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Background Although recent sequencing studies have revealed that 10% of childhood gliomas are caused by rare germline mutations, the role of common variants is undetermined and no genome-wide significant risk loci for pediatric central nervous system tumors have been identified to date. Methods Meta-analysis of 3 population-based genome-wide association studies comprising 4069 children with glioma and 8778 controls of multiple genetic ancestries. Replication was performed in a separate case–control cohort. Quantitative trait loci analyses and a transcriptome-wide association study were conducted to assess possible links with brain tissue expression across 18 628 genes. Results Common variants in CDKN2B-AS1 at 9p21.3 were significantly associated with astrocytoma, the most common subtype of glioma in children (rs573687, P-value of 6.974e-10, OR 1.273, 95% CI 1.179–1.374). The association was driven by low-grade astrocytoma (P-value of 3.815e-9) and exhibited unidirectional effects across all 6 genetic ancestries. For glioma overall, the association approached genome-wide significance (rs3731239, P-value of 5.411e-8), while no significant association was observed for high-grade tumors. Predicted decreased brain tissue expression of CDKN2B was significantly associated with astrocytoma (P-value of 8.090e-8). Conclusions In this population-based genome-wide association study meta-analysis, we identify and replicate 9p21.3 (CDKN2B-AS1) as a risk locus for childhood astrocytoma, thereby establishing the first genome-wide significant evidence of common variant predisposition in pediatric neuro-oncology. We furthermore provide a functional basis for the association by showing a possible link to decreased brain tissue CDKN2B expression and substantiate that genetic susceptibility differs between low- and high-grade astrocytoma.

Leukemia is the most common cancer in children in industrialized countries, and its initiation often occurs prenatally. Folic acid is a key vitamin in the production and modification of DNA, and prenatal folic acid intake is known to reduce the risk of childhood leukemia. We characterized the one-carbon (folate) metabolism nutrients that may influence risk of childhood acute lymphoblastic leukemia (ALL) among 122 cases diagnosed at age 0–14 years during 1988–2011 and 122 controls matched on sex, age, and race/ethnicity. Using hydrophilic interaction chromatography (HILIC) applied to neonatal dried blood spots, we evaluated 11 folate pathway metabolites, overall and by sex, race/ethnicity, and age at diagnosis. To conduct the prediction analyses, the 244 samples were separated into learning (75%) and test (25%) sets, maintaining the matched pairings. The learning set was used to train classification methods which were evaluated on the test set. High classification error rates indicate that the folate pathway metabolites measured have little predictive capacity for pediatric ALL. In conclusion, the one-carbon metabolism nutrients measured at birth were unable to predict subsequent leukemia in children. These negative findings are reflective of the last weeks of pregnancy and our study does not address the impact of these nutrients at the time of conception or during the first trimester of pregnancy that are critical for the embryo’s DNA methylation programming.

Acute lymphoblastic leukemia (ALL) in children is associated with a distinct neonatal cytokine profile. The basis of this neonatal immune phenotype is unknown but potentially related to maternal-fetal immune receptor interactions. We conducted a case-control study of 226 case child-mother pairs and 404 control child-mother pairs to evaluate the role of interaction between HLA genotypes in the offspring and maternal killer immunoglobulin-like receptor (KIR) genotypes in the etiology of childhood ALL, while considering potential mediation by neonatal cytokines and the immune-modulating enzyme arginase-II (ARG-II). We observed different associations between offspring HLA-maternal KIR activating profiles and the risk of ALL in different predicted genetic ancestry groups. For instance, in Latino subjects who experience the highest risk of childhood leukemia, activating profiles were significantly associated with a lower risk of childhood ALL (odds ratio [OR] = 0.59; 95% confidence interval [CI], 0.49-0.71) and a higher level of ARG-II at birth (coefficient = 0.13; 95% CI, 0.04-0.22). HLA-KIR activating profiles were also associated with a lower risk of ALL in non-Latino Asians (OR = 0.63; 95% CI, 0.38-1.01), although they had a lower tumor necrosis factor-α level (coefficient = −0.27; 95% CI, −0.49 to −0.06). Among non-Latino White subjects, no significant association was observed between offspring HLA-maternal KIR interaction and ALL risk or cytokine levels. The current study reports the association between offspring HLA-maternal KIR interaction and the development of childhood ALL with variation by predicted genetic ancestry. We also observed some associations between activating profiles and immune factors related to cytokine control; however, cytokines did not demonstrate causal mediation of the activating profiles on 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 2789 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 9.5 X 10–4). 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 = 3.42 X 10–6) and Hispanic (rs111709726 in EFHD1, adjusted OR = 3.57, 95% CI 1.99–6.40, P-value = 1.41 X 10–6) 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.

INTRODUCTION: Pediatric gliomas constitute a majority of pediatric brain tumors and intermediate to high grade gliomas have high mortality. While some advances have been made over recent years with regards to pediatric glioma etiology, genetic predisposition has not been investigated thoroughly. In this study, the role of rare germline variants on risk of pediatric glioma was evaluated in 322 astrocytoma patients (predominantly grade II and III) using whole-exome sequencing and detailed evaluation of 162 known cancer-related genes. METHODS: DNA samples were extracted from neonatal dried bloodspots from 322 pediatric glioma patients born and diagnosed in California, and sequenced using the Personalis ACE whole-exome sequencing platform. Exome alignment and variant calling was performed using Samtools and GATK 3.8. SnpEff and Combined Annotation Dependent Depletion (CADD) tools were used for variant annotation. Only variants that were not present in the 1000 Genomes dataset, had allele frequency smaller than 0.01% in the Exome Aggregation Consortium (ExAC) database, a CADD score greater than 20, and a moderate or high variant effect impact were included to identify rare putatively deleterious variants. RESULTS: All samples passed quality control and the mean read depth was 41.4. Seventy-one (22.0%) samples harbored a mutation that was potentially deleterious in at least one of the 162 cancer-related genes. The most commonly affected gene encodes a specific receptor tyrosine kinase (RTK) (28 patients, 8.7%), followed by a DNA polymerase enzyme(5 patients), and a specific mismatch repair protein(5 patients). Alterations of the tyrosine kinase protein may impact cell growth, mutation, and maturation of nerve cells. CONCLUSION: This study supports a role for rare germline mutations in the etiology of pediatric glioma and implicates RTK biology in glioma predisposition. These findings have translational implications for risk prediction and targeted therapy.