Walking pathways with positive feedback loops reveal DNA methylation biomarkers of colorectal cancer

作者：Alexander E Kel, Ul'yana A. Boyarskikh, Philip Stegmaier, Leonid Leskov, Andrey V. Sokolov, Ivan Yevshin, Nikita Mandrik, Daria Stelmashenko, Jeannette Koschmann, Olga V Kel-Margoulis, Mathias Krull, Anna Martínez‐Cardús, Sebastián Morán, Manel Esteller, Fedor Kolpakov, М. Л. Филипенко, Edgar Wingender · 发表于：BMC Bioinformatics · 年份：2019 · DOI：10.1186/s12859-019-2687-7 · 被引用次数：61 · 研究领域：Epigenetics and DNA Methylation、Cancer Genomics and Diagnostics、Bioinformatics and Genomic Networks

BACKGROUND: The search for molecular biomarkers of early-onset colorectal cancer (CRC) is an important but still quite challenging and unsolved task. Detection of CpG methylation in human DNA obtained from blood or stool has been proposed as a promising approach to a noninvasive early diagnosis of CRC. Thousands of abnormally methylated CpG positions in CRC genomes are often located in non-coding parts of genes. Novel bioinformatic methods are thus urgently needed for multi-omics data analysis to reveal causative biomarkers with a potential driver role in early stages of cancer. METHODS: We have developed a method for finding potential causal relationships between epigenetic changes (DNA methylations) in gene regulatory regions that affect transcription factor binding sites (TFBS) and gene expression changes. This method also considers the topology of the involved signal transduction pathways and searches for positive feedback loops that may cause the carcinogenic aberrations in gene expression. We call this method "Walking pathways", since it searches for potential rewiring mechanisms in cancer pathways due to dynamic changes in the DNA methylation status of important gene regulatory regions ("epigenomic walking"). RESULTS: In this paper, we analysed an extensive collection of full genome gene-expression data (RNA-seq) and DNA methylation data of genomic CpG islands (using Illumina methylation arrays) generated from a sample of tumor and normal gut epithelial tissues of 300 ...