Functional polymorphisms in FAS, FASL and CASP8 genes and risk of childhood acute lymphoblastic leukemia: a case–control study

Surrogate measures of infectious exposures have been consistently associated with lower childhood acute lymphoblastic leukemia (ALL) risk. However, recent reports have suggested that physician-diagnosed early-life infections increase ALL risk, thereby raising the possibility that stronger responses to infections might promote risk. We examined whether medically diagnosed infections were related to childhood ALL risk in an integrated health-care system in the United States. Cases of ALL (n=435) diagnosed between 1994-2014 among children aged 0-14 years, along with matched controls (n=2,170), were identified at Kaiser Permanente Northern California. Conditional logistic regression was used to estimate risk of ALL associated with history of infections during first year of life and across the lifetime (up to diagnosis). History of infection during first year of life was not associated with ALL risk (odds ratio (OR)=0.85, 95% confidence interval (CI): 0.60, 1.21). However, infections with at least 1 medication prescribed (i.e., more "severe" infections) were inversely associated with risk (OR=0.42, 95% CI: 0.20, 0.88). Similar associations were observed when the exposure window was expanded to include medication-prescribed infections throughout the subjects' lifetime (OR=0.52, 95% CI: 0.32, 0.85).

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.

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.

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.

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

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

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

Caesarean delivery and risk of childhood leukaemia: a pooled analysis from the Childhood Leukemia International Consortium (CLIC)

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.

ObjectiveTo ascertain whether there was an association between parental occupational exposure to pesticides and increased risk of acute lymphoblastic leukaemia (ALL) in the offspring.MethodA population-based case–control study of childhood ALL...

There is growing evidence supporting a role for infections in the aetiology of childhood leukaemia. Hypotheses proposed by both Greaves and Kinlen describe childhood leukaemia to be a rare response to one or more common infections acquired through personal contacts. Previous epidemiological studies have used day-care attendance as an indicator of the increased likelihood of early and frequent exposure to infections. It is well-documented that in developed countries, exposures to common infections occur more frequently in this type of setting. Within the Northern California Childhood Leukaemia Study, the role of social contact has been assessed and a unique 'child-hours' summary measure incorporating information on the number of months attending a day-care, mean hours per week at this day-care and the number of children in the day-care setting was constructed. In this review, the previously reported day-care results have been described, showing that in non-Hispanic White children, children in the highest category of total child-hours of exposure had a reduced risk of acute lymphoblastic leukaemia (ALL), particularly common B-cell precursor ALL (c-ALL), compared with children without such exposures, with evidence of a dose-response effect. In addition, a literature review of relevant studies has been conducted, examining the relationship between day-care attendance and risk of childhood ALL. Overall, the 14 studies identified provided consistent support for this hypothesis, with the majority of studies reporting some evidence of a reduced risk. A meta-analysis is currently underway, which will provide a quantitative evaluation of the overall consistency and strength of the association between day-care attendance or social contact and risk of childhood ALL.

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.

Implication of Genetic Variations of Ikzf1, ARIDB5, and CEBPE Genes In the Risk of Childhood Acute Lymphoblastic Leukemia In Korea