Childhood acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy among children, yet its molecular etiology remains largely unclear. Matrix metalloproteinase-12 (MMP-12), although less studied than other MMPs, has emerged as a potential player in tumor progression. This study aimed to explore the association of two MMP-12 polymorphisms (rs2276109 and rs652438) with childhood ALL risk and prognosis in a Taiwanese pediatric population. A total of 266 childhood patients with ALL and 266 age- and sex-matched cancer-free controls were genotyped for MMP-12 rs2276109 and rs652438. Genotypic and allelic distributions were compared, and associations with clinical features were assessed. Neither rs2276109 nor rs652438 was significantly associated with childhood ALL susceptibility. For rs2276109, individuals with AG [odds ratio (OR)=0.84, 95% confidence interval (CI)=0.47-1.50, p=0.6557] or GG genotypes (OR=0.98, 95%CI=0.06-15.82, p=1.0000) had no increased risk compared to AA. Similarly, no significant association was found under dominant or recessive models (dominant: OR=0.84, 95%CI=0.47-1.50, p=0.6614; recessive: OR=1.00, 95%CI=0.06-16.07, p=1.0000). For rs652438, the variant G allele showed no significant risk (OR=1.12, 95%CI=0.76-1.64, p=0.6254). However, rs652438 AG+GG genotypes were significantly correlated with aggressive risk classification (OR=2.17, 95%CI=1.30-3.61, p=0.0040) and shorter survival (<5 years; OR=2.52, 95%CI=1.31-4.84, p=0.0073). While MMP-12 rs2276109 and rs652438 polymorphisms do not appear to affect susceptibility to childhood ALL, rs652438 variant genotypes may serve as prognostic biomarkers for disease severity and outcome. Further functional validation and multicenter studies are warranted to confirm these findings and assess their clinical utility in childhood ALL risk stratification.

Cesarean section (CS) rates have been increasing beyond medically warranted thresholds, despite potential long‐term adverse outcomes. Previous research on CS delivery and childhood leukemia is conflicting but suggests an increased acute lymphoblastic leukemia (ALL) risk in children delivered by planned CS. It has been suggested that maternal and pregnancy conditions predisposing to pregnancy complications might confound such an association; therefore, we aimed to elucidate the relationship between delivery mode and ALL in Swedish children. To this end, we studied all children born in Sweden between 1982–1989 and 1999–2014, when comprehensive information on delivery mode was available (n = 2,442,330). Pregnancy conditions, delivery mode, and childhood ALL diagnoses (<20 years) were retrieved from nationwide registers. Cox proportional hazards regression was used to assess the association between delivery mode and childhood ALL, adjusting for maternal and pregnancy conditions. We observed an increased ALL risk among children delivered by planned CS (HR = 1.21, 95% CI 0.96–1.54), driven by B‐cell precursor ALL (HR = 1.29, 95% CI 1.01–1.67). The associations were concentrated among boys and at peak ages of ALL incidence (≤5 years) and persisted after accounting for potential confounders, including maternal and perinatal factors. Unplanned CS was not associated with increased risk of childhood ALL. Our nationwide study supports an association between planned CS and an increased B‐cell precursor ALL risk in Swedish children, irrespective of maternal and pregnancy conditions. Possible underlying mechanisms, such as lack of exposure to maternal vaginal microbiota or decreased stress hormones at birth, require further exploration.

Per‐ and polyfluoroalkyl substances (PFAS) are ubiquitous. Young children are commonly exposed to these chemicals via ingestion of settled dust. Several PFAS have been associated with cancers in adults, yet little is known about the risk in children. We investigated whether PFAS concentrations in residential dust were associated with childhood acute lymphoblastic leukemia (ALL). Vacuum bags were collected in homes of 178 children diagnosed with ALL and 204 healthy controls (age 0–7 years) residing in California (2001–2007). Dust samples were sieved and analyzed for 19 PFAS using targeted liquid chromatography mass spectrometry analysis. The effects of individual PFAS and PFAS mixtures were estimated for eight PFAS with at least 50% above the limit of quantification (LOQ) using logistic regression, G‐computation, and generalized additive modeling (GAM). In the model mutually adjusting for eight PFAS, a statistically significant association was seen only for N‐ethyl perfluorooctane sulfonamido acetic acid (EtFOSAA) (ORcontinuous = 1.40, 95% CI = 1.05–1.86 and OR4thvs.1stquartile=2.58, 95% CI = 1.16–5.71). Using G‐computation, the eight PFAS mixture was positively associated with childhood ALL (OR = 1.60, 95% CI = 1.15–2.24), with positive weights for EtFOSAA, perfluoro‐n‐hexanoic acid (PFHxA), perfluoro‐1‐decanesulfonate (PFDS), and perfluoro‐1‐octanesulfonate (PFOS), and negative weights for perfluoro‐1‐hexanesulfonate (PFHxS) and bis(1H,1H,2H,2H‐perfluorooctyl)phosphate (6:2 diPAP). Using GAM, the OR for the mixture reached a maximum of 2.24, at the highest value of log10 EtFOSAA and lowest value of log10 PFHxS. Exposure to a mixture of PFAS in settled dust was associated with an overall elevated risk of childhood ALL, with EtFOSAA and PFHxS being the main contributors to the positive and negative weights, respectively.

The disruption of cell-cycle control can lead to an imbalance in cell proliferation, often accompanied by genomic instability, which in turn can facilitate carcinogenesis. This study aimed to examine the impact of CDKN1A rs1801270 and rs1059234 polymorphisms on the risk of childhood acute lymphocytic leukemia (ALL) in Taiwan. The genotypes of CDKN1A rs1801270 and rs1059234 in 266 childhood ALL cases and 266 controls were determined using PCR-RFLP techniques. The genotypic and allelic frequencies for CDKN1A rs1801270 and rs1059234 did not significantly differ between childhood ALL cases and controls (all p>0.05). However, stratified analysis revealed that the CDKN1A rs1801270 AA variant was associated with a reduced risk of childhood ALL in males (OR=0.40, 95%CI=0.20-0.82, p=0.0178). Additionally, the AC and AA genotypes of rs1801270 were linked to a lower risk classification for childhood ALL and longer survival times (OR=0.57 and 0.31, 95%CI=0.33-0.97 and 0.18-0.56, p=0.0538 and 0.0001, respectively). No significant associations were found for rs1059234 in the stratified analyses (p>0.05 for all). Although CDKN rs1801270 and rs1059234 genotypes were not associated with an overall risk of childhood ALL, CDKN1A rs1801270 polymorphism may serve as a protective predictor in males and as a potential marker for better prognosis of childhood ALL. Validation in larger and more diverse populations is necessary to confirm the feasibility of this predictor.

Acute lymphoblastic leukemia (ALL) is the most common type of cancer among children. Tobacco exposure during gestation has been investigated as a potential risk factor, but its role remains undefined. Given tobacco's toxicologic profile as a DNA-damaging agent, we examined the impact of DNA repair gene variability as a source of vulnerability to tobacco exposure risk for ALL. Leveraging demographic and genotype data from two large California-based ALL epidemiology studies, we used logistic regression, MinimumP (minP) statistical method, and permutation tests to examine interactions between DNA repair genes and prenatal tobacco exposure. We found statistically significant interactions between prenatal tobacco exposure and DNA repair genes RECQL (minP = 1.00 × 10-4, FDR-P value = 1.86 × 10-2) and TDG (minP = 1.00 × 10-4, FDR-P value = 1.86 × 10-2) with regard to childhood ALL risk. Notable interactions in the homologous recombination pathway were observed among Latino children, whereas non-Latino White children displayed significant interactions in the base excision repair and nucleotide excision repair pathways. Our study highlights the significance of DNA repair genes and pathways when evaluating environmental exposure to tobacco smoke, suggesting that genetic variability within these pathways could impact vulnerability in the development of childhood ALL. This study highlights the significant impact of genetic variation interacting with prenatal tobacco exposure on ALL risk. Further research is needed to understand these interactions and their implications for ALL etiology. Expanding studies to other gene-environment interactions will aid in developing targeted prevention, diagnosis, and treatment strategies for pediatric oncology.

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

Breastfeeding has been suggested to protect against childhood cancers, particularly acute lymphoblastic leukemia (ALL). However, the evidence stems from case-control studies alone. To investigate whether longer duration of exclusive breastfeeding is associated with decreased risk of childhood ALL and other childhood cancers. This population-based cohort study used administrative data on exclusive breastfeeding duration from the Danish National Child Health Register. All children born in Denmark between January 2005 and December 2018 with available information on duration of exclusive breastfeeding were included. Children were followed up from age 1 year until childhood cancer diagnosis, loss to follow-up or emigration, death, age 15 years, or December 31, 2020. Data were analyzed from March to October 2023. Duration of exclusive breastfeeding in infancy. Associations between duration of exclusive breastfeeding and risk of childhood cancer overall and by subtypes were estimated as adjusted hazard ratios (AHRs) with 95% CIs using stratified Cox proportional hazards regression models. A total of 309 473 children were included (51.3% boys). During 1 679 635 person-years of follow-up, 332 children (0.1%) were diagnosed with cancer at ages 1 to 14 years (mean [SD] age at diagnosis, 4.24 [2.67] years; 194 boys [58.4%]). Of these, 124 (37.3%) were diagnosed with hematologic cancers (81 [65.3%] were ALL, 74 [91.4%] of which were B-cell precursor [BCP] ALL), 44 (13.3%) with central nervous system tumors, 80 (24.1%) with solid tumors, and 84 (25.3%) with other and unspecified malignant neoplasms. Compared with exclusive breastfeeding duration of less than 3 months, exclusive breastfeeding for 3 months or longer was associated with a decreased risk of hematologic cancers (AHR, 0.66; 95% CI, 0.46-0.95), which was largely attributable to decreased risk of BCP-ALL (AHR, 0.62; 95% CI, 0.39-0.99), but not with risk of central nervous system tumors (AHR, 0.96; 95% CI, 0.51-1.88) or solid tumors (AHR, 0.87; 95% CI, 0.55-1.41). In this cohort study, longer duration of exclusive breastfeeding was associated with reduced risk of childhood BCP-ALL, corroborating results of previous case-control investigations in this field. To inform future preemptive interventions, continued research should focus on the potential biologic mechanisms underlying the observed association.

Background: Acute lymphoblastic leukemia(ALL) is the most common pediatric malignancy. Infection and bleeding are the leading cause of death during induction chemotherapy in childhood ALL. So, proper knowledge about anticipated infection and bleeding are very important during this period. But the duration of clinical remission and recovery of peripheral blood count during induction chemotherapy is not well reported in literature. Objective: The aim of the study was to determine the time of attainment of clinical remission and recovery of peripheral blood count after initiation of induction chemotherapy and to determine if the duration of clinical remission and peripheral blood count recovery differs between therapeutic risk groups. Methods: This prospective observational study was conducted from January 2021 to December 2021 in the Department of Paediatric Haematology and Oncology, BSMMU. Newly diagnosed admitted Eighty-Six ALL of both sexes aged 1 to 17.9 years were included. After commencing chemotherapy, physical examination was recorded every day until clinical remission and complete blood count (CBC) was recorded one to two days interval until peripheral blood count recovery. The number of packed red blood cell (PRBC) and platelet transfusions and the number of days of intravenous antibiotics were recorded. Results: Mean duration of clinical remission, complete Hemoglobin (Hb), Absolute neutrophil count(ANC) and platelet recovery was 8.4 ± 4.5 days, 25±7.9 days, 23.3±5.6 days and 21.8±6.4 days respectively (p&lt;0.01). Time to attain partial recovery of platelet was 14.0±4.9 days in high risk and 19.2±5.3 days in standard risk group. PRBC transfusion requirement was 2.2±1.2 units in high risk group and 1.7±0.8 units in standard risk group (p&lt;0.05). Time to attain partial recovery of ANC, number of days with I/V antibiotics and duration of treatment interruption were higher in high risk group. Conclusion: Time of clinical remission was similar between risk group. Platelet recovery occurred earlier than Hemoglobin (Hb) and absolute neutrophil count (ANC) recovery. Transfusion and supportive care requirement were more in high risk group during induction chemotherapy. So, more supportive care should be arranged up to three weeks of induction period to increase survival of high risk childhood ALL. Bangladesh Med Res Counc Bull 2023; 49: 177-182

Interleukin 8 (IL-8) is highly expressed in refractory acute lymphocytic leukemia (ALL) cells. This study aimed to investigate the contribution of IL-8 polymorphisms to the risk of childhood ALL. The genotypes of IL-8 rs4073, rs2227306, rs2227543, and rs1126647 were determined in 266 childhood ALL cases and 266 controls using the PCR-RFLP method. Additionally, we assessed whether the interactions of these genotypes with age and sex contributed to childhood ALL risk. The distributions of genotypic and allelic frequencies of IL-8 rs4073, rs2227306, rs2227543, and rs1126647 were not significantly different between childhood ALL cases and controls (all p>0.05). However, carriers of the variant AA genotype at IL-8 rs4073 had a significantly higher risk of childhood ALL among those aged ≤3.5 years and among girls (OR=2.39 and 3.32, 95%CI=1.21-4.73 and 1.51-7.30, p=0.0182 and 0.0042, respectively). In the stratification analysis, IL-8 rs4073 AT and AA genotypes were associated with higher childhood ALL risk classification and shorter survival time (OR=2.21 and 4.13, 95%CI=1.29-3.78 and 1.87-9.10, p=0.0054 and 0.0002, respectively). There was no positive association for rs2227306, rs2227543, or rs1126647 (all p>0.05). The A allele of IL-8 rs4073 can serve as a diagnostic predictor for childhood ALL, but only in girls and patients younger than or equal to 3.5 years old. More importantly, it can serve as a prognostic marker for high-risk classification and shorter survival time. Further validation studies can help extend the use of this prognostic predictor in clinical practice.

Heritable Variation in Lymphocyte-Related Traits and Risk of Down Syndrome Acute Lymphoblastic Leukemia: A Mendelian Randomization Study

While associations between maternal infections during pregnancy and childhood leukemia in offspring have been extensively studied, the evidence for other types of childhood cancers is limited. Additionally, antibiotic exposure during pregnancy could potentially increase the risk of childhood cancers. Our study investigates associations between maternal infections and antibiotic prescriptions during pregnancy and the risk of childhood cancer in Taiwan. We conducted a population-based cohort study using the Taiwan Maternal and Child Health Database (TMCHD), linked with national health and cancer registries. The study included 2 267 186 mother-child pairs, and the median follow-up time was 7.96 years. Cox proportional hazard models were utilized to estimate effects. Maternal infections during pregnancy were associated with a moderate increase in the risk of childhood hepatoblastoma (adjusted hazard ratio [HR] = 1.34; 95% confidence interval [CI]: 0.90-1.98) and a weaker increase in the risk of childhood acute lymphoblastic leukemia (ALL) (adjusted HR = 1.15; 95% CI: 0.99-1.35). Antibiotic prescriptions during pregnancy were also associated with an elevated risk of childhood ALL (adjusted HR = 1.30; 95% CI: 1.04-1.63), particularly with tetracyclines (adjusted HR = 2.15; 95% CI: 1.34-3.45). Several specific antibiotics were also associated with an increased risk of hepatoblastoma and medulloblastoma. Children exposed in utero to antibiotic prescription or both infections and antibiotics during pregnancy were at higher risk of developing ALL. Our findings suggest that there are associations between maternal infections, antibiotic use during pregnancy and the risk of several childhood cancers in addition to ALL and highlight the importance of further research in this area.

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

Dysregulation of microRNAs (miRNAs) targeting genes in the PI3K/Akt pathway has been implicated in the pathogenesis of childhood acute lymphoblastic leukemia (ALL). However, the impact of genetic variants in these miRNAs on ALL susceptibility has not been extensively explored in the Chinese population. To address this gap, we conducted a case-control study to evaluate the association between genetic variants in five PI3K/AKT pathway-related miRNAs (miR-149, miR-126, miR-492, miR-612, and miR-423) and childhood ALL susceptibility in the Chinese population. Additionally, we investigated the effects of the rs2292832 mutation on ALL cell proliferation and apoptosis. Our analyses revealed that the miR-149 rs2292832 mutant heterozygous CT genotype was more frequent in the control group than in the ALL cases, indicating a protective effect against ALL (adjusted odds ratio [OR]=0.78, 95% confidence interval [CI]=0.63-0.97, p=.024). Stratification analyses further revealed that the miR-149 rs2292832 CC genotype was associated with an increased risk of childhood ALL in subgroups of older children, females, those with parents who never smoked or drank alcohol, those living in painted houses, those with B-ALL, and those with high-risk ALL. Finally, we observed that the rs2292832 mutation inhibited ALL cell proliferation and induced apoptosis (p=.001), providing a potential mechanism by which this genetic variant may influence ALL susceptibility. Our study highlights the significant association between the miR-149 rs2292832 genetic variant and childhood ALL susceptibility in the Chinese population. These findings expand our understanding of the complex genetic landscape underlying ALL and have implications for the development of personalized therapeutic strategies.

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

Various studies have shown that single nucleotide polymorphisms in the AT-rich interaction domain 5B (ARID5B), IKAROS family zinc finger 1 (IKZF1), phosphatidylinositol-5-phosphate 4-kinase type 2 alpha (PIP4K2A), and GATA binding protein 3 (GATA3) genes may be associated with the susceptibility and prognosis of childhood acute lymphoblastic leukemia (ALL). The present study aimed to investigate the association of ARID5B rs10821936, IKZF1 rs4132601, PIP4K2A rs7088318, and GATA3 rs3824662 gene polymorphisms with the susceptibility and prognosis of childhood ALL in China. We found that the C allele of rs10821936 (ARID5B) and the A allele of rs3824662 (GATA3) were associated with an increased risk of childhood ALL in the Chinese population. There was no significant difference in frequencies of rs4132601 (IKZF1) and rs7088318 (PIP4K2A) genotypes and alleles between the childhood ALL and control groups. We observed that CC genotype of rs10821936 (ARID5B) was associated with increased rates of high-risk and moderate-risk childhood ALL. The rs10821936 (ARID5B) could serve as a potential biomarker for assessing the risk of childhood ALL in Chinese children.

Glyphosate in house dust and risk of childhood acute lymphoblastic leukemia in California

Acute lymphoblastic leukemia (ALL) is the most common type of cancer in children (age 0–14 years); however, the etiology remains incompletely understood. Several environmental exposures have been linked to risk of childhood ALL, including air pollution. Closely related to air pollution and human development is artificial light at night (ALAN), which is believed to disrupt circadian rhythm and impact health. We sought to evaluate outdoor ALAN and air pollution on risk of childhood ALL. The California Linkage Study of Early-Onset Cancers is a large population-based case–control in California that identifies and links cancer diagnoses from the California Cancer Registry to birth records. For each case, 50 controls with the same year of birth were obtained from birth records. A total of 2,782 ALL cases and 139,100 controls were identified during 2000–2015. ALAN was assessed with the New World Atlas of Artificial Night Sky Brightness and air pollution with an ensemble-based air pollution model of particulate matter smaller than 2.5 microns (PM2.5). After adjusting for known and suspected risk factors, the highest tertile of ALAN was associated with an increased risk of ALL in Hispanic children (odds ratio [OR] = 1.15, 95% confidence interval [CI] 1.01–1.32). There also appeared to be a borderline association between PM2.5 level and risk of ALL among non-Hispanic White children (OR per 10 µg/m3 = 1.24, 95% CI 0.98–1.56). We observed elevated risk of ALL in Hispanic children residing in areas of greater ALAN. Further work is needed to understand the role of ALAN and air pollution in the etiology of childhood ALL in different racial/ethnic groups.

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.

Racial and Ethnic Disparities in Childhood Acute Lymphoblastic Leukemia Risk Due to an IKZF1 Noncoding Regulatory Variant

PAX5 fusion genes are frequent in poor risk childhood acute lymphoblastic leukaemia and can be targeted with BIBF1120.