Region-Specific Methylation Profiling in Acute Myeloid Leukemia

Abstract

Alteration of DNA methylation level in cancer diseases leads to deregulation of gene expression—silencing of tumor suppressor genes and enhancing of protooncogenes. There are several tools devoted to the problem of identification of CpG sites' demethylation but majority of them focuses on single site level and does not allow for quantification of region methylation changes. The aim was to create an adaptive algorithm supporting detection of differentially methylated CpG sites and genomic regions specific for acute myeloid leukemia. Knowledge on AML methylation fingerprint helps in better understanding the epigenetics of leukemogenesis. Proposed algorithm is data driven and does not use predefined quantification thresholds. Gaussian mixture modeling supports classification of CpG sites to several levels of demethylation. p value integration allows for translation from single site demethylation to the demethylation of gene promoter and body regions. Methylation profiles of healthy controls and AML patients were examined (GEO:GSE63409). The differences in whole genome methylation profiles were observed. The methylation profile differs significantly among genomic regions. The lowest methylation level was observed for promoter regions, while sites from intergenic regions were by average higher methylated. The observed number of AML related down methylated sites has not substantially exceeded the expected number by chance. Intergenic regions were characterized by the highest percentage of AML up methylated sites. Methylation enhancement/diminution is the most frequent for intergenic region while methylation compensation (positive or negative) is specific for promoter regions. Functional analysis performed for AML down methylated or extreme high up methylated genes showed strong connection to the leukemic processes.Electronic supplementary materialThe online version of this article (10.1007/s12539-018-0285-4) contains supplementary material, which is available to authorized users.

Targeting epigenetics for cancer therapy

“…Aberrant DNA methylation patterns, both hyper- and hypo-methylation, have been reported in many different types of cancer, including prostate, breast, gastric, liver, lung, glioblastoma, and leukemia (Sun et al 2010 ; Barbano et al 2013 ; Chao et al 2013 ; Mehta et al 2015 ; Liu and Brenner 2016 ; Cecotka and Polanska 2018 ; Klughammer et al 2018 ). First cancer implication was the global hypomethylation at CpG sites of DNA repetitive elements identified in tumor cells (Bedford and van Helden 1987 ; Lin et al 2001 ).…”

DNA Methylation: From Cancer Biology to Clinical Perspectives

“…Tumors often present a global DNA hypomethylation with gains of focal DNA hypermethylation at CpGrich sites [15,16]. An aberrant DNA methylation landscape has been reported in a variety of tumors, including both hematological malignancies and solid tumors [17][18][19][20][21][22][23]. The mechanisms of carcinogenesis induced by DNA methylation events are displayed in Fig.…”

Genome-wide DNA methylation analysis in pediatric acute myeloid leukemia

“…Most previous studies have analyzed only the DNA methylation status of promoter regions, although some reports suggest the importance of DNA methylation in other regions, particularly in the gene body. 10,11 In contrast to gene expression analysis, DNA methylation analysis is considered highly credible because it provides excellent quantitative determinations and absolute values, without requiring endogenous controls. Thus, we analyzed genome-wide DNA methylation in 64 pediatric patients with AML to reveal the differences of DNA methylation patterns among various cytogenetic alterations, particularly in the PRDM16 expression value, and investigate the associations of methylation patterns with other genetic alterations.…”