Breastfeeding and risk of childhood brain tumors : a report from the Childhood Cancer and Leukemia International Consortium

PURPOSE: Studies report mixed findings regarding the association of breastfeeding with childhood brain tumors (CBT), the leading causes of cancer-related mortality in young people. Our objective was to determine whether breastfeeding is associated with CBT incidence. METHODS: We pooled data on N = 2610 cases with CBT (including 697 cases with astrocytoma, 447 cases with medulloblastoma/primitive neuroectodermal tumor [PNET], 167 cases with ependymoma) and N = 8128 age- and sex-matched controls in the Childhood Cancer and Leukemia International Consortium. We computed unconditional logistic regression models to estimate the odds ratio (OR) and 95% confidence interval (CI) of CBT, astrocytoma, medulloblastoma/PNET, and ependymoma according to breastfeeding status, adjusting for study, sex, mode of delivery, birthweight, age at diagnosis/interview, maternal age at delivery, maternal educational attainment, and maternal race/ethnicity. We evaluated any breastfeeding versus none and breastfeeding ≥ 6 months versus none. We subsequently performed random effects meta-analysis to confirm our findings, identify potential sources of heterogeneity, and evaluate for outliers or influential studies. RESULTS: Breastfeeding was reported by 64.8% of control mothers and 64.5% of case mothers and was not associated with CBT (OR 1.04, 95% CI 0.94-1.15), astrocytoma (OR 1.01, 95% CI 0.87-1.17), medulloblastoma/PNET (OR 1.11, 95% CI 0.93-1.32), or ependymoma (OR 1.06, 95% CI 0.81-1.40). Results were similar when we restricted to breastfeeding ≥ 6 months and in meta-analyses. CONCLUSION: Our data suggest that breastfeeding does not protect against CBT

Residence in a Hispanic Enclave Is Associated with Inferior Overall Survival among Children with Acute Lymphoblastic Leukemia

Hispanic children with acute lymphoblastic leukemia (ALL) experience poorer overall survival (OS) than non-Hispanic White children; however, few studies have investigated the social determinants of this disparity. In Texas, many Hispanic individuals reside in ethnic enclaves—areas with high concentrations of immigrants, ethnic-specific businesses, and language isolation, which are often socioeconomically deprived. We determined whether enclave residence was associated with ALL survival, overall and among Hispanic children. We computed Hispanic enclave index scores for Texas census tracts, and classified children (N = 4083) as residing in enclaves if their residential tracts scored in the highest statewide quintile. We used Cox regression to evaluate the association between enclave residence and OS. Five-year OS was 78.6% for children in enclaves, and 77.8% for Hispanic children in enclaves, both significantly lower (p < 0.05) than the 85.8% observed among children not in enclaves. Children in enclaves had increased risk of death (hazard ratio (HR) 1.20, 95% confidence interval (CI) 1.01–1.49) after adjustment for sex, age at diagnosis, year of diagnosis, metropolitan residence and neighborhood socioeconomic deprivation and after further adjustment for child race/ethnicity (HR 1.19, 95% CI 0.97–1.45). We observed increased risk of death when analyses were restricted to Hispanic children specifically (HR 1.30, 95% CI 1.03–1.65). Observations suggest that children with ALL residing in Hispanic enclaves experience inferior OS

Epigenomic signature of major congenital heart defects in newborns with Down syndrome

BackgroundCongenital heart defects (CHDs) affect approximately half of individuals with Down syndrome (DS), but the molecular reasons for incomplete penetrance are unknown. Previous studies have largely focused on identifying genetic risk factors associated with CHDs in individuals with DS, but comprehensive studies of the contribution of epigenetic marks are lacking. We aimed to identify and characterize DNA methylation differences from newborn dried blood spots (NDBS) of DS individuals with major CHDs compared to DS individuals without CHDs.MethodsWe used the Illumina EPIC array and whole-genome bisulfite sequencing (WGBS) to quantitate DNA methylation for 86 NDBS samples from the California Biobank Program: (1) 45 DS-CHD (27 female, 18 male) and (2) 41 DS non-CHD (27 female, 14 male). We analyzed global CpG methylation and identified differentially methylated regions (DMRs) in DS-CHD versus DS non-CHD comparisons (both sex-combined and sex-stratified) corrected for sex, age of blood collection, and cell-type proportions. CHD DMRs were analyzed for enrichment in CpG and genic contexts, chromatin states, and histone modifications by genomic coordinates and for gene ontology enrichment by gene mapping. DMRs were also tested in a replication dataset and compared to methylation levels in DS versus typical development (TD) WGBS NDBS samples.ResultsWe found global CpG hypomethylation in DS-CHD males compared to DS non-CHD males, which was attributable to elevated levels of nucleated red blood cells and not seen in females. At a regional level, we identified 58, 341, and 3938 CHD-associated DMRs in the Sex Combined, Females Only, and Males Only groups, respectively, and used machine learning algorithms to select 19 Males Only loci that could distinguish CHD from non-CHD. DMRs in all comparisons were enriched for gene exons, CpG islands, and bivalent chromatin and mapped to genes enriched for terms related to cardiac and immune functions. Lastly, a greater percentage of CHD-associated DMRs than background regions were differentially methylated in DS versus TD samples.ConclusionsA sex-specific signature of DNA methylation was detected in NDBS of DS-CHD compared to DS non-CHD individuals. This supports the hypothesis that epigenetics can reflect the variability of phenotypes in DS, particularly CHDs

Epigenomic signature of major congenital heart defects in newborns with Down syndrome

Abstract Background Congenital heart defects (CHDs) affect approximately half of individuals with Down syndrome (DS), but the molecular reasons for incomplete penetrance are unknown. Previous studies have largely focused on identifying genetic risk factors associated with CHDs in individuals with DS, but comprehensive studies of the contribution of epigenetic marks are lacking. We aimed to identify and characterize DNA methylation differences from newborn dried blood spots (NDBS) of DS individuals with major CHDs compared to DS individuals without CHDs. Methods We used the Illumina EPIC array and whole-genome bisulfite sequencing (WGBS) to quantitate DNA methylation for 86 NDBS samples from the California Biobank Program: (1) 45 DS-CHD (27 female, 18 male) and (2) 41 DS non-CHD (27 female, 14 male). We analyzed global CpG methylation and identified differentially methylated regions (DMRs) in DS-CHD versus DS non-CHD comparisons (both sex-combined and sex-stratified) corrected for sex, age of blood collection, and cell-type proportions. CHD DMRs were analyzed for enrichment in CpG and genic contexts, chromatin states, and histone modifications by genomic coordinates and for gene ontology enrichment by gene mapping. DMRs were also tested in a replication dataset and compared to methylation levels in DS versus typical development (TD) WGBS NDBS samples. Results We found global CpG hypomethylation in DS-CHD males compared to DS non-CHD males, which was attributable to elevated levels of nucleated red blood cells and not seen in females. At a regional level, we identified 58, 341, and 3938 CHD-associated DMRs in the Sex Combined, Females Only, and Males Only groups, respectively, and used machine learning algorithms to select 19 Males Only loci that could distinguish CHD from non-CHD. DMRs in all comparisons were enriched for gene exons, CpG islands, and bivalent chromatin and mapped to genes enriched for terms related to cardiac and immune functions. Lastly, a greater percentage of CHD-associated DMRs than background regions were differentially methylated in DS versus TD samples. Conclusions A sex-specific signature of DNA methylation was detected in NDBS of DS-CHD compared to DS non-CHD individuals. This supports the hypothesis that epigenetics can reflect the variability of phenotypes in DS, particularly CHDs

Additional file 1 of Epigenomic signature of major congenital heart defects in newborns with Down syndrome

Additional file 1: Table S1. Study characteristics: description of sample traits included in study. Table S2. Sample traits: values of traits for each sample. Table S3. Welch’s t test for differences in sample traits in DS-CHD versus DS non-CHD samples. Table S4. Pearson correlation coefficients and p values (unadjusted and adjusted) for sample traits. Table S5. EPIC array beta values. Table S6. Logistic regression for CHD and linear regression for global methylation. Table S7. Annotated Sex Combined DMRs (adjusted for sex, age of blood collection, cell types). Table S8. Annotated Females Only DMRs (adjusted for age of blood collection, cell types). Table S9. Annotated Males Only DMRs (adjusted for age of blood collection, cell types). Table S10. Annotated Males Only DMRs (adjusted for age of blood collection, cell types) Sensitivity Analysis (5 samples with nRBC > 20% removed). Table S11. Machine Learning DMRs. Table S12. Smoothed methylation of Sex-combined DMRs in replication dataset. Table S13. Smoothed methylation of Females Only DMRs in replication dataset. Table S14. Smoothed methylation of Males Only DMRs in replication dataset. Table S15. Stats from permutation testing of DMR overlaps from Sex Combined, Females Only, and Males Only comparisons. Table S16. Chromosome location enrichments of Sex Combined, Females Only, and Males Only DMRs. Table S17. CpG and Genic enrichments for Sex Combined, Females Only, and Males Only comparisons. Table S18. GREAT gene ontology enrichments for Sex-Combined DMRs compared to background regions. Table S19. GREAT gene ontology enrichments for Females Only DMRs compared to background regions. Table S20. GREAT gene ontology enrichments for Males Only DMRs compared to background regions. Table S21. Smoothed methylation of Sex-combined DMRs in DSvTD dataset. Table S22. Smoothed methylation of Females Only DMRs in DSvTD dataset. Table S23. Smoothed methylation of Males Only DMRs in DSvTD dataset

Maternal folate genes and aberrant DNA hypermethylation in pediatric acute lymphoblastic leukemia

<div><p>Background</p><p>There is evidence that maternal genotypes in folate-related genes are associated with pediatric acute lymphoblastic leukemia (ALL) independent of offspring genotype. We evaluated the relationship between maternal genotypes in methionine synthase (<i>MTR</i>) and DNA methylation status in ALL to better characterize the molecular mechanism underlying this association.</p><p>Procedure</p><p>We obtained bone marrow samples from 51 patients with ALL at diagnosis and from 6 healthy donors. Mothers of patients provided a saliva sample and were genotyped at 11 tagSNPs in <i>MTR</i>. DNA methylation was measured in bone marrow mononuclear cells of patients and six healthy marrow donors. We used hierarchical clustering to identify patients with a hypermethylator phenotype based on 281 differentially methylated promoter CpGs. We used logistic regression to estimate the effects of maternal genotype on the likelihood of DNA hypermethylation in ALL and Ingenuity Pathway Analysis to identify networks enriched for differentially methylated genes.</p><p>Results</p><p>Twenty-two cases (43%) demonstrated promoter hypermethylation, which was more frequent among those with <i>ETV6-RUNX1</i> fusion and initial white blood cell count < 50 x 10⁹/L. Maternal rs12759827 was associated with aberrant DNA methylation (odds ratio [OR] 4.67, 95% confidence interval 1.46–16.31); non-significantly elevated ORs were observed for all other SNPs. Aberrantly methylated promoter CpGs aligned to genes with known cancer-related functions.</p><p>Discussion</p><p>Maternal folate metabolic genotype may be associated with DNA methylation patterns in ALL in their offspring. Therefore, the effect of maternal genotypes on ALL susceptibility may act through aberrant promoter methylation, which may contribute to the <i>in utero</i> origins of ALL.</p></div

Demographic and clinical information of pediatric all patients.

<p>Demographic and clinical information of pediatric all patients.</p

Differential DNA methylation patterns according to case-control status and maternal <i>MTR</i> rs12759827 genotype.

<p><b>(A)</b> Log ratio of methylation density comparing cases to controls across all genomic locations. Horizontal black lines represent the log ratio of mean methylation density in cases compared to controls. <b>(B)</b> Hierarchical clustering demonstrates differential promoter methylation between controls (green) and CIMP- cases (pink) compared to CIMP+ cases (purple).</p