The Genome-Wide Impact of Trisomy 21 on DNA Methylation and Its Implications for Hematologic Malignancies
2019
Children with Down syndrome (DS), caused by constitutive trisomy of chromosome 21, have a 20-fold increased risk of acute lymphoblastic leukemia (DS-ALL) and 500-fold increased risk of acute megakaryoblastic leukemia (DS-AMKL). At least 10-15% of DS neonates are born with the pre-leukemic syndrome transient abnormal myelopoiesis (TAM). Trisomy 21 affects hematopoiesis and leukemia risk; however, the underlying mechanisms are not fully understood. Previous small-scale studies (sample N DNA was extracted from newborn dried bloodspots from 196 children born with DS and 442 non-DS controls from the California Biobank Program, and assayed using Illumina Infinium MethylationEPIC arrays containing >850,000 CpG probes. Data preprocessing was performed using the SeSAMe R package, and the conumee package confirmed trisomy 21 or euploidy in DS and non-DS subjects. Cell type deconvolution was performed, and blood cell proportions compared between DS and non-DS newborns using linear regression adjusting for covariates. ReFACTor principal components (PCs) were used to adjust for cell type heterogeneity and EPISTRUCTURE PCs to adjust for ancestry. Epigenome-wide association studies (EWAS) were performed overall, and stratified by ethnicity, using linear regression models adjusting for sex, plate, first six ReFACTor PCs, and first six ancestry-related PCs. Differentially methylated regions (DMRs) were evaluated using DMRcate and comb-p, with a consensus list of significant DMRs using the overlap. Deconvolution of blood cell proportions revealed highly significant (P Intriguingly, PC analysis and hierarchical clustering of DNA methylation data identified a subset of DS subjects (N=34/196, 17%) that clustered separately: these all had significantly higher nRBC proportions than other subjects and possibly represent DS neonates with TAM, although further investigation is needed for confirmation. Removing this cluster did not affect our main findings in our EWAS or DMR analyses. Constitutive trisomy 21 has profound effects on DNA methylation across the genome, in particular resulting in repression of known regulators of hematopoiesis including RUNX1 and FLI1. Our findings highlight potential mechanisms for the increased risk of both lymphoid and myeloid malignancies in children with DS. Disclosures No relevant conflicts of interest to declare.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
0
References
1
Citations
NaN
KQI