Absence of an embryonic stem cell DNA methylation signature in human cancer

Abstract

Background Differentiated cells that arise from stem cells in early development contain DNA methylation features that provide a memory trace of their fetal cell origin (FCO). The FCO signature was developed to estimate the proportion of cells in a mixture of cell types that are of fetal origin and are reminiscent of embryonic stem cell lineage. Here we implemented the FCO signature estimation method to compare the fraction of cells with the FCO signature in tumor tissues and their corresponding nontumor normal tissues. Methods We applied our FCO algorithm to discovery data sets obtained from The Cancer Genome Atlas (TCGA) and replication data sets obtained from the Gene Expression Omnibus (GEO) data repository. Wilcoxon rank sum tests, linear regression models with adjustments for potential confounders and non-parametric randomization-based tests were used to test the association of FCO proportion between tumor tissues and nontumor normal tissues. P -values of < 0.05 were considered statistically significant. Results Across 20 different tumor types we observed a consistently lower FCO signature in tumor tissues compared with nontumor normal tissues, with 18 observed to have significantly lower FCO fractions in tumor tissue (total n = 6,795 tumor, n = 922 nontumor, P < 0.05). We replicated our findings in 15 tumor types using data from independent subjects in 15 publicly available data sets (total n = 740 tumor, n = 424 nontumor, P < 0.05). Conclusions The results suggest that cancer development itself is substantially devoid of recapitulation of normal embryologic processes. Our results emphasize the distinction between DNA methylation in normal tightly regulated stem cell driven differentiation and cancer stem cell reprogramming that involves altered methylation in the service of great cell heterogeneity and plasticity. Electronic supplementary material The online version of this article (10.1186/s12885-019-5932-6) contains supplementary material, which is available to authorized users.

Integrative Pan-Cancer Analysis Reveals Decreased Melatonergic Gene Expression in Carcinogenesis and RORA as a Prognostic Marker for Hepatocellular Carcinoma

“…The Wilcoxon rank sum test was used to identify differential methylation sites between cancerous and normal samples ( 39 ). If a gene was mapped by multiple CpG sites that were both hypermethylated and hypomethylated, the gene was not included in the following analysis.…”

Down Syndrome Altered Cell Composition in Blood, Brain, and Buccal Swab Samples Profiled by DNA-Methylation-Based Cell-Type Deconvolution

“…EpiDISH (version 2.12.0, Shijie Zheng, Shanghai, China) was used to infer three buccal swab cell types, including immune cell, epithelial cell, and fibroblast [ 40 ]. Cells that arise from a fetal lineage in the early stages of life contain DNA methylation features that provide a memory trace of their fetal cell origin (FCO) [ 28 ]. The FCO DNA methylation signature was employed in all samples to estimate the proportion of cells that are of fetal lineages [ 27 ].…”

“…Buccal swab deconvolution methods were also developed in previous studies by other research groups [ 25 , 26 ]. Furthermore, we devised a DNA methylation biomarker to trace cells of fetal origins in various tissues [ 27 , 28 ].…”

Biophysical Modeling of the Ionizing Radiation Influence on Cells Using the Stochastic (Monte Carlo) and Deterministic (Analytical) Approaches

“…The parameter estimation was obtained by partial model calibration on experimental data for dedicated processes. 3 , 29 , 39 – 51 a Parameters { β } for bystander effects were calculated for human-hamster hybrid fibroblasts irradiated by α radiation 39 (see equations ( 2 ) and ( 3 )). …”

“…The parameter estimation was obtained by partial model calibration on experimental data for dedicated processes. 3,29,[39][40][41][42][43][44][45][46][47][48][49][50][51] Effect from Table 2 Value of Parameter Cell is hit by radiation a hit ¼ 1:3 Gy À1 Natural death of a healthy cell…”