A noncoding regulatory variant in IKZF1 increases acute lymphoblastic leukemia risk in Hispanic/Latino children.

Hispanic/Latino children have the highest risk of acute lymphoblastic leukemia (ALL) in the US compared to other racial/ethnic groups, yet the basis of this remains incompletely understood. Through genetic fine-mapping analyses, we identified a new independent childhood ALL risk signal near IKZF1 in self-reported Hispanic/Latino individuals, but not in non-Hispanic White individuals, with an effect size of ∼1.44 (95% confidence interval = 1.33-1.55) and a risk allele frequency of ∼18% in Hispanic/Latino populations and <0.5% in European populations. This risk allele was positively associated with Indigenous American ancestry, showed evidence of selection in human history, and was associated with reduced IKZF1 expression. We identified a putative causal variant in a downstream enhancer that is most active in pro-B cells and interacts with the IKZF1 promoter. This variant disrupts IKZF1 autoregulation at this enhancer and results in reduced enhancer activity in B cell progenitors. Our study reveals a genetic basis for the increased ALL risk in Hispanic/Latino children.

Effect of parental adverse childhood experiences on intergenerational DNA methylation signatures from peripheral blood mononuclear cells and buccal mucosa.

In this study, the effect of cumulative ACEs experienced on human maternal DNA methylation (DNAm) was estimated while accounting for interaction with domains of ACEs in prenatal peripheral blood mononuclear cell samples from the Maternal and Developmental Risks from Environmental Stressors (MADRES) pregnancy cohort. The intergenerational transmission of ACE-associated DNAm was also explored used paired maternal (N = 120) and neonatal cord blood (N = 69) samples. Replication in buccal samples was explored in the Children's Health Study (CHS) among adult parental (N = 31) and pediatric (N = 114) samples. We used a four-level categorical indicator variable for ACEs exposure: none (0 ACEs), low (1-3 ACEs), moderate (4-6 ACEs), and high (>6 ACEs). Effects of ACEs on maternal DNAm (N = 240) were estimated using linear models. To evaluate evidence for intergenerational transmission, mediation analysis (N = 60 mother-child pairs) was used. Analysis of maternal samples displayed some shared but mostly distinct effects of ACEs on DNAm across low, moderate, and high ACEs categories. CLCN7 and PTPRN2 was associated with maternal DNAm in the low ACE group and this association replicated in the CHS. CLCN7 was also nominally significant in the gene expression correlation analysis among maternal profiles (N = 35), along with 11 other genes. ACE-associated methylation was observed in maternal and neonatal profiles in the COMT promoter region, with some evidence of mediation by maternal COMT methylation. Specific genomic loci exhibited mutually exclusive maternal ACE effects on DNAm in either maternal or neonatal population. There is some evidence for an intergenerational effect of ACEs, supported by shared DNAm signatures in the COMT gene across maternal-neonatal paired samples.

Evaluation of the genetic basis of familial-associated early-onset hematologic cancers in an ancestral/ethnically diverse population.

Genetic predisposition to hematologic malignancies has historically been addressed utilizing patients recruited from clinical trials and pedigrees constructed at major treatment centers. Such efforts leave unexplored the genetic basis of variations in risk by race/ethnic group shown in population-based surveillance data where cancer registration, compulsory by law, delivers universal enrollment. To address this, we performed exome sequencing on DNA isolated from newborn bloodspots derived from sibling pairs with early-onset cancers across California in which at least one of the siblings developed a hematologic cancer, using unbiased recruitment from the full state population. We identified pathogenic/likely pathogenic (P/LP) variants among 1172 selected cancer genes that were private or present at low allele frequencies in reference populations. Within 64 subjects from 32 families, we found 9 LP variants shared between siblings, and an additional 7 such variants in singleton children (not shared with their sibling). In eight of the shared cases, the ancestral origin of the local haplotype that carries P/LP variants matched the dominant global ancestry of study participant families. This was the case for Latino sibling pairs on FLG and CBLB, non-Latino White sibling pairs in TP53 and NOD2, and a shared GATA2 variant for a non-Latino Black sibling pair. A new inherited mutation in HABP2 was identified in a sibling pair, one with diffuse large B-cell lymphoma and the other with neuroblastoma. Overall, the profile of P/LP germline variants across ancestral/ethnic groups suggests that rare alleles contributing to hematologic diseases originate within their race/ethnic origin parental populations, demonstrating the value of this discovery process in diverse, population-based registries.

Association between county-level socioeconomic status and the incidence of and surgical treatment for pituitary adenoma.

OBJECTIVE: The objective of this study was to evaluate the association between county-level socioeconomic status (SES) and the incidence of and surgical treatment for pituitary adenoma (PA). METHODS: Using the Centers for Disease Control and Prevention's National Program of Cancer Registries and the National Cancer Institute's Surveillance, Epidemiology, and End Results database, the authors identified the average annual age-adjusted incidence rates and calculated odds ratios (ORs) for surgical treatment of PA, stratified by a county-level index for SES, race/ethnicity, metropolitan status, and other confounders. RESULTS: From 2006 to 2018, 167,121 PA cases were identified. There was no significant trend in the incidence of PA by county-level SES overall (incidence rate ratio [IRR] 0.98, 95% CI 0.96-1.00, p = 0.05, comparing highest to lowest quintile of SES). Among Asian or Pacific Islander (API; IRR 0.82, 95% CI 0.71-0.95, p = 0.007) and American Indian/Alaska Native (AIAN) participants (IRR 0.82, 95% CI 0.71-0.95, p = 0.009), the incidence of PA was statistically significantly lower with higher SES, while among Black individuals, the incidence of PA was higher with higher SES (IRR 1.10, 95% CI 1.05-1.15, p < 0.001, comparing 5th to 1st quintile of SES). Higher SES quintile was associated with surgical treatment of PA (OR 1.04, 95% CI 0.99-1.09, comparing highest to lowest quintile, p value for trend = 0.02). Males were more likely than females to undergo surgery (OR 1.50, 95% CI 1.47-1.53, p < 0.001), and Black (OR 0.89, 95% CI 0.86-0.91, p < 0.001) and AIAN individuals (OR 0.88, 95% CI 0.78-0.99, p = 0.04) were less likely to undergo surgery than White individuals, whereas API individuals were more likely to undergo surgery (OR 1.15, 95% CI 1.09-1.21, p < 0.001). CONCLUSIONS: Higher county-level SES in the US was associated with a higher incidence of PA among Black individuals, but not among White individuals, while API and AIAN individuals had a lower PA incidence with higher SES. After multivariable adjustment, higher county-level SES was associated with surgical treatment of PA, and White and API individuals were significantly more likely to undergo surgery than Black or AIAN individuals.

Maternal Prenatal Use of Alcohol, Tobacco, and Illicit Drugs and Associations with Childhood Cancer Subtypes.

BACKGROUND: The association between childhood cancer risk and maternal prenatal substance use/abuse remains uncertain due to modest sample sizes and heterogeneous study designs. METHODS: We surveyed parents of children with cancer regarding maternal gestational use of tobacco, alcohol, and illicit drugs, using a Likert-type scale, and demographic, perinatal, and clinical variables. Multivariable log-Poisson regression assessed differences in frequency of prenatal substance use across fifteen childhood cancer subtypes, adjusting for birthweight, gestational age, and demographic factors. RESULTS: Respondents from 3,145 unique families completed the survey (92% biological mothers). A minority reported gestational use of tobacco products (14%), illicit drugs including marijuana or cocaine (4%), or more than a moderate amount of alcohol (2%). Prenatal illicit drug use was associated with increased prevalence of intracranial embryonal tumors [prevalence ratio (PR) = 1.94; confidence interval [CI], 1.05-3.58], including medulloblastoma (PR = 1.82) and supratentorial primitive neuroectodermal tumors (PNET; PR = 2.66), and was also associated with retinoblastoma (PR = 3.11; CI, 1.20-8.08). Moderate to heavy alcohol consumption was strongly associated with elevated prevalence of non-Hodgkin lymphoma (PR = 5.94; CI, 1.84-19.21). Prenatal smoking was not associated with elevated prevalence of any childhood cancer subtype. CONCLUSIONS: We identify novel associations between illicit drug use during pregnancy and increased prevalence of nonglioma central nervous system tumors, including medulloblastoma, supratentorial PNETs, and retinoblastoma. Gestational exposure to alcohol was positively associated with non-Hodgkin lymphoma. IMPACT: Although alcohol and tobacco use during pregnancy has declined, gestational cannabis use has risen. Investigating its impact on neurodevelopment and brain tumorigenesis is vital, with important implications for childhood cancer research and public health education.

Evaluating Genomic Polygenic Risk Scores for Childhood Acute Lymphoblastic Leukemia in Latinos.

The utility of polygenic risk score (PRS) models has not been comprehensively evaluated for childhood acute lymphoblastic leukemia (ALL), the most common type of cancer in children. Previous PRS models for ALL were based on significant loci observed in genome-wide association studies (GWAS), even though genomic PRS models have been shown to improve prediction performance for a number of complex diseases. In the United States, Latino (LAT) children have the highest risk of ALL, but the transferability of PRS models to LAT children has not been studied. In this study we constructed and evaluated genomic PRS models based on either non-Latino white (NLW) GWAS or a multi-ancestry GWAS. We found that the best PRS models performed similarly between held-out NLW and LAT samples (PseudoR2 = 0.086 ± 0.023 in NLW vs. 0.060 ± 0.020 in LAT), and can be improved for LAT if we performed GWAS in LAT-only (PseudoR2 = 0.116 ± 0.026) or multi-ancestry samples (PseudoR2 = 0.131 ± 0.025). However, the best genomic models currently do not have better prediction accuracy than a conventional model using all known ALL-associated loci in the literature (PseudoR2 = 0.166 ± 0.025), which includes loci from GWAS populations that we could not access to train genomic PRS models. Our results suggest that larger and more inclusive GWAS may be needed for genomic PRS to be useful for ALL. Moreover, the comparable performance between populations may suggest a more oligo-genic architecture for ALL, where some large effect loci may be shared between populations. Future PRS models that move away from the infinite causal loci assumption may further improve PRS for ALL.

Gene-Environment Analyses Reveal Novel Genetic Candidates with Prenatal Tobacco Exposure in Relation to Risk for Childhood Acute Lymphoblastic Leukemia.

BACKGROUND: Associations between maternal tobacco exposure during pregnancy and childhood acute lymphoblastic leukemia (ALL) have yielded mixed results. This may be due to biases in self-reported smoking or other differences in individual-level risk factors. We utilized a biological marker of maternal tobacco exposure to evaluate the association between maternal tobacco exposure during pregnancy, genetics, and subsequent childhood ALL risk in two large population-based studies of childhood ALL in California. METHODS: Maternal exposure to tobacco smoke was assessed with a validated methylation marker (cg05575921) of the aryl hydrocarbon receptor repressor (AHRR) gene in newborn dried blood spots. We adjusted for sex, birthweight, gestational age, mode of delivery, year of birth, AHRR quantitative trait locus (mQTL) rs77111113, and a polygenetic risk score for childhood ALL. We additionally adjusted for principal components in a gene-environment interaction testing method that incorporates gene-only and environment-only effects along with interactions. RESULTS: AHRR hypomethylation overall was not associated with childhood ALL. In gene-environment interaction testing, several genetic variants displayed significant interaction with AHRR hypomethylation and childhood ALL. CONCLUSIONS: Our results suggest that novel candidates in PTPRK and DPP6 may play a role in tobacco-related leukemogenesis. Further research is necessary to better understand the effects of tobacco and these variants on childhood ALL risk. IMPACT: Despite the lack of an overall "main effect," tobacco exposure during pregnancy affects childhood ALL risk depending on specific genetic variants.

Evaluating Genomic Polygenic Risk Scores for Childhood Acute Lymphoblastic Leukemia in Latinos.

The utility of polygenic risk score (PRS) models has not been comprehensively evaluated for childhood acute lymphoblastic leukemia (ALL), the most common type of cancer in children. Previous PRS models for ALL were based on significant loci observed in genome-wide association studies (GWAS), even though genomic PRS models have been shown to improve prediction performance for a number of complex diseases. In the United States, Latino (LAT) children have the highest risk of ALL, but the transferability of PRS models to LAT children has not been studied. In this study we constructed and evaluated genomic PRS models based on either non-Latino white (NLW) GWAS or a multi-ancestry GWAS. We found that the best PRS models performed similarly between held-out NLW and LAT samples (PseudoR 2 = 0.086 ± 0.023 in NLW vs. 0.060 ± 0.020 in LAT), and can be improved for LAT if we performed GWAS in LAT-only (PseudoR 2 = 0.116 ± 0.026) or multi-ancestry samples (PseudoR 2 = 0.131 ± 0.025). However, the best genomic models currently do not have better prediction accuracy than a conventional model using all known ALL-associated loci in the literature (PseudoR 2 = 0.166 ± 0.025), which includes loci from GWAS populations that we could not access to train genomic PRS models. Our results suggest that larger and more inclusive GWAS may be needed for genomic PRS to be useful for ALL. Moreover, the comparable performance between populations may suggest a more oligo-genic architecture for ALL, where some large effect loci may be shared between populations. Future PRS models that move away from the infinite causal loci assumption may further improve PRS for ALL.

Effect of Parental Adverse Childhood Experiences on Intergenerational DNA Methylation Signatures.

Adverse Childhood Experiences (ACEs) are events that occur before a child turns 18 years old that may cause trauma. In this study, the effect of cumulative ACEs experienced on human maternal DNA methylation (DNAm) was estimated while accounting for interaction with domains of ACEs in prenatal peripheral blood mononuclear cell samples from the Maternal and Developmental Risks from Environmental Stressors (MADRES) pregnancy cohort. The intergenerational transmission of ACE-associated DNAm was also explored used paired maternal and neonatal cord blood samples. Replication in buccal samples was explored in the Children's Health Study (CHS). We used a four-level categorical indicator variable for ACEs exposure: none (0 ACEs), low (1-3 ACEs), moderate (4-6 ACEs), and high (> 6 ACEs). Effects of ACEs on maternal DNAm (N = 240) were estimated using linear models. To evaluate evidence for intergenerational transmission, mediation analysis was used. Analysis of maternal samples displayed some shared but mostly distinct effects of ACEs on DNAm across low, moderate, and high ACEs categories. CLCN7 and PTPRN2 was associated with maternal DNAm in the low ACE group and this association replicated in the CHS. ACE-associated methylation was observed in maternal and neonatal profiles in the COMT promoter region, with some evidence of mediation by maternal COMT methylation. Specific genomic loci exhibited mutually exclusive maternal ACE effects on DNAm in either maternal or neonatal population. There is some evidence for an intergenerational effect of ACEs, supported by shared DNAm signatures in the COMT gene across maternal-neonatal paired samples.

High Ambient Temperature in Pregnancy and Risk of Childhood Acute Lymphoblastic Leukemia.

Background: High ambient temperature is increasingly common due to climate change and is associated with risk of adverse pregnancy outcomes. Acute lymphoblastic leukemia (ALL) is the most common malignancy in children, the incidence is increasing, and in the United States it disproportionately affects Latino children. We aimed to investigate the potential association between high ambient temperature in pregnancy and risk of childhood ALL. Methods: We used data from California birth records (1982-2015) and California Cancer Registry (1988-2015) to identify ALL cases diagnosed <14 years and 50 times as many controls matched by sex, race/ethnicity, and date of last menstrual period. Ambient temperatures were estimated on a 1-km grid. Association between ambient temperature and ALL was evaluated per gestational week, restricted to May-September, adjusting for confounders. Bayesian meta-regression was applied to identify critical exposure windows. For sensitivity analyses, we evaluated a 90-day pre-pregnancy period (assuming no direct effect before pregnancy) and constructed an alternatively matched dataset for exposure contrast by seasonality. Findings: Our study included 6,258 ALL cases and 307,579 controls. The peak association between ambient temperature and risk of ALL was observed in gestational week 8, where a 5 °C increase was associated with an odds ratio of 1.09 (95% confidence interval 1.04-1.14) and 1.05 (95% confidence interval 1.00-1.11) among Latino and non-Latino White children, respectively. The sensitivity analyses supported this. Interpretation: Our findings suggest an association between high ambient temperature in early pregnancy and risk of childhood ALL. Further replication and investigation of mechanistic pathways may inform mitigation strategies.

Birth characteristics and risk of Ewing sarcoma.

PURPOSE: The incidence of Ewing sarcoma varies according to race and ethnicity, and genetic susceptibility is known to affect disease risk. Apart from these factors, the etiology of Ewing sarcoma is largely unknown. METHODS: We compared the birth characteristics of a population-based series of 556 Ewing sarcoma cases born in California in 1978-2015 and diagnosed in 1988-2015 with those of 27,800 controls selected from statewide birth records and frequency-matched to cases on the year of birth, using multivariable logistic regression models. We also assessed whether Ewing sarcoma clustered within families. RESULTS: Compared to non-Hispanic White subjects, Black (odds ratio [OR] = 0.07, 95% confidence interval [CI] 0.03-0.18), Asian (OR = 0.57, 95% CI 0.41-0.80), and Hispanic (OR = 0.73, 95% CI 0.62-0.88) individuals had a significantly lower risk of Ewing sarcoma. Race and ethnicity differences were more profound for metastatic Ewing sarcoma. Birthweight was also identified as a significant risk factor (OR = 1.09, 95% CI 1.00-1.18 for each 500 g increase in birthweight). A separate family-based cancer clustering analysis did not suggest any strong role for familial predisposition alleles. CONCLUSIONS: This population-based study with minimal selection bias provides support for a role of accelerated fetal growth in the etiology of Ewing sarcoma in addition to more precise estimates of racial and ethnic variations in disease risk. This comparatively large analysis of birth characteristics and Ewing sarcoma in a multiethnic population should stimulate further investigations into genetic and environmental causes.

Association between birth characteristics and incidence of pituitary adenoma and craniopharyngioma: a registry-based study in California, 2001-2015.

PURPOSE: To evaluate the association between birth characteristics, including parental sociodemographic characteristics, and early-onset pituitary adenoma (PA) and craniopharyngioma. METHODS: Leveraging the population-based California Linkage Study of Early-onset Cancers, we identified the birth characteristics of incident cases with PA (n = 1,749) or craniopharyngioma (n = 227) who were born from 1978 to 2015 and diagnosed 1988-2015, as well as controls in a 50:1 ratio matched on birth year. Adjusted odds ratios (OR) and 95% confidence interval (CI) estimates were computed using unconditional multivariable logistic regression. RESULTS: Males had a lower risk of PA than females (OR = 0.37, 95%CI: 0.34-0.41), and Black (OR = 1.55, 95%CI: 1.30-1.84) or Hispanic (OR = 1.53, 95%CI: 1.34-1.74) individuals had a higher risk compared to non-Hispanic Whites. Older maternal age was positively associated with PA (OR = 1.09, 95%CI: 1.04-1.15 per 5 years, p < 0.01), as was higher maternal education (OR = 1.12, 95%CI: 1.04-1.20 per year, p < 0.01). There were no statistically significant associations between birthweight (OR = 1.04, 95%CI: 0.99-1.09 per 500 g, p = 0.12), birth plurality, or birth order and PA. When stratified by race and ethnicity, the significant association with maternal education was identified only for non-Hispanic White individuals. On multivariable logistic regression, no statistically significant associations were identified between birth characteristics and incidence of craniopharyngioma, except that risk was higher among Hispanic (OR = 1.45, 95%CI: 1.01-2.08) compared to non-Hispanic White individuals. CONCLUSION: In this large, population-based study, female sex, older maternal age, higher maternal education, and Hispanic ethnicity and Black race compared to non-Hispanic White race, were associated with an increased risk of PA in children and young adults.

Infections and Acute Lymphoblastic Leukemia: Is the Sum Worth More than the Parts? Evidence from Birth Characteristics.

The etiology of childhood acute lymphoblastic leukemia (ALL) has long been studied piecemeal with investigations leading to a lengthy list of putative risk factors including several with immune modulatory effects. The ubiquity of many of these factors (e.g., daycare attendance, low parity, breastfeeding, normal vaccinations) belies the rarity of ALL as an outcome. In this commentary, Pombo-de-Oliveira and colleagues show that a key feature may be the combination of particular risk factors, as the birth characteristics "cesarean section" and "birth order" when combined interact to impart higher risk of ALL than would be suggested by the additive risk of both factors. This statistical interaction would be predicted by the "delayed infection hypothesis" wherein infant immune isolation promotes developmental vulnerability to ALL upon infection exposure later in childhood. Pombo-de-Oliveira and colleagues show further that lack of breastfeeding, a postnatal factor leading to further immune isolation, induces additional risk. In sum, the data reveal a combination of factors that together could impart a healthy "trained" immune system allowing for moderated responses to later exposures with microbial and viral antigens. Such priming of the immune system avoids maladaptive immunologic consequences of delayed antigenic stimulation leading to ALL and other diseases. Further research utilizing biomarkers of specific exposures (in addition to the proxy measures used here) will be helpful to realize the full potential for immune modification for ALL prevention. See related article by Pombo-de-Oliveira et al., p. 371.

Evaluation of Maternal Infection During Pregnancy and Childhood Leukemia Among Offspring in Denmark.

Importance: Maternal infection is common during pregnancy and is an important potential cause of fetal genetic and immunological abnormalities. Maternal infection has been reported to be associated with childhood leukemia in previous case-control or small cohort studies. Objective: To evaluate the association of maternal infection during pregnancy with childhood leukemia among offspring in a large study. Design, Setting, and Participants: This population-based cohort study used data from 7 Danish national registries (including the Danish Medical Birth Register, the Danish National Patient Registry, the Danish National Cancer Registry, and others) for all live births in Denmark between 1978 and 2015. Swedish registry data for all live births between 1988 and 2014 were used to validate the findings for the Danish cohort. Data were analyzed from December 2019 to December 2021. Exposures: Maternal infection during pregnancy categorized by anatomic locations identified from the Danish National Patient Registry. Main Outcomes and Measures: The primary outcome was any leukemia; secondary outcomes were acute lymphoid leukemia (ALL) and acute myeloid leukemia (AML). Offspring childhood leukemia was identified in the Danish National Cancer Registry. Associations were first assessed in the whole cohort using Cox proportional hazards regression models, adjusted for potential confounders. A sibling analysis was performed to account for unmeasured familial confounding. Results: This study included 2 222 797 children, 51.3% of whom were boys. During the approximately 27 million person-years of follow-up (mean [SD], 12.0 [4.6] years per person), 1307 children were diagnosed with leukemia (ALL, 1050; AML, 165; or other, 92). Children born to mothers with infection during pregnancy had a 35% increased risk of leukemia (adjusted hazard ratio [HR], 1.35 [95% CI, 1.04-1.77]) compared with offspring of mothers without infection. Maternal genital and urinary tract infections were associated with a 142% and 65% increased risk of childhood leukemia, with HRs of 2.42 (95% CI, 1.50-3.92) and 1.65 (95% CI, 1.15-2.36), respectively. No association was observed for respiratory tract, digestive, or other infections. The sibling analysis showed comparable estimates to the whole-cohort analysis. The association patterns for ALL and AML were similar to that for any leukemia. No association was observed for maternal infection and brain tumors, lymphoma, or other childhood cancers. Conclusions and Relevance: In this cohort study of approximately 2.2 million children, maternal genitourinary tract infection during pregnancy was associated with childhood leukemia among offspring. If confirmed in future studies, our findings may have implications for understanding the etiology and developing preventive measures for childhood leukemia.

One-Carbon (Folate) Metabolism Pathway at Birth and Risk of Childhood Acute Lymphoblastic Leukemia: A Biomarker Study in Newborns.

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.

Multi-ancestry genome-wide association study of 4069 children with glioma identifies 9p21.3 risk locus.

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.