History of Early Childhood Infections and Acute Lymphoblastic Leukemia Risk Among Children in a US Integrated Health-Care System.

Objective:Tobacco smoke contains carcinogens known to damage somatic and germ cells. In this study, we investigated the effect of tobacco smoking on the risk of childhood acute lymphoblastic leukemia (ALL) and myeloid leukemia (AML).Methods:Information about tobacco smoking exposures of the mother before, during, and after pregnancy was collected via PubMed, Embase, and Web of Science databases through November 5, 2018. We performed to evaluate the association between smoking exposure and the risk of childhood ALL and AML. Study selection, data abstraction, and quality assessment were performed by 2 independent reviewers. Random effects models were used to obtain summary odds ratios (ORs) and 95% confidence intervals (CIs).Results:Nineteen case–control studies of childhood leukemia (age < 15 years) conducted in 9 countries from 1974 to 2018. Maternal smoking exposures did not a significant association with childhood ALL (OR = 1.004, 95% CI 0.953–1.058, P = .881) and AML (OR = 0.92, 95% CI 0.815–1.038, P = .177) during exposure time windows. However, there was an association with paternal smoking and ALL (OR = 1.15, 95% CI 1.038–1.275, P = .007). Paternal smoking in AML showed there was no association with smoking exposures and childhood AML (OR = 1.133, 95% CI 0.943–1.362, P = .181). Next, maternal daily cigarettes consumption showed no associations with ALL (OR = 1.08, 95% CI 1.000–1.168, P = .051) during pregnancy. No association with maternal daily smoking and AML (OR = 0.909, 95% CI 0.682–1.211, P = .514). Paternal daily cigarettes consumption was associated with increased risks of childhood ALL (OR = 1.200, 95% CI 1.112–1.302, P = .000). The higher consumption of paternal smoking (more than 10 per day) was significantly related to childhood ALL. Paternal daily smoking consumption also was related to AML (OR = 1.242, 95% CI 1.031–1.496, P = .022).Conclusion:Maternal smoking before, during, or after pregnancy was not associated with childhood ALL or AML. However, paternal smoking was related to a significantly elevated risk of childhood ALL during pregnancy, but not for AML. Maternal daily smoking consumption was not associated with ALL or AML during pregnancy. The higher consumption of paternal smoking were, the higher the risk of childhood ALL or AML.

BackgroundRecently, there have been a number of studies on the association between XRCC1 polymorphisms and childhood acute lymphoblastic leukemia (ALL) risk. However, the results of previous reports are inconsistent. Thus, we performed a meta-analysis to clarify the effects of XRCC1 variants on childhood ALL risk.MethodsA meta-analysis was performed to examine the association between XRCC1 polymorphisms (Arg399Gln, Arg194Trp, and Arg280His) and childhood ALL risk. We critically reviewed 7 studies with a total of 880 cases and 1311 controls for Arg399Gln polymorphism, 3 studies with a total of 345 cases and 554 controls for Arg280His polymorphism, and 6 studies with a total of 783 cases and 1180 controls for Arg194Trp polymorphism, respectively. Odds ratio (OR) and its 95% confidence interval (CI) were used.ResultsSignificant association between XRCC1 Arg399Gln polymorphism and childhood ALL risk was observed in total population analyses (ORadditive model = 1.501, 95% CI 1.112–2.026, POR = 0.008; ORdominant model = 1.316, 95% CI = 1.104–1.569, POR = 0.002) and Asian subgroup analyses (ORadditive model = 2.338, 95%CI = 1.254–4.359, POR = 0.008; ORdominant model = 2.108, 95%CI = 1.498–2.967, POR = 0.000). No association was detected in Caucasians, Metizo and mixed populations. Ethnicity was considered as a significant source of heterogeneity in the meta-regression model. For the other two XRCC1 polymorphisms, no association with childhood ALL risk was found.ConclusionsThe meta-analysis results suggested that XRCC1 Arg399Gln polymorphism might be associated with elevated childhood ALL risk among Asian population.

Childhood acute lymphoblastic leukaemia (ALL) is suggested to result from a dysregulated immune response to infections in children with a preleukaemic state. Childcare in early life supposedly may protect against childhood ALL by facilitating sufficient exposure to infections to stimulate and ensure normal maturation of the immune system. We assessed the association between childcare attendance before age 2 years and risk of childhood ALL in a register-based cohort study, including all children aged 2 to 14 years born in Denmark during 1991 to 2014 with available childcare information recorded in the Danish Childcare Database (n=1 116 185). Cox regression was used to estimate hazard ratios (HRs) comparing children enrolled in childcare and children not enrolled before age 2 years. Further, we assessed the association according to age at enrolment, type of childcare facility and specific ALL subtypes. During 10 460 811 person-years of follow-up, 460 children developed ALL at ages 2 to 14 years. Of these, 57 (12.4%) never attended childcare before age 2 years compared with 10.6% in the total cohort. Compared with homecare, childcare attendance before age 2 years was associated with a statistically non-significantly, marginally decreased risk of childhood ALL with adjusted HR=0.87 (95% confidence interval [CI]: 0.65-1.16). Risk estimates did neither vary statistically significantly by age at enrolment nor by type of childcare facility and also not between childhood ALL subtypes, including frequently prenatally initiated ALL subtypes. Results from this large, nationwide register-based study provided no evidence that childcare attendance in the first years of life protects against childhood ALL.

Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms have been implicated in childhood acute lymphoblastic leukemia (ALL) risk, but previously published studies were inconsistent and recent meta-analyses were not adequate. In a meta-analysis of 21 publications with 4,706 cases and 7,414 controls, we used more stringent inclusion method and summarized data on associations between MTHFR C677T and A1298C polymorphisms and childhood ALL risk. We found an overall association between 677T variant genotypes and reduced childhood ALL risk. Specifically, in the dominant genetic model, an association was found in a fixed-effect (TT + CT vs. CC: OR = 0.92; 95% CI = 0.85-0.99) but not random-effect model, whereas such an association was observed in both homozygote genetic model (TT vs. CC: OR = 0.80; 95% CI = 0.70-0.93 by fixed effects and OR = 0.78; 95% CI = 0.65-0.93 by random effects) and recessive genetic model (TT vs. CC + CT: OR = 0.83; 95% CI = 0.72-0.95 by fixed effects and OR = 0.84; 95% CI = 0.73-0.97 by random effects). These associations were also observed in subgroups by ethnicity: for Asians in all models except for the dominant genetic model by random effect and for Caucasians in all models except for the recessive genetic model. However, the A1298C polymorphism did not appear to have an effect on childhood ALL risk. These results suggest that the MTHFR C677T, but not A1298C, polymorphism is a potential biomarker for childhood ALL risk.

Genetic polymorphisms in the promoter regions of FAS, FASL and CASP8 involved in the apoptotic signaling pathway are thought to be associated with susceptibility to cancer. We hypothesized that these functional genetic variants might be associated with the risk of childhood acute lymphoblastic leukemia (ALL). A case–control study in a Chinese population with 361 cases of ALL and 519 controls was performed to evaluate the association between FAS, FASL and CASP8 variants and risk of childhood ALL. Individuals with FAS − 1377AG had an odds ratio (OR) of 0.72 for the risk of ALL compared to − 1377GG and the variant FASL − 844CC was associated with a statistically significantly decreased risk of childhood ALL (OR = 0.38). Furthermore, combined genotypes with 5–8 protective alleles were associated with a significantly decreased risk of childhood ALL compared with those with 0–4 variants, and this decreased risk was more pronounced among the subgroups of age < 6 years, female, parental never-drinking status and never house-painting. Our results provide evidence that FAS–FASL–CASP8 polymorphisms contributed to a reduced risk of childhood ALL in our population. Larger studies are warranted to validate our findings.

The association between CCAAT/enhancer binding protein-ε (CEBPE) rs2239633 polymorphism and acute lymphoblastic leukemia (ALL) risk has been reported, but results of previous studies remain controversial and ambiguous. To assess the association between CEBPE rs2239633 polymorphism and childhood ALL risk, a meta-analysis was performed. Based on comprehensive searches of the PubMed, Embase, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biomedical Literature Database (CBM), we identified outcome data from all articles estimating the association between CEBPE rs2239633 polymorphism and childhood ALL risk. The pooled odds ratio (OR) with 95% confidence intervals (CIs) were calculated. A significant association between CEBPE rs2239633 polymorphism with childhood ALL was found (OR = 1.19, 95% CI 1.11-1.28, P < 0.01). Subgroup analysis stratified by ethnicity also suggested a significant association between this polymorphism and childhood ALL in the Caucasian subgroup (OR = 1.19, 95% CI 1.09-1.30, P < 0.01) and Hispanic subgroup (OR = 1.39, 95% CI 1.18-1.63, P < 0.01). No significant association was observed in the Asian subgroup (OR = 1.05, 95% CI 0.90-1.22, P = 0.53). The CEBPE rs2239633 polymorphism increased B cell ALL risk (OR = 1.29, 95% CI 1.15-1.44, P < 0.01) and B hyperdiploid ALL risk (OR = 1.84, 95% CI 1.40-2.43, P < 0.01). This meta-analysis demonstrated that the CEBPE rs2239633 polymorphism was significantly associated with childhood ALL risk.

Association of three polymorphisms in ARID5B, IKZF1and CEBPE with the risk of childhood acute lymphoblastic leukemia in a Chinese population

Polycyclic aromatic hydrocarbons in residential dust and risk of childhood acute lymphoblastic leukemia

The mammalian target of rapamycin (mTOR) is an important protein kinase regulating cell survival and apoptosis. To determine whether genetic variations in mTOR are associated with risk of acute lymphoblastic leukemia (ALL) in Chinese children, we genotyped two tag single nucleotide poymorphisms (SNPs) in mTOR (rs2536 and rs2295080) in a case–control study. We observed that the variant genotype TC of mTOR rs2536 was associated with a significantly decreased risk of childhood ALL (adjusted odds ratio [OR] = 0.67, 95% confidence interval [CI] = 0.46–0.96), and the association was more pronounced in high-risk ALL and T-phenotype ALL groups. Additionally, we found that the combined genotypes TC/CC decreased the risk of ALL only in the high-risk ALL group (adjusted OR = 0.54, 95% CI = 0.32–0.91) and T-phenotype ALL group (adjusted OR = 0.29, 95% CI = 0.10–0.84). These results suggest that the mTOR rs2536 polymorphism is involved in the susceptibility to childhood ALL in a Chinese population.

Genetic Polymorphisms in the Folate Pathway and Risk of Childhood Acute Lymphoblastic Leukemia (ALL): MTHFR, MTHFD1, RFC1 and TS.

Many epidemiological studies have assessed the association between maternal antibiotic exposure during pregnancy and childhood acute lymphoblastic leukemia (ALL), while reaching inconsistent conclusions. In order to clarify the association, the publications in English that provided information about maternal antibiotic exposure during pregnancy and ALL risk in offspring in the PubMed, Embase, and Web of Science databases were systematically reviewed and we performed a meta-analysis using the random-effect models. Results of pooled analysis showed that maternal antibiotic intake during pregnancy is not associated with childhood ALL risk (pooled odds ratio 1.07, 95% confidence interval 0.98-1.18) without significant heterogeneity (I2 = 13.7%, P = 0.310). This finding was consistent across subgroups stratified by type of study design, measurement method, sample size, study quality, and pregnancy stage. Our findings suggest that maternal antibiotic consumption during pregnancy was not associated with ALL risk in progeny. Further investigations are needed to confirm the results and assess any risk differences of ALL by types of antibiotics.Conclusions: Our findings suggest that maternal antibiotics consumption during pregnancy was not associated with ALL risk in progeny. Further investigations are needed to confirm the results and assess any risk differences of ALL by types of antibiotics. What is Known: • It is not unusual for pregnant woman to receive antibiotics for local or systematic use during pregnancy. • The conclusions regarding the associations between maternal antibiotics use during pregnancy and childhood ALL risk were inconsistent. What is New: • Maternal antibiotics consumption during pregnancy was not associated with the increased ALL risk in offspring. • Further laboratory evidences are needed to confirm the results.

The Australian Study of Causes of Acute Lymphoblastic Leukemia in Children (Aus-ALL) was designed to test the hypothesis, raised by a previous Western Australian study, that maternal folic acid supplementation during pregnancy might reduce the risk of childhood acute lymphoblastic leukemia (ALL). Aus-ALL was a national, population-based, multicenter case-control study that prospectively recruited 416 cases and 1,361 controls between 2003 and 2007. Detailed information was collected about maternal use of folic acid and other vitamin supplements before and during the index pregnancy. Data were analyzed using logistic regression, adjusting for matching factors and potential confounders. A meta-analysis with the results of previous studies of folic acid supplementation was also conducted. We found weak evidence of a protective effect of maternal folate supplementation before pregnancy against risk of childhood ALL, but no evidence for a protective effect of its use during pregnancy. A meta-analysis including this and 2 other studies, but not the study that raised the hypothesis, also found little evidence that folate supplementation during pregnancy protects against ALL: the summary odds ratios (ORs) for folate supplementation were 1.06 [95% confidence interval (CI): 0.77-1.48] with reference to no folate supplementation and 1.02 (95% CI: 0.86-1.20) with reference to no vitamin supplementation. For vitamin supplementation in general, the summary OR from a meta-analysis of 5 studies-including Aus-ALL-was 0.83 (95% CI: 0.73-0.94). Vitamin supplementation in pregnancy may protect against childhood ALL, but this effect is unlikely to be large or, if real, specifically due to folate.

Microsomal epoxide hydrolase, EPHX1, plays a central role in the detoxification of potentially genotoxic epoxide intermediates. In this study, we firstly aimed to investigate the relationship between EPHX1 Tyr113His and His139Arg variants, and the risk of incidence of childhood acute lymphoblastic leukemia (ALL) in Turkish population, comprised of 190 healthy controls and 167 ALL patients. In exon 3 Tyr113His polymorphism, 113His/His homozygous mutant genotype with slow activity was 18.6% in ALL patients and 9% in controls, indicating 113His/His slow activity genotype was significantly associated with an increased risk of childhood ALL (OR: 2.3, 95% CI, 1.2-4.4, P = 0.01). No significant association was found between exon 4 His139Arg variant and the risk of ALL. When both exon 3 Tyr113His and exon 4 His139Arg polymorphisms were considered together, only the exon 3 113His/His, homozygous mutant, slow activity genotype with exon 4 wild-type genotype 139His/His was significantly increased the risk of ALL 2.4-fold (OR: 2.4, P = 0.02). We also evaluated whether haplotype analysis for EPHX1 Tyr113His polymorphism together with DNA protein XRCC1 Arg399Gln variant known for its deficient DNA repair capacity would represent more prominent risk factors for the development of childhood ALL. Accordingly, the co-presence of Tyr113His variant of EPHX1 and Arg399Gln variant of XRCC1 in the same individuals significantly increased the risk of childhood ALL up to 2.1-fold (OR = 2.1, P = 0.03). Moreover, homozygous mutant genotype for both genes significantly and considerably increased the risk of childhood ALL 8.5-fold (OR: 8.5, P = 0.03). In conclusion, individuals with EPHX1 113His/His slow activity genotype may not detoxify reactive carcinogenic epoxides efficiently, binding of reactive epoxides to DNA cause DNA damage. With the inadequate polymorphic DNA repair protein, XRCC1, this situation ultimately leads to significantly increased susceptibility for childhood ALL.

Introduction: Recent meta-analyses have reported modest but significant associations between birth by cesarean delivery (CD) and subsequent risk of immune-related disorders. An association of CD with childhood leukemia has not been established, although two recent case-control studies showed an increased risk of acute lymphoblastic leukemia (ALL) among young children born by CD, and elective CD (E-CD) in particular. Methods: We pooled data from 12 case-control studies in the Childhood Leukemia International Consortium. We analyzed CD overall and according to indications that likely resulted in E-CD (multiple birth and previous CD). Odds ratios (OR) and 95% confidence intervals (CIs) for risk of ALL and acute myeloid leukemia (AML) were estimated using multivariable logistic regression, adjusting for child's birth weight, sex, age, ethnicity, parental education, maternal age, and study center. Results: Delivery method was known for 8017 ALL cases, 659 AML cases, and 21273 controls. Among three studies with information on indication for CD, data were available for 3677 ALL cases, 114 AML cases, and 3929 controls. The association between CD and ALL (pooled OR: 1.06 [95% CI: 0.99, 1.14]) was not statistically significant, whereas birth by E-CD was associated with an increased risk of ALL (pooled OR: 1.27 [95% CI: 1.06, 1.52]). Subgroup analysis by immunophenotype revealed an association between E-CD and B-ALL (pooled OR: 1.28 [95% CI: 1.04, 1.57]), but not T-ALL. Pooled ORs for AML were 1.02 (95% CI: 0.82, 1.27) for overall CD and 1.39 (95% CI: 0.76, 2.53) for E-CD. Conclusions: Findings derived from a pooled analysis of data from several countries suggest a higher risk of childhood ALL following E-CD. More comprehensive assessment of the indications for E-CD in consortia studies will allow investigators to further explore the potential for confounding by indication. If this association is causal, maladaptive immune activation due to lack of stress response before birth and differential colonization of the microbiome in children born by E-CD should be considered as potential mechanisms. Risk of childhood leukemia associated with cesarean delivery overall and elective cesarean deliveryCesarean delivery (all indications)Pre-labor elective cesarean deliveryNumber of studiesExposed controlsExposed casesOR (95% CI)Number of studiesExposed controlsExposed casesOR (95% CI)Overall12340419241.06 (0.99, 1.14)32513081.27 (1.06, 1.52)ALL12340417491.06 (0.99, 1.14)32512901.27 (1.06, 1.52)AML824781221.02 (0.82, 1.27)1126161.39 (0.76, 2.53)ImmunophenotypeB-cell9313212201.07 (0.99, 1.16)22241961.28 (1.04, 1.57)T-cell931321300.95 (0.77, 1.18)2224241.18 (0.75, 1.88)Age012251561.08 (0.73, 1.60)36102.89 (0.93, 8.89)1-512221212261.05 (0.96, 1.15)31711921.22 (0.98, 1.53)6-10126693481.09 (0.93, 1.28)350591.34 (0.90, 2.01)11-14112721190.97 (0.74, 1.26)324291.25 (0.70, 2.24)Year of birth1970-1979464551.06 (0.70, 1.60)29111.13 (0.46, 2.80)1980-198997235351.01 (0.88, 1.15)31021221.30 (0.99, 1.72)1990-19991215296671.06 (0.95, 1.19)362741.32 (0.92, 1.90)2000-2009810524741.14 (0.98, 1.33)173781.14 (0.78, 1.65)2010-2013336181.93 (0.57, 6.51)1551.81 (0.16, 20.4)Gestational ageEarly preterm11126451.19 (0.67, 2.11)3650.58 (0.10, 3.24)Late preterm112581281.13 (0.84, 1.52)313151.56 (0.61, 3.98)Early term116943481.11 (0.93, 1.32)364851.27 (0.87, 1.86)Full term1113196331.01 (0.90, 1.14)31001311.31 (0.99, 1.72)Late term105482571.02 (0.86, 1.22)3760.95 (0.31, 2.90) Citation Format: Erin Marcotte, Thomas Thomopoulos, Jacqueline Clavel, John Dockerty, Sameera Ezzat, Stephen S. Francis, Claire Infante-Rivard, Corrado Magnani, Catherine Metayer, Ana Maria Mora, Beth A. Mueller, Wafaa M. Rashed, Michael E. Scheurer, Joachim Schuz, Catharina Wesseling, Alkistis Skalkidou, Eleni Petridou, Logan Spector. Cesarean delivery and risk of childhood leukemia: findings from the Childhood Leukemia International Consortium (CLIC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-194. doi:10.1158/1538-7445.AM2015-LB-194

It is plausible that exposure of the parents before birth or of the child to sources of benzene increases the risk of childhood acute lymphoblastic leukaemia (ALL). The aim of this analysis was to investigate whether refuelling a vehicle with petrol before birth or burning wood to heat the home before or after the child's birth increased the risk of childhood ALL. Data from 389 cases and 876 frequency-matched controls were analysed using unconditional logistic regression, adjusting for study matching factors and potential confounders. The odds ratio (OR) for the mother ever refuelling a vehicle with petrol for non-occupational purposes before or during the pregnancy was 0.97 [95% confidence interval (CI) 0.69, 1.38]. The OR for the father for this exposure in the year before conception was 0.88 [95% CI 0.52, 1.48]. The OR for use of a closed wood burner to heat the home in the year before or during pregnancy was 1.41 [95% CI 1.02, 1.94] and 1.25 [95% CI 0.92, 1.70] after birth. We found no evidence that non-occupational refuelling a vehicle with petrol in the year before or during pregnancy increased the risk of ALL in the offspring. There was weak evidence that burning wood in a closed burner to heat the home increased the risk, but there was no dose-response relationship and chance could explain the finding.