BACKGROUND:Causes of childhood cancer remain poorly understood. Using data from the case-control studies of the Childhood Cancer and Leukemia International Consortium (CLIC), we explored how maternal education as a key socioeconomic status (SES) indicator, varies across studies/countries and contributes to understanding of potential environmental and lifestyle risk factors. METHODS:Control group data from cancer-free children matched by diagnosis date of cases from 16 studies were included, using both interview-based and health registry sources. Maternal education, the primary SES measure used in previous analyses with pooled CLIC data, was categorized as low, medium, or high according to the International Standard Classification of Education. Multinomial logistic regression assessed associations between maternal education and perinatal/lifestyle factors, calculating crude and adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) for high vs. low education. RESULTS:Maternal education levels varied across studies and over time, with the highest proportions of highly educated mothers in the U.S. and lowest in Costa Rica, Italy, and Egypt. Higher maternal education was generally positively associated with higher birthweight, breastfeeding, daycare attendance, and maternal prenatal alcohol consumption. Higher maternal education was generally inversely associated with lower birthweight, younger maternal age, paternal occupational pesticide exposure, maternal prenatal smoking, and having more siblings. The direction of associations for older maternal age and for caesarean delivery differed substantially across regions. Exclusion of mothers < 21 years at birth of the index child had little effect on the results. CONCLUSION:This multi-country analysis supports the use of maternal education for adjustment as a proxy for SES, showing largely consistent associations with various behaviors and exposures. While the direction of associations was generally consistent, the strengths varied sometimes considerably by geographical region. These findings support the inclusion of maternal education as a covariate in analyses of childhood cancer risk when pooling CLIC studies.

Childhood cancers are rare, but incidence has risen modestly in countries with robust registration, partly reflecting improved diagnosis. In high-income countries, cancer is the leading cause of disease-related death in children. Marked inequities in incidence, survival, and research capacity underscore the need for large-scale collaboration to identify environmental, genetic, and contextual determinants of risk. The Childhood Cancer and Leukemia International Consortium (CLIC) was established in 2007 to study the etiology of childhood leukemia and later expanded in 2019 to include other childhood cancers, principally solid tumors. CLIC pools harmonized, individual-level data from case-control and cohort studies, obtained through interviews, record linkage (insurance claims, registries), or geographic information systems, and integrates germline genomic data where available. Membership has grown from 13 studies in 9 countries to 57 studies in 21 countries; recruitment spans the early 1960s to the present and encompasses approximately 150,000 cases across all tumor types and 300,000 controls with clinical, demographic, and exposure data, centralized via harmonized data dictionaries at the Data Coordination Center, established in 2014 at the International Agency for Research on Cancer, and supported by a secure analysis platform. Pooled analyses across diverse populations have implicated parental age, prenatal vitamin or folic acid use, mode of delivery, fetal growth, selected congenital anomalies, occupational or household exposures (e.g., pesticides), paternal smoking, and markers of early-life immune modulation (e.g., breastfeeding, daycare attendance) in leukemia risk, informing carcinogen evaluation and prevention. The integration of genetic ancestry and germline susceptibility data is clarifying ancestry-related differences in leukemia biology and outcomes, while confirming risk loci with population-specific effects. CLIC is now adding polygenic risk scores and exposomic data to refine etiologic subtyping and identify modifiable pathways, while broadening representation from underserved regions through partnership-building and capacity-strengthening.

Background:Ependymoma is a malignancy of the neuroepithelium-derived ependyma that lines the spinal cord and ventricles of the brain, occurring most frequently in young children and older adults. Genetic susceptibility to ependymoma has proven difficult to assess due to disease rarity. Methods:We performed genome-wide association studies (GWAS) of 478 ependymoma patients and 4,841 disease-free controls of European ancestry. Ependymoma patients consisted of 117 children (<18 years old) with whole-genome sequencing (WGS), 142 children with genotyping, and 219 adults (≥18 years old) with genotyping. Genotyped samples were imputed using the 1,000 Genomes Project as the reference panel and underwent quality control filtering. The GWAS was performed separately by age group and technology (genotyped or WGS). GWAS variants were considered significant at P < 5 × 10-8. Results:Among pediatric subjects with WGS data, we identified a significant intronic variant in EDIL3 (rs149378, P = 1.9 × 10-8) and a nearly significant intronic variant in LHX4 (rs79008224, P = 7.2 × 10-8). In pediatric subjects with genotyped data, two significant intronic variants were detected: FAM149A (rs6852180, P = 1.8 × 10-8) and CYS1 (rs61052588, P = 3.0 × 10-8). Additionally, an intergenic variant near C1orf94 (rs1404350, P = 1.2 × 10-14) was highly significant. In genotyped adult subjects, a single variant was observed in KCNQ3 (rs79089725, P = 2.0 × 10-8). Conclusion:Our analysis represents one of the most extensive ependymoma-specific GWAS conducted to date. Several significant intronic variants were harbored in genes associated with cancer and neurological disease. Future studies are needed to investigate the role of these age-specific alterations in ependymoma pathogenesis.

BACKGROUND:Maternal prenatal infections may affect fetal development, increasing the immunological vulnerability of offspring to childhood leukaemia (CL). The role of maternal infections in CL is unclear and might vary by subtype (lymphoblastic, ALL; myeloid, AML) or other characteristics. Understanding this potentially modifiable risk factor could inform prevention strategies. METHODS:Seventeen hospital- and population-based case-control studies of children born in 1972-2019 within the Childhood Cancer and Leukemia International Consortium with self-questionnaires or health-registry data on maternal infection were included (13 638 cases; 26 870 controls). Meta-analyses assessed CL and maternal infection (overall, viral, bacterial, respiratory, influenza/cold, urinary, genital) stratified by subtype, infection timing, race and ethnicity, and diagnosis age. RESULTS:The adjusted meta-analysis odds ratio (OR) for any maternal prenatal infection was 1.13 [95% confidence interval (CI) 0.91-1.40], with similar estimates for ALL and AML. Infection-specific estimates varied. ORs for first-trimester infections were highest for CL and ALL, but not AML, although all CIs contained one. We found modest risk differences between White and Hispanic/Latino children, most notably for CL diagnosed at <2 years (White children: OR 1.25, 95% CI 1.02-1.53; Hispanic/Latino children: OR 0.79, 95% CI 0.34-1.81, subgroup difference P = .05), with similar differences for viral and respiratory/influenza/cold infections. CONCLUSION:Although findings only modestly support an association between maternal prenatal infections and CL, some infections might increase the risk more markedly in young White children compared with Hispanic/Latino children. Risk patterns across race and ethnicity, type, and timing of maternal prenatal infection merit further investigation, as do studies with documented exposure information.

Often relying on mother's recollections of past events, the possible relationship between maternal illness in pregnancy and risk of malignancy in their offspring has long been a focus of research. Free from recall bias, this study of childhood cancer (0-14 years) examined these associations using data abstracted from mothers' primary-care (1623 cases, 2521 controls) and obstetric (2721 cases, 5169 controls) records. Maternal infections and other illnesses in pregnancy were examined for any possible associations with childhood leukaemia, lymphoma, CNS or embryonal tumours using pooled information from the two medical record sources (2885 cases and 5499 controls), accounting for potential confounders. Maternal anaemia was associated with childhood acute myeloid leukaemia (AML) (odds ratio, OR = 2.07, 95%CI [1.40-3.08]). Anaemia during pregnancy was also recorded more frequently in the notes of mothers of children with medulloblastoma, retinoblastoma and embryonal rhabdomyosarcoma: ORs 2.36 [1.36-4.11], 1.83 [1.01-3.33] and 2.91 [1.64-5.16] respectively. Other associations included urinary tract infections (UTIs) and non-Hodgkin lymphoma (NHL); preeclampsia and NHL; and polyhydramnios with both AML and NHL. No evidence was found to suggest that influenza during pregnancy impacted on childhood leukaemia risk. In conclusion, our findings are supportive of an association between maternal anaemia in pregnancy and childhood AML, and maternal anaemia and embryonal tumours; underscoring the need for further research exploring the potential causes and roles of iron and vitamin deficiencies. Due to small numbers and lack of corroborative evidence, the associations observed for UTIs, preeclampsia, and polyhydramnios must be treated cautiously.

Contexte La période périnatale suscite beaucoup d'intérêt concernant l’étiologie des cancers chez l'enfant, avec la plupart des études réalisées sur les leucémies de l'enfant. Ce travail visait à étudier les associations entre les facteurs liés à la grossesse et périnataux et les lymphomes pédiatriques. Méthodes Nous avons mené une analyse poolée de deux études cas-témoins nationales françaises en population générale. Les données sur les facteurs sociodémographiques, périnataux et liés au mode de vie ont été recueillies par entretiens standardisés avec les mères. Les rapports de cotes (OR) et les intervalles de confiance (IC) à 95 % ont été calculés à l'aide de modèles de régression logistique ajustés, séparément pour le lymphome non hodgkinien (LNH) et le lymphome de Hodgkin (LH). Des analyses spécifiques ont également porté sur le LNH de Burkitt et le LH scléro-nodulaire, deux types histologiques les plus fréquents chez l'enfant. Résultats Au total, 328 LH, 305 LNH et 2415 témoins ont été inclus. Aucune association n'a été observée avec les indicateurs de croissance fœtale, les malformations congénitales, les facteurs liés à la fertilité maternelle et aux antécédents reproductifs, ou le tabagisme maternel pendant la grossesse. La consommation de café pendant la grossesse était associée aux LNH (>2 tasses/jour, OR 1,5 (IC95% 1,1-2,1)), avec une relation dose-effet ; tandis que la consommation maternelle d'alcool était associée au LNH de Burkitt sans tendance (OR 1,5 (1,1-2,2)). L'allaitement maternel n’était pas significativement associé aux LH ni aux LNH, mais on observait toutefois une tendance linéaire inverse avec la durée d'allaitement pour les LNH (p=0,04). Conclusion Les consommations maternelles de café et d'alcool pendant la grossesse pourraient être associées au risque de LNH pédiatriques. Bien que nécessitant d’être répliqués, ces résultats pourraient avoir des implications importantes en termes de prévention.

Background: Childhood brain tumours (CBTs) are the leading cause of cancer death in children under the age of 20 years globally. Though the aetiology of CBT remains poorly understood, it is thought to be multifactorial. We aimed to synthesize potential risk factors for CBT to inform primary prevention.Methods: We conducted a systematic review and meta-analysis of epidemiological studies indexed in the PubMed, Web of Science, and Embase databases from the start of those resources through 27 July 2023. We included data from case-control or cohort studies that reported effect estimates for each risk factor around the time of conception, during pregnancy and/or during post-natal period. Random effects meta-analysis was used to estimate summary effect sizes (ES) and 95% confidence intervals (CIs). We also quantified heterogeneity (I-2) across studies.Findings: A total of 4040 studies were identified, of which 181 studies (85 case-control and 96 cohort studies) met our criteria for inclusion. Of all eligible studies, 50% (n = 91) were conducted in Europe, 32% (n = 57) in North America, 9% (n = 16) in Australia, 8% (n = 15) in Asia, 1% (n = 2) in South America, and none in Africa. We found associations for some modifiable risk factors including childhood domestic exposures to insecticides (ES 1.44, 95% CI 1.20-1.73) and herbicides (ES 2.38, 95% CI 1.31-4.33). Maternal domestic exposure to insecticides (ES 1.45, 95% CI 1.09-1.94), maternal consumption of cured meat (ES 1.51, 95% CI 1.05-2.17) and coffee >= 2 cups/day (ES 1.45, 95% 95% CI 1.07-1.95) during pregnancy, and maternal exposure to benzene (ES 2.22; 95% CI 1.01-4.88) before conception were associated with CBTs in case-control studies. Also, paternal occupational exposure to pesticides (ES 1.48, 95% CI 1.23-1.77) and benzene (ES 1.74, 95% CI 1.10-2.76) before conception and during pregnancy were associated in case-control studies and in combined analysis. On the other hand, assisted reproductive technology (ART) (ES 1.32, 95% CI 1.05-1.67), caesarean section (CS) (ES 1.12, 95% CI 1.01-1.25), paternal occupational exposure to paint before conception (ES 1.56, 95% CI 1.02-2.40) and maternal smoking > 10 cigarettes per day during pregnancy (ES 1.18, 95% CI 1.00-1.40) were associated with CBT in cohort studies. Maternal intake of vitamins and folic acid during pregnancy was inversely associated in cohort studies. Hormonal/infertility treatment, breastfeeding, child day-care attendance, maternal exposure to electric heated waterbed, tea and alcohol consumption during pregnancy were among those not associated with CBT in both case-control and cohort studies.Conclusion: Our results should be interpreted with caution, especially as most associations between risk factors and CBT were discordant between cohort and case-control studies. At present, it is premature for any CBT to define specific primary prevention guidelines.

BACKGROUND:Prenatal folate supplementation has been consistently associated with a reduced risk of childhood acute lymphoblastic leukemia (ALL). Previous germline genetic studies examining the one carbon (folate) metabolism pathway were limited in sample size, scope, and population diversity and led to inconclusive results. METHODS:We evaluated whether ∼2,900 single-nucleotide polymorphisms (SNP) within 46 candidate genes involved in the folate metabolism pathway influence the risk of childhood ALL, using genome-wide data from nine case-control studies in the Childhood Cancer and Leukemia International Consortium (n = 9,058 cases including 4,510 children of European ancestry, 3,018 Latinx, and 1,406 Asians, and 92,364 controls). Each study followed a standardized protocol for quality control and imputation of genome-wide data and summary statistics were meta-analyzed for all children combined and by major ancestry group using METAL software. RESULTS:None of the selected SNPs reached statistical significance, overall and for major ancestry groups (using adjusted Bonferroni P-value of 5 × 10-6 and less-stringent P-value of 3.5 × 10-5 accounting for the number of "independent" SNPs). None of the 10 top (nonsignificant) SNPs and corresponding genes overlapped across ancestry groups. CONCLUSIONS:This large meta-analysis of original data does not reveal associations between many common genetic variants in the folate metabolism pathway and childhood ALL in various ancestry groups. IMPACT:Genetic variants in the folate pathway alone do not appear to substantially influence childhood acute lymphoblastic leukemia risk. Other mechanisms such as gene-folate interaction, DNA methylation, or maternal genetic effects may explain the observed associations with self-reported prenatal folate intake.

CONTEXT:There is much interest in the perinatal period in relation to childhood cancer aetiology, with most studies focussing on childhood leukaemia. This work aimed to investigate the associations between pregnancy-related and perinatal factors and childhood lymphoma. METHODS:We conducted a pooled analysis of two French nationwide population-based case-control studies. Data on sociodemographic, perinatal and lifestyle factors were collected through maternal interviews. Odds ratios (OR) and 95% confidence intervals (CIs) were computed using adjusted logistic regression models, separately for non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). Specific analyses also investigated Burkitt NHL and nodular sclerosis HL, two most common histological types in children. RESULTS:We included 305 NHL, 328 HL and 2415 controls in this study. No associations were observed with gestational age, foetal growth indicators, folic acid supplementation, factors related to maternal fertility and reproductive history, or maternal smoking during pregnancy. Maternal coffee consumption during pregnancy was associated with NHL (>2 cups/day, OR = 1.5 [95% CI: 1.1-2.1]), with a dose-response relationship; while maternal alcohol consumption was associated with Burkitt NHL (OR = 1.5 [1.1-2.2]). Paternal smoking during preconception/pregnancy was associated with NHL (OR = 1.4 [1.1-1.8]). Breastfeeding (ever/never) was not significantly associated with NHL and HL, but an inverse log-linear trend was observed with the duration of breastfeeding for NHL (p = 0.04). CONCLUSION:Maternal coffee and alcohol consumptions during pregnancy and paternal smoking during preconception/pregnancy might increase the risk of childhood NHL. While warranting replication, these findings could help us better understand the aetiology of childhood lymphoma.

Abstract Background Studies examining the potential impact of mothers’ health during pregnancy on the health of their offspring often rely on self-reported information gathered several years later. To assess the validity of this approach, we analysed data from a national case–control study of childhood cancer (diagnosed <15 years) that collected health information from both interviews and medical records. Methods Mothers’ interview reports of infections and medications in pregnancy were compared with primary care records. Taking clinical diagnoses and prescriptions as the reference, sensitivity and specificity of maternal recall along with kappa coefficients of agreement were calculated. Differences in the odd ratios estimated using logistic regression for each information source were assessed using the proportional change in the odds ratio (OR). Results Mothers of 1624 cases and 2524 controls were interviewed ∼6 years (range 0–18 years) after their child’s birth. Most drugs and infections were underreported; in general practitioner records, antibiotic prescriptions were nearly three times higher and infections >40% higher. Decreasing with increasing time since pregnancy, sensitivity was ⩽40% for most infections and all drugs except ‘anti-epileptics and barbiturates’ (sensitivity 80% among controls). ORs associated with individual drug/disease categories that were based on self-reported data varied from 26% lower to 26% higher than those based on medical records; reporting differences between mothers of cases and controls were not systematically in the same direction. Conclusions The findings highlight the scale of under-reporting and poor validity of questionnaire-based studies conducted several years after pregnancy. Future research using prospectively collected data should be encouraged to minimize measurement errors.

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. 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 Breastfeeding was reported by 64.8

Purpose The United Kingdom Childhood Cancer Study’s (UKCCS’s) matched cohort was established to examine the longer term morbidity and mortality of individuals previously diagnosed with cancer before 15 years of age, comparing future healthcare patterns in 5-year cancer survivors to baseline activity seen in age- and sex-matched individuals from the general population.Participants Predicated on a national childhood cancer case-control study conducted in the early 1990s (4430 cases, 9753 controls) in England, Scotland and Wales, the case population comprises 3125 cancer survivors (>5 years), and the control population 7156 age- and sex-matched individuals from the general population who did not have cancer as a child. Participants are now being followed up via linkage to national administrative healthcare databases (deaths, cancers and secondary care hospital activity).Findings to date Enabling the creation of cohorts with minimal selection bias and loss to follow-up, the original case-control study registered all newly diagnosed cases of childhood cancer and their corresponding controls, regardless of their family’s participation. Early findings based on the registered case population found marked survival variations with age and sex across subtypes and differences with deprivation among acute lymphoblastic leukaemia (ALL) survivors. More recently, comparing the health-activity patterns of the case and control populations revealed that survivors of childhood ALL experienced excess outpatient and inpatient activity across their teenage/young adult years. Adding to increased risks of cancer and death and involving most clinical specialties, excesses were not related to routine follow-up monitoring and showed no signs of diminishing over time.Future plans With annual linkage updates, the UKCCS’s maturing population-based matched cohorts provide the foundation for tracking the health of individuals through their lifetime. Comparing the experience of childhood cancer survivors to that of unaffected general-population counterparts, this will include examining subsequent morbidity and mortality, secondary care hospital activity and the impact of deprivation on longer term outcomes.

Increasing evidence suggests that breastfeeding may protect from childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). However, most studies have limited their analyses to any breastfeeding, and only a few data have examined exclusive breastfeeding, or other exposures such as formula milk. We performed pooled analyses and individual participant data metaanalyses of data from 16 studies (N = 17 189 controls; N = 10 782 ALL and N = 1690 AML cases) from the Childhood Leukemia International Consortium (CLIC) to characterize the associations of breastfeeding duration with ALL and AML, as well as exclusive breastfeeding duration and age at introduction to formula with ALL. In unconditional multivariable logistic regression analyses of pooled data, we observed decreased odds of ALL among children breastfed 4 to 6 months (0.88, 95% CI 0.81‐0.96) or 7 to 12 months (OR 0.85, 0.79‐0.92). We observed a similar inverse association between breastfeeding ≥4 months and AML (0.82, 95% CI 0.71‐0.95). Odds of ALL were reduced among children exclusively breastfed 4 to 6 months (OR 0.73, 95% CI 0.63‐0.85) or 7 to 12 months (OR 0.70, 95% CI 0.53‐0.92). Random effects metaanalyses produced similar estimates, and findings were unchanged in sensitivity analyses adjusted for race/ethnicity or mode of delivery, restricted to children diagnosed ≥1 year of age or diagnosed with B‐ALL. Our pooled analyses indicate that longer breastfeeding is associated with decreased odds of ALL and AML. Few risk factors for ALL and AML have been described, therefore our findings highlight the need to promote breastfeeding for leukemia prevention.

Context A negative association between a history of allergy and childhood acute lymphoblastic leukemia (ALL) has been reported in previous studies, but remains debated. This work aimed to investigate this association accounting for genetic polymorphisms of the Th2 pathway cytokines (IL4, IL10, IL13, and IL4R). Methods Analyses were based on the French case-control study ESTELLE (2010-2011). The complete sample included 629 ALL cases and 1421 population-based controls frequency-matched on age and gender. The child's medical history was collected through standardized maternal interview. Biological samples were collected, and genotyping data were available for 411 cases and 704 controls of European origin. Odds ratios (OR) were estimated using unconditional regression models adjusted for potential confounders. Results In the complete sample, a significant inverse association was observed between ALL and reported history of allergic rhinitis or sinusitis (OR = 0.65 [0.42-0.98]; P = 0.04), but there was no obvious association with allergies overall. There was an interaction between genetic polymorphisms in IL4 and IL4R (P-interaction = 0.003), as well as a gene-environment interaction between IL4R-rs1801275 and a reported history of asthma (IOR = 0.23; P-int = 0.008) and eczema (IOR = 0.47; P-int = 0.06). We observed no interaction with the candidate polymorphisms in IL4 and IL13. Conclusion These results suggest that the association between allergic symptoms and childhood ALL could be modified by IL4R-rs1801275, and that this variant could also interact with a functional variant in IL4 gene. Although they warrant confirmation, these results could help understand the pathological mechanisms under the reported inverse association between allergy and childhood ALL.

Abstract Despite extensive research, a small proportion of the variants contributing to the genetic architecture of brain tumors have been reported. The published GWAS have been largely performed on pooled histological subtypes of glioma and most of these studies have been conducted primarily for adult tumors. Therefore, we aimed to perform the first GWAS specifically for ependymoma to identify the genetic variants associated with the risk of these tumors and to investigate the similarities/differences between the genetic architectures of adult and pediatric ependymomas. Germline SNP-array data of ependymoma cases were obtained from nine studies or biobanks across the United States and Europe. Controls were randomly selected with the ratio of 10:1 from three of those studies and a separate publicly available database. Additionally, germline whole genome sequencing data on cases and controls from St Jude Cloud were utilized. In total, 483 pediatric cases and 265 adult cases and 5592 controls were included. The same quality control procedures were applied to all studies. Data were imputed based on the Haplotype Reference Consortium using EAGLE. Meta-analyses were performed based on GMMAT and logistic regression. The results were adjusted for sex, ancestry and PCs. PAINTOR was used to identify the plausible causal variants, and eQTL and gene enrichment analyses were performed. We identified 16 independent significant SNPs which were specifically associated with pediatric ependymoma risk, of which 10 SNPs were plausible causal. The significant variants were located on 1q32.2 (KCNH1), 2p14 (MEIS1-AS3), 4p15.32 (LDB2), 6p21.32 (HLA-DQA), 6p21.33 (BX927178/CR759828), 7p21.3 (UMAD1), 11p12 (LRRC4C), 11q24.2 (KRT18P59), 14q24.3 (SPTLC2), and 21q11.2 (LOC112268283/FEM1AP1). The 18 identified independent significant SNPs associated with risk of adult ependymoma were located on 4p16.1 (SORCS2), 6p11.2, 6p21.31(KCTD20), 6p21.32 (HLA-DQA1), 7q31.32, 8p23.1 (LOC157273), 8q24.3 (PLEC), 10p13 (PTER), 11q23.3 (GRIK4), 19q13.11 (CEP89), and 22q11.1 (XKR3), of which 8 variants were plausible causal. One intronic variant associated with susceptibility of both pediatric and adult ependymomas was detected; rs68160486 (CCDC85A 2p16.1 PPediatric=3.41x10-8, PAdult=2.12x10-8). The genetic architectures of adult and pediatric ependymomas appear to largely differ from one another. We identified novel variants for these tumors that have not been previously reported for GWAS of combined glioma subtypes. This analysis highlights the need to conduct additional GWAS of more refined glioma subtypes, perhaps even utilizing newer data on molecularly defined subtypes that are emerging in updated pathological classification schemes. Citation Format: Maral Adel Fahmideh, Spiridon Tsavachidis, Stephen C. Mack, Xiao Xiangjun, Terri S. Armstrong, Mark R. Gilbert, NCI-Connect, iPSYCH Consortium, GICC, Lisa Mirabello, Smita Bhatia, Wendy M. Leisenring, Lindsay M. Morton, Gregory T. Armstrong, Jon Foss-Skiftesvik, Christian M. Hagen, Jonas Bybjerg-Grauholm, Manel Ghozal, Audrey Bonaventure, Jacqueline Clavel, Melissa L. Bondy, Christopher I. Amos, Michael E. Scheurer. Novel specific susceptibility loci identified for pediatric and adult ependymoma in first histology-specific genome-wide association study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1448.

Parental occupational exposures around conception (father) or during pregnancy (mother) have been hypothesized as potential predisposing factors for childhood leukaemia. We investigated parental exposure to several known occupational carcinogens and childhood leukaemia risk. We conducted a pooled analysis using case-control data from four European countries (3362 childhood leukemia cases and 6268 controls). Parental occupational exposures to polycyclic aromatic hydrocarbons (PAH), diesel engine exhaust (DEE), chromium, nickel, crystalline silica, and asbestos were assessed by a general population job-exposure matrix. We estimated odd ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression models for all childhood leukaemia combined, by leukaemia type (ALL and AML) and by ALL subtype (B-lineage and T-lineage). We found an association between high paternal occupational exposure to crystalline silica and childhood ALL (OR 2.20, CI 1.60–3.01) with increasing trend from no exposure to high exposure (P = <0.001), and also for AML (OR 2.03, CI 1.04–3.97; P for trend = 0.008). ORs were similar for B- and T-lineage ALL. For ALL, ORs were also slightly elevated with wide confidence intervals for high paternal occupational exposure to chromium (OR 1.23, CI 0.77–1.96), and DEE (OR 1.21, CI 0.82–1.77). No associations were observed for paternal exposures to nickel, PAH and asbestos. For maternal occupational exposure we found several slightly elevated odds ratios but mostly with very wide confidence intervals due to low numbers of exposed mothers. This is a first study suggesting an association between fathers’ occupational exposure to crystalline silica and an increased risk of childhood leukaemia in their offspring. As this association was driven by certain occupations (field crop farmers and miners) where other potentially relevant exposures like pesticides and radon may also occur, more research is needed to confirm our findings of an association with crystalline silica, and if so, mechanistic studies to understand the pathways.