinoma samples from six smokers and six nonsmokers. We identified that smoking-induced DNA methylations were enriched in the calcium signaling and neuroactive ligand receptor signaling pathways, which are closely related to smoking-induced lung cancers. Interestingly, we discovered that two genes in the mitogen-activated protein kinase signaling pathway (RPS6KA3 and ARAF) were hypomethylated in smokers but not in nonsmokers. In addition, we found that the smoking-induced lung cancer-specific DNA methylations were mostly enriched in nuclear activities, including regulation of gene expression and chromatin remodeling. Moreover, the smoking-induced hypermethylation could only be seen in lung adenocarcinoma tissue but not in adjacent normal lung tissue. We also used differentially methylated DNA loci to construct a diagnostic model to distinguish smoking-associated lung cancer from nonsmoking lung cancer with a sensitivity of 88.9% and specificity of 83.2%. Our results provided novel evidence to support that smoking can cause dramatic changes in the DNA methylation landscape of lung cancer, suggesting that epigenetic regulation of specific oncogenic signaling pathways plays an important role in the development of lung cancer.

No MeSH data available.


Related in: MedlinePlus