Refuelling of vehicles, the use of wood burners and the risk of acute lymphoblastic leukaemia in childhood

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.

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.

The relation between intrauterine growth and risk of childhood acute lymphoblastic leukemia was investigated in an Australian population-based case-control study that included 347 cases and 762 controls aged <15 years recruited from 2003 to 2006. Information on proportion of optimal birth weight, a measure of the appropriateness of fetal growth, was collected from mothers by questionnaire. Data were analyzed by using logistic regression. Risk of acute lymphoblastic leukemia was positively associated with proportion of optimal birth weight; the odds ratio for a 1-standard-deviation increase in proportion of optimal birth weight was 1.18 (95% confidence interval: 1.04, 1.35) after adjustment for the matching variables and potential confounders. This association was also present among children who did not have a high birth weight, suggesting that accelerated growth, rather than high birth weight per se, is associated with risk of acute lymphoblastic leukemia. Similar associations between proportion of optimal birth weight and acute lymphoblastic leukemia were observed for both sexes and across age groups and leukemia subtypes. Results of this study confirm earlier findings of a positive association between rapidity of fetal growth and subsequent risk of acute lymphoblastic leukemia in childhood, and they are consistent with a role for insulin-like growth factors in the causal pathway.

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

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).

The association between parental smoking and risk of childhood acute lymphoblastic leukemia (ALL) was investigated in an Australian population-based case-control study that included 388 cases and 868 controls aged <15 years, recruited from 2003 to 2006. Both of the child's parents provided information about their smoking habits for each year from age 15 years to the child's birth. Data were analyzed by logistic regression. Maternal smoking was not associated with risk of childhood ALL, but the odds ratio for paternal smoking of ≥15 cigarettes per day around the time of the child's conception was 1.35 (95% confidence interval: 0.98, 1.86). The associations between parental smoking risk of childhood ALL did not differ substantially by immunophenotypic or cytogenetic subtype. Meta-analyses of paternal smoking, including results from the Australian Study of Causes of Acute Lymphoblastic Leukemia in Children and those of previous studies, produced summary odds ratios of 1.15 (95% confidence interval: 1.06, 1.24) for any paternal smoking around the time of the child's conception and 1.44 (95% confidence interval: 1.24, 1.68) for smoking ≥20 cigarettes per day at that time. Study results suggest that heavier paternal smoking around the time of conception is a risk factor for childhood ALL. Men should be strongly encouraged to cease smoking, particularly when planning to start a family.

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.

Glutathione S-transferase T1 (GSTT1) genetic polymorphism has been considered as a risk factor for developing malignant diseases including acute lymphoblastic leukemia; however, the results from previous studies are inconsistent. We performed a meta-analysis of 16 published studies to investigate the association between GSTT1 null variant and risk of acute lymphoblastic leukemia in childhood. Between-study heterogeneity was assessed using the I (2) statistic method. Odds ratios (ORs) with corresponding 95 % confidence intervals (95 %CI) were pooled to assess the association. Those 16 studies were from 14 publications and included a total of 2,424 cases and 3,447 controls. Meta-analysis of a total of 16 studies showed that GSTT1 null variant was significantly associated with risk of childhood acute lymphoblastic leukemia (fixed-effect OR = 1.22, 95 %CI 1.07-1.39, P = 0.003, I (2) = 35 %). Subgroup analysis showed that GSTT1 null variant was significantly associated with risk of childhood acute lymphoblastic leukemia in Asians (fixed-effect OR = 1.47, 95 %CI 1.16-1.85, P = 0.001, I (2) = 0 %). However, there was no obvious association in both Caucasians (random-effect OR = 1.07, 95 %CI 0.83-1.38, P = 0.59, I (2) = 53 %) and Africans (random-effect OR = 0.99, 95 %CI 0.31-3.10, P = 0.98, I (2) = 72 %). Therefore, the GSTT1 null variant is significantly associated with susceptibility to childhood acute lymphoblastic leukemia in Asians.

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

A Task-Based Assessment of Parental Occupational Exposure to Organic Solvents and Other Compounds and Risk of Acute Lymphoblastic Leukemia in the OffspringAbstract Number:2249 Catherine Metayer*, Ghislaine Scélo, Alice Y. Kang, Robert B. Gunier, Kyndaron Reinier, C. Suzanne Lea, Jeffrey S. Chang, Steve Selvin, Janice Kirsch, Monique Does, Patricia Quinlan, and S. Katharine Hammond Catherine Metayer* University of California, Berkeley, United States, E-mail Address: [email protected] Search for more papers by this author , Ghislaine Scélo International Agency for Research on Cancer, France, E-mail Address: [email protected] Search for more papers by this author , Alice Y. Kang University of California, Berkeley, United States, E-mail Address: [email protected] Search for more papers by this author , Robert B. Gunier University of California, Berkeley, United States, E-mail Address: [email protected] Search for more papers by this author , Kyndaron Reinier Cedars-Sinai Medical Center, United States, E-mail Address: [email protected] Search for more papers by this author , C. Suzanne Lea East Carolina University, United States, E-mail Address: [email protected] Search for more papers by this author , Jeffrey S. Chang National Institute of Cancer Research, Taiwan, E-mail Address: [email protected] Search for more papers by this author , Steve Selvin University of California, Berkeley, United States, E-mail Address: [email protected] Search for more papers by this author , Janice Kirsch Medical oncologist and hematologist, United States, E-mail Address: [email protected] Search for more papers by this author , Monique Does University of California, Berkeley, United States, E-mail Address: [email protected] Search for more papers by this author , Patricia Quinlan University of California, San Francisco, United States, E-mail Address: [email protected] Search for more papers by this author , and S. Katharine Hammond University of California, Berkeley, United States, E-mail Address: [email protected] Search for more papers by this author AbstractBackground: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Studies examining paternal occupational exposures and risk of childhood ALL have mainly relied on job titles lacking specificity.Methods: We examined the relationship between the father’s workplace exposures before and after birth and risk of ALL in the offspring. Children with ALL (n=667) and controls (n=1,020) were enrolled in a population-based case-control study in California (2000-2008). We developed 19 task-based job modules (JMs) based on the prevalence of occupations in the study area and the probability of exposures to carcinogens. Expert assessment was then applied to estimate exposure to organic solvents and other compounds. Unconditional logistic regression models adjusted for socio-demographic factors were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).Results: Of 1,634 fathers, 903 were assigned a JM and 643 (71%) completed the interview (55% Hispanic origin). Occupations were stable over time. Among children with non-Hispanic fathers, no associations were observed with any exposures evaluated. In contrast in children with Hispanic fathers, the OR for exposure to organic solvents was 1.48 (95% CI: 1.01-2.16). In multivariable analyses, the OR for chlorinated hydrocarbons was 2.28 (95% CI: 0.97- 5.37; n=31 exposed cases vs. 17 controls) and close to one for aromatic hydrocarbons, glycol ethers, and other hydrocarbon mixtures. Moderate elevated risks were seen with exposure to combustion exhausts, metals, paints, structural pesticides (data on agricultural pesticides are presented separately), and wood dust, although not statistically significant in univariate or multivariable models.Conclusion: Our data support associations between paternal occupational exposures to known carcinogens contained in organic solvents for children of Hispanic origins, specifically chlorinated hydrocarbons. Explanations for ethnic differences are under investigation.

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.

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.

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...

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.

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.