Down syndrome (DS) is caused by constitutional trisomy of chromosome 21 and is associated with an up to 30-fold increased risk of acute lymphoblastic leukemia (ALL). While DS is associated with alterations in epigenetic markers, including DNA methylation, and gene expression. These mechanisms have not been fully explored in relation to DS-ALL etiology. Because the epigenome is sensitive to genetic and environmental influences during fetal development and can be leveraged to characterize blood cell proportions, we sought to evaluate the role of the neonatal methylome in children with DS on subsequent ALL risk.
Background: Childhood glioblastoma multiforme (GBM) is a highly aggressive disease with low survival, and its etiology, especially concerning germline genetic risk, is poorly understood. Mitochondria play a key role in putative tumorigenic processes relating to cellular oxidative metabolism, and mitochondrial DNA variants were not previously assessed for association with pediatric brain tumor risk.
Methods: We conducted an analysis of 675 mitochondrial DNA variants in 90 childhood GBM cases and 2,789 controls to identify enrichment of mitochondrial variant associated with GBM risk.
We performed a trans-ethnic GWAS of childhood ALL in a discovery panel of 76,317 individuals, including 3482 cases and 72,835 controls distributed across four ethnic cohorts (African Americans, AFR; East Asian Americans, EAS; Latino Americans, LAT; Non-Latino White Americans, NLW; Supplemen- tary Information). After quality control filtering, our dataset consisted of 124, 318, 1878, 1162 cases and 2067, 5017, 8410, 57,341 controls in AFR, EAS, LAT, and NLW, respectively. Furthermore, we tested the association at 7,628,894 imputed SNPs, including low frequency (minor allele frequency, MAF, between 1–5%) variants that were not previously systematically tested.
Background: Parental smoking is implicated in the etiology of acute lymphoblastic leukemia (ALL), the most common childhood cancer. We recently reported an association between an epigenetic biomarker of early-life tobacco smoke exposure at the AHRR gene and increased frequency of somatic gene deletions among ALL cases.
Methods: Here, we further assess this association using two epigenetic biomarkers for maternal smoking during pregnancy-DNA methylation at AHRR CpG cg05575921 and a recently established polyepigenetic smoking score-in an expanded set of 482 B-cell ALL (B-ALL) cases in the California Childhood Leukemia Study with available Illumina 450K or MethylationEPIC array data.
Abstract
Down syndrome is associated with genome-wide perturbation of gene expression, which may be mediated by epigenetic changes. We perform an epigenome-wide association study on neonatal bloodspots comparing 196 newborns with Down syndrome and 439 newborns without Down syndrome, adjusting for cell-type heterogeneity, which identifies 652 epigenome-wide significant CpGs (P < 7.67 × 10−8) and 1,052 differentially methylated regions. Differential methylation at promoter/enhancer regions correlates with gene expression changes in Down syndrome versus non-Down syndrome fetal liver hematopoietic stem/progenitor cells (P < 0.