TY - JOUR
T1 - Integrative Network Analysis of Differentially Methylated and Expressed Genes for Biomarker Identification in Leukemia
AU - Sanchez, Robersy
AU - Mackenzie, Sally A.
N1 - Funding Information:
We wish to thank Dr. Xiaodong Yang and Thomas Maher for valuable discussions during the development of these studies. This study was supported by a grant from the Bill and Melinda Gates Foundation (OPP1088661) and NIH (NIH (R01 GM134056-01) to S.A.M.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Genome-wide DNA methylation and gene expression are commonly altered in pediatric acute lymphoblastic leukemia (PALL). Integrated network analysis of cytosine methylation and expression datasets has the potential to provide deeper insights into the complex disease states and their causes than individual disconnected analyses. With the purpose of identifying reliable cancer-associated methylation signal in gene regions from leukemia patients, we present an integrative network analysis of differentially methylated (DMGs) and differentially expressed genes (DEGs). The application of a novel signal detection-machine learning approach to methylation analysis of whole genome bisulfite sequencing (WGBS) data permitted a high level of methylation signal resolution in cancer-associated genes and pathways. This integrative network analysis approach revealed that gene expression and methylation consistently targeted the same gene pathways relevant to cancer: Pathways in cancer, Ras signaling pathway, PI3K-Akt signaling pathway, and Rap1 signaling pathway, among others. Detected gene hubs and hub sub-networks were integrated by signature loci associated with cancer that include, for example, NOTCH1, RAC1, PIK3CD, BCL2, and EGFR. Statistical analysis disclosed a stochastic deterministic relationship between methylation and gene expression within the set of genes simultaneously identified as DEGs and DMGs, where larger values of gene expression changes were probabilistically associated with larger values of methylation changes. Concordance analysis of the overlap between enriched pathways in DEG and DMG datasets revealed statistically significant agreement between gene expression and methylation changes. These results support the potential identification of reliable and stable methylation biomarkers at genes for cancer diagnosis and prognosis.
AB - Genome-wide DNA methylation and gene expression are commonly altered in pediatric acute lymphoblastic leukemia (PALL). Integrated network analysis of cytosine methylation and expression datasets has the potential to provide deeper insights into the complex disease states and their causes than individual disconnected analyses. With the purpose of identifying reliable cancer-associated methylation signal in gene regions from leukemia patients, we present an integrative network analysis of differentially methylated (DMGs) and differentially expressed genes (DEGs). The application of a novel signal detection-machine learning approach to methylation analysis of whole genome bisulfite sequencing (WGBS) data permitted a high level of methylation signal resolution in cancer-associated genes and pathways. This integrative network analysis approach revealed that gene expression and methylation consistently targeted the same gene pathways relevant to cancer: Pathways in cancer, Ras signaling pathway, PI3K-Akt signaling pathway, and Rap1 signaling pathway, among others. Detected gene hubs and hub sub-networks were integrated by signature loci associated with cancer that include, for example, NOTCH1, RAC1, PIK3CD, BCL2, and EGFR. Statistical analysis disclosed a stochastic deterministic relationship between methylation and gene expression within the set of genes simultaneously identified as DEGs and DMGs, where larger values of gene expression changes were probabilistically associated with larger values of methylation changes. Concordance analysis of the overlap between enriched pathways in DEG and DMG datasets revealed statistically significant agreement between gene expression and methylation changes. These results support the potential identification of reliable and stable methylation biomarkers at genes for cancer diagnosis and prognosis.
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U2 - 10.1038/s41598-020-58123-2
DO - 10.1038/s41598-020-58123-2
M3 - Article
C2 - 32034170
AN - SCOPUS:85079082683
SN - 2045-2322
VL - 10
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 2123
ER -
