Integrative analysis with expanded DNA methylation data reveals common key regulators and pathways in cancers

Abstract

The integration of genomic and DNA methylation data has been demonstrated as a powerful strategy in understanding cancer mechanisms and identifying therapeutic targets. The TCGA consortium has mapped DNA methylation in thousands of cancer samples using Illumina Infinium Human Methylation 450 K BeadChip (Illumina 450 K array) that only covers about 1.5% of CpGs in the human genome. Therefore, increasing the coverage of the DNA methylome would significantly leverage the usage of the TCGA data. Here, we present a new model called EAGLING that can expand the Illumina 450 K array data 18 times to cover about 30% of the CpGs in the human genome. We applied it to analyze 13 cancers in TCGA. By integrating the expanded methylation, gene expression, and somatic mutation data, we identified the genes showing differential patterns in each of the 13 cancers. Many of the triple-evidenced genes identified in majority of the cancers are biomarkers or potential biomarkers. Pan-cancer analysis also revealed the pathways in which the triple-evidenced genes are enriched, which include well known ones as well as new ones, such as axonal guidance signaling pathway and pathways related to inflammatory processing or inflammation response. Triple-evidenced genes, particularly TNXB, RRM2, CELSR3, SLC16A3, FANCI, MMP9, MMP11, SIK1, and TRIM59 showed superior predictive power in both tumor diagnosis and prognosis. These results have demonstrated that the integrative analysis using the expanded methylation data is powerful in identifying critical genes/pathways that may serve as new therapeutic targets.

Salt inducible kinases as novel Notch interactors in the developing Drosophila retina

“…The misregulation of Sik2 and Sik3 being detected in several cancer cases [39,48] at both genetic and epigenetic levels [69], and Sik3 being established as an ovary cancer marker [70] are consistent with our finding that Siks can promote tumorigenesis. In addition to the previous correlation studies, our experiment shows that Sik misregulation can be causative for tumor formation.…”

CDC20, A Hypermethylated Gene in Senescent Cells, is Associated with Hepatocellular Carcinoma Prognosis

“…Furthermore, epigenetic alternation occupies an important position in tumor progression [22], such as DNA methylation. Abnormal DNA methylation leads to cancer [23]. The AFP regulated by methylation status of promoter had a predictive value for HCC [24].…”

Genome wide methylation profiling of selected matched soft tissue sarcomas identifies methylation changes in metastatic and recurrent disease

“…Downregulation of this gene enables cell proliferation, migration, and invasion leading to cancer progression in multiple cancer types, which has been correlated with advanced disease and poor clinical outcome [52][53][54][55][56] . TNXB encodes a tenascin which promotes epithelial mesenchymal transition (EMT) and is downregulated in cancer 57,58 , wherein methylation correlates with gene expression [59][60][61][62][63][64][65] . In agreement with the known downregulation of these genes in cancer, both TNXB and WT1-AS were unmethylated in Mets/Rec samples of SS, indicative of gene loss/ downregulation during progression of SS, which has not been previously identified in this tumour type.…”