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Gene-set Analysis with CGI Information for Differential DNA Methylation Profiling.

Chang CW, Lu TP, She CX, Feng YC, Hsiao CK - Sci Rep (2016)

Bottom Line: Here we aimed to include both pathway information and CGI status to rank competing gene-sets and identify among them the genes most likely contributing to DNA methylation changes.Results show that, based on probabilities, the importance of pathways and genes can be determined.The findings confirm that some of these genes are cancer-related and may hold the potential to be targeted in drug development.

View Article: PubMed Central - PubMed

Affiliation: Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei 10055, Taiwan.

ABSTRACT
DNA methylation is a well-established epigenetic biomarker for many diseases. Studying the relationships among a group of genes and their methylations may help to unravel the etiology of diseases. Since CpG-islands (CGIs) play a crucial role in the regulation of transcription during methylation, including them in the analysis may provide further information in understanding the pathogenesis of cancers. Such CGI information, however, has usually been overlooked in existing gene-set analyses. Here we aimed to include both pathway information and CGI status to rank competing gene-sets and identify among them the genes most likely contributing to DNA methylation changes. To accomplish this, we devised a Bayesian model for matched case-control studies with parameters for CGI status and pathway associations, while incorporating intra-gene-set information. Three cancer studies with candidate pathways were analyzed to illustrate this approach. The strength of association for each candidate pathway and the influence of each gene were evaluated. Results show that, based on probabilities, the importance of pathways and genes can be determined. The findings confirm that some of these genes are cancer-related and may hold the potential to be targeted in drug development.

No MeSH data available.


Related in: MedlinePlus

(A) Heatmap of differences in DNAm for leading probes. (A) These probes are those having the largest probabilities of hypermethylation (yellow) or hypomethylation (red), under each competing pathway in the lung cancer study. (B) These probes are the top 50 probes with the largest probabilities of hypermethylation (yellow) or hypomethylation (red) in the p53 pathway.
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f5: (A) Heatmap of differences in DNAm for leading probes. (A) These probes are those having the largest probabilities of hypermethylation (yellow) or hypomethylation (red), under each competing pathway in the lung cancer study. (B) These probes are the top 50 probes with the largest probabilities of hypermethylation (yellow) or hypomethylation (red) in the p53 pathway.

Mentions: Figure 5A is the heatmap of θij for the leading genes in each of the four competing pathways. Most genes in the axonal guidance signaling pathway showed a hypermethylation effect in tumor tissue; while most in the prolactin signaling pathway and glycosphingolipid pathway showed hypomethylation. Within each pathway, the DMGs with large probability of hypermethylation and hypomethylation are listed in Table 3 and Supplementary Table S2. Although the major function of the axonal guidance signaling pathway is to regulate the growth of neuronal cells, many studies have reported its association with lung cancer394041. For instance, migration and invasion in lung adenocarcinoma cells can be substantially inhibited through the blockage of the complex LIMK1/PAK4/cofilin42, and methylation changes of CDKN2A may interact with HRAS to regulate the activity of MAPK1 in lung adenocarcinoma43. Table 3 also lists the expression changes of genes in this pathway. Regarding the other three pathways shown in Table S2, previous reports have indicated their biological impact in lung cancer with expression data as well44454647. Therefore, these results further demonstrate that methylation change is a causative mechanism in regulating the activity of signaling pathways involved in tumor development and growth.


Gene-set Analysis with CGI Information for Differential DNA Methylation Profiling.

Chang CW, Lu TP, She CX, Feng YC, Hsiao CK - Sci Rep (2016)

(A) Heatmap of differences in DNAm for leading probes. (A) These probes are those having the largest probabilities of hypermethylation (yellow) or hypomethylation (red), under each competing pathway in the lung cancer study. (B) These probes are the top 50 probes with the largest probabilities of hypermethylation (yellow) or hypomethylation (red) in the p53 pathway.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4836301&req=5

f5: (A) Heatmap of differences in DNAm for leading probes. (A) These probes are those having the largest probabilities of hypermethylation (yellow) or hypomethylation (red), under each competing pathway in the lung cancer study. (B) These probes are the top 50 probes with the largest probabilities of hypermethylation (yellow) or hypomethylation (red) in the p53 pathway.
Mentions: Figure 5A is the heatmap of θij for the leading genes in each of the four competing pathways. Most genes in the axonal guidance signaling pathway showed a hypermethylation effect in tumor tissue; while most in the prolactin signaling pathway and glycosphingolipid pathway showed hypomethylation. Within each pathway, the DMGs with large probability of hypermethylation and hypomethylation are listed in Table 3 and Supplementary Table S2. Although the major function of the axonal guidance signaling pathway is to regulate the growth of neuronal cells, many studies have reported its association with lung cancer394041. For instance, migration and invasion in lung adenocarcinoma cells can be substantially inhibited through the blockage of the complex LIMK1/PAK4/cofilin42, and methylation changes of CDKN2A may interact with HRAS to regulate the activity of MAPK1 in lung adenocarcinoma43. Table 3 also lists the expression changes of genes in this pathway. Regarding the other three pathways shown in Table S2, previous reports have indicated their biological impact in lung cancer with expression data as well44454647. Therefore, these results further demonstrate that methylation change is a causative mechanism in regulating the activity of signaling pathways involved in tumor development and growth.

Bottom Line: Here we aimed to include both pathway information and CGI status to rank competing gene-sets and identify among them the genes most likely contributing to DNA methylation changes.Results show that, based on probabilities, the importance of pathways and genes can be determined.The findings confirm that some of these genes are cancer-related and may hold the potential to be targeted in drug development.

View Article: PubMed Central - PubMed

Affiliation: Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei 10055, Taiwan.

ABSTRACT
DNA methylation is a well-established epigenetic biomarker for many diseases. Studying the relationships among a group of genes and their methylations may help to unravel the etiology of diseases. Since CpG-islands (CGIs) play a crucial role in the regulation of transcription during methylation, including them in the analysis may provide further information in understanding the pathogenesis of cancers. Such CGI information, however, has usually been overlooked in existing gene-set analyses. Here we aimed to include both pathway information and CGI status to rank competing gene-sets and identify among them the genes most likely contributing to DNA methylation changes. To accomplish this, we devised a Bayesian model for matched case-control studies with parameters for CGI status and pathway associations, while incorporating intra-gene-set information. Three cancer studies with candidate pathways were analyzed to illustrate this approach. The strength of association for each candidate pathway and the influence of each gene were evaluated. Results show that, based on probabilities, the importance of pathways and genes can be determined. The findings confirm that some of these genes are cancer-related and may hold the potential to be targeted in drug development.

No MeSH data available.


Related in: MedlinePlus