Mammalian X chromosome dosage compensation balances X-linked gene products between sexes and is coordinated by the long noncoding RNA (lncRNA) Xist. Multiple cis and trans-acting factors modulate Xist expression; however, the primary competence factor responsible for activating Xist remains a subject of dispute. The lncRNA Jpx is a proposed competence factor, yet it remains unknown if Jpx is sufficient to activate Xist expression in mice. Here, we utilize a novel transgenic mouse system to demonstrate a dose-dependent relationship between Jpx copy number and ensuing Jpx and Xist expression. By localizing transcripts of Jpx and Xist using RNA Fluorescence in situ Hybridization (FISH) in mouse embryonic cells, we provide evidence of Jpx acting in both trans and cis to activate Xist. Our data contribute functional and mechanistic insight for lncRNA activity in mice, and argue that Jpx is a competence factor for Xist activation in vivo.
Double vs single autologous stem cell transplantation for newly diagnosed multiple myeloma: long-term follow-up (10-years) analysis of randomized phase 3 studies.
DNA methylation is a labile modification associated with gene expression control and environmental adaptations. High throughput, scalable and quantitative assessments of specific DNA methylation modifications in complex genomic regions for use in large population studies are needed. The performance of Droplet Digital™ PCR (ddPCR™) was investigated for DNA methylation detection against next-generation bisulfite sequencing (NGS) to demonstrate the ability of ddPCR to detect and validate DNA methylation levels and complex patterns among neighboring CpGs in regions associated with prenatal tobacco exposure. While both techniques are reproducible, ddPCR demonstrates a unique advantage for high-throughput DNA methylation analysis in large-scale population studies and provides the specificity to accurately measure DNA methylation of target CpGs in complex regions.
Aberrant DNA methylation constitutes a key feature of pediatric acute lymphoblastic leukemia at diagnosis, however its role as a predisposing or early contributor to leukemia development remains unknown. Here, we evaluate DNA methylation at birth in 41 leukemia-discordant monozygotic twin pairs using the Illumina EPIC array on archived neonatal blood spots to identify epigenetic variation associated with development of pediatric acute lymphoblastic leukemia, independent of genetic influence. Through conditional logistic regression we identify 240 significant probes and 10 regions associated with the discordant onset of leukemia. We identify a significant negative coefficient bias, indicating DNA hypomethylation in cases, across the array and enhanced in open sea, shelf/shore, and gene body regions compared to promoter and CpG island regions. Here, we show an association between global DNA hypomethylation and future development of pediatric acute lymphoblastic leukemia across disease-discordant genetically identical twins, implying DNA hypomethylation may contribute more generally to leukemia 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 also performed this analysis for other glioma subtypes including pilocytic astrocytoma. Nuclear-encoded mitochondrial gene variants were also analyzed. Results We identified m1555 A>G was significantly associated with GBM risk (adjusted OR 29.30, 95% CI 5.25-163.4, P value 9.5X10 -4). No association was detected for other subtypes. Haplotype analysis further supported the independent risk contributed by m1555 G>A, instead of a haplogroup joint effect. Nuclear-encoded mitochondrial gene variants identified significant associations in European (rs62036057 in WWOX, adjusted OR = 2.99, 95% CI 1.88-4.75, P value = 3.42X10 -6) and Hispanic (rs111709726 in EFHD1, adjusted OR = 3.57, 95% CI 1.99-6.40, P value = 1.41X10 -6) populations in ethnicity-stratified analyses. Conclusion We report for the first time a potential role played by a functional mitochondrial ribosomal RNA variant in childhood GBM risk, and a potential role for both mitochondrial and nuclear-mitochondrial DNA polymorphisms in GBM tumorigenesis. These data implicate cellular oxidative metabolic capacity as a contributor to the etiology of pediatric glioblastoma.
Childhood infections and cytomegalovirus (CMV) are associated with pediatric acute lymphoblastic leukemia (ALL). CMV dysregulates the host immune system and alters the immune response to subsequent antigenic exposures. We suspect that this immune dysregulation contributes to increased numbers of symptomatic infections in childhood allowing for expansion of pre‐leukemic clones. We explored the association between childhood infections, maternal infections during pregnancy and CMV‐positive ALL. Using a droplet digital PCR assay, we screened diagnostic ALL bone marrow samples from the California Childhood Leukemia Study (1995‐2015) for the presence of CMV DNA identifying CMV‐positive and CMV‐negative cases. We performed a case‐only analysis (n = 524) comparing the number and types of childhood infections and maternal infections during pregnancy between CMV‐positive and CMV‐negative ALL cases using logistic regression. With increasing numbers of infections in the first 12 months of life, children were more likely to classify to the highest tertile of CMV DNA in the bone marrow at diagnosis (OR: 1.04, 95% CI: 1.01‐1.08). Specifically, those reporting cough or flu in the first 12 months were more likely to be CMV‐positive at ALL diagnosis (OR: 2.15, 95% CI: 1.06‐4.37 and OR: 2.06, 95% CI: 1.17‐3.63 respectively). Furthermore, those with a history of maternal infection during pregnancy were more likely to be CMV‐positive (OR: 2.12, 95% CI: 1.24‐3.62). We hypothesize that children with underlying immune dysregulation develop more symptomatic infections in childhood and ultimately CMV‐positive ALL; this underlying immune dysregulation may be due to early immune system alterations via CMV exposure (in utero or early infancy) proposing a potential link between CMV and ALL etiology.
Background Pilocytic astrocytoma (PA) is the most common pediatric brain tumor. PA has at least a 50% higher incidence in populations of European ancestry compared to other ancestral groups, which may be due in part to genetic differences. Methods We first compared the global proportions of European, African, and Amerindian ancestries in 301 PA cases and 1185 controls of self-identified Latino ethnicity from the California Biobank. We then conducted admixture mapping analysis to assess PA risk with local ancestry. Results We found PA cases had a significantly higher proportion of global European ancestry than controls (case median = 0.55, control median = 0.51, P value = 3.5x10-3). Admixture mapping identified 13 SNPs in the 6q14.3 region (SNX14) contributing to risk, as well as three other peaks approaching significance on chromosomes 7, 10 and 13. Downstream fine mapping in these regions revealed several SNPs potentially contributing to childhood PA risk. Conclusions There is a significant difference in genomic ancestry associated with Latino PA risk and several genomic loci potentially mediating this risk.
Background: Aberrant patterns of DNA methylation constitute a key feature of pediatric acute lymphoblastic leukemia (ALL) at diagnosis, however its role as a predisposing or early contributor to the development of ALL remains unknown. We employed a discordant monozygotic twin model to identify epigenetic variation associated with future development of pediatric ALL through evaluation of DNA methylation at birth. Methods: Twin pairs discordant for the development of pediatric ALL were identified using linked data from the California Cancer Registry and California Birth Statistical Master File spanning from 1989 to 2015. Archived dried neonatal blood spots were obtained from 86 same-gender twin pairs with available materials from the California Biobank Program. Following isolation of genomic DNA from DBS samples, monozygosity was confirmed in 43 of 86 twin pairs through an identity-by-descent analysis from a genome-wide SNP-array. Epigenome-wide DNA methylation assessment of the 43 discordant monozygotic twin pairs was conducted using the Illumina Infinium MethylationEPIC BeadChip kit (Illumina, San Diego, CA, USA). Data preprocessing and quality control measures were conducted in R, using SeSAMe for data normalization. Two twin pairs were omitted due to failure to pass quality control measures. Within-pair analysis was conducted through identification of array probes with absolute differences in methylation beta values greater than 15% between case and control siblings of a twin pair unit. Differentially methylated probes (DMP) were identified using a conditional logistic regression model accounting for array-specific variation, nucleated cell proportions, and appropriate control for the paired nature of the dataset. Differentially methylated regions (DMR) were defined by regional correlation of p-values from the conditional logistic regression model. Gene set enrichment analysis was conducted on significant probes identified through the within pair and regression analysis. Results: The discordant twin cohort (n = 41 pairs) included 24 female and 17 male pairs. Median gestational age was 258 days, ranging from 184 to 306 days. Age of diagnosis in the case twin ranged from <1 to 23 years (median = 5). There was no significant association between birthweight and case status (paired Wilcoxon signed rank test p = 0.22). No significant differences in nucleated cell proportions were identified in deconvolution analysis. Within-pair analysis identified a total of 18,001 probes with absolute methylation variation greater than 15% across the 41 twin pairs, with 3,984 recurrently variable across more than one pair. Gene ontology analysis of these recurrently variable sites revealed an enrichment of immune-related processes in 7 of the top 15 terms with nominal p-value <0.05, though no terms were significant after correction for multiple comparisons. Conditional logistic regression was conducted on 37 twin pairs, with T-cell cases (n=4) omitted to improve data resolution. This resulted in 240 significant DMPs with p-values below an FDR threshold of 0.05. Of these significant probes, 20 associate with genes previously reported to have altered DNA methylation in ALL at diagnosis. Regional analysis identified 10 significant DMRs with adjusted p-values below 0.05, with the top association encompassing a 454bp region on chromosome 6 located near TRIM39-RPP21 (adjusted p-value 2.39e-05). Notably, conditional regression analysis revealed a significant negative bias in coefficients (409,812 of 710,010 probes, binomial exact test p <2.2e-16), indicating a global tendency toward hypomethylation in cases compared to unaffected siblings (Figure 1). The strength of this bias was greater in probes associated with open sea regions compared to those in island regions, as well as promoter-associated probes. Conclusions: This novel analysis of DNA methylation at birth in ALL-discordant monozygotic twins identified sites of differential methylation associated with immune regulation. In addition, these results provide evidence of an association between global DNA hypomethylation and future development of ALL in one member of a genetically identical twin pair. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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