Persistence of Diffusion Capacity Impairment and Its Relationship with Dyspnea 12 Months after Hospitalization for COVID-19.

Background: Dyspnea is a common persistent symptom after acute coronavirus disease 2019 illness (COVID-19). One potential explanation for post-COVID-19 dyspnea is a reduction in diffusion capacity. This longitudinal study investigated diffusion capacity and its relationship with dyspnea on exertion in individuals previously hospitalized with COVID-19. Methods: Eligible participants had been hospitalized for the treatment of acute COVID-19 and were assessed at 6 weeks, 6 months, and 12 months after discharge. Pulmonary function testing, diffusion capacity of carbon monoxide (DLCO), blood gas analysis and the level of dyspnea (Borg scale; before and after a 6 min walk test [6 MWT]) were performed. Participants were divided into subgroups based on the presence or absence of dyspnea during the 6 MWT at 12 months after hospitalization. Results: Seventy-two participants (twenty-two female, mean age 59.8 ± 13.5 years) were included. At 12 months after discharge, 41/72 participants (57%) had DLCO below the lower limit of normal and 56/72 (78%) had DLCO < 80% of the predicted value. Individuals with exertional dyspnea had significantly lower DLCO than those without exertional dyspnea (p = 0.001). In participants with DLCO data being available at three timepoints over 12 months (baseline, 6 months, and 12 months) after discharge (n = 25), DLCO improved between 6 weeks and 6 months after hospital discharge, but not thereafter (p = 0.017). Conclusions: About 2/3 of the post-COVID individuals in this study had impaired diffusion capacity at 12 months after hospital discharge. There was an association between persisting dyspnea on exertion and significantly reduced DLCO. Impaired diffusion capacity improved over the first 6 months after hospitalization but not thereafter.

Pre- and Postnatal Exposures to Tobacco Smoking and Survival of Childhood Acute Lymphoblastic and Myeloid Leukemias in California, United States.

BACKGROUND: Tobacco smoke adversely affects the prognosis of adult cancers including myeloid leukemia, but less is known in children. METHODS: We evaluated whether pre- and postnatal exposures to tobacco smoke decrease 5-year survival of 1,235 childhood acute lymphoblastic leukemia (ALL) and 188 childhood acute myeloid leukemia (AML) cases derived from a population-based case-control study in California. Cases were diagnosed between 1995 and 2015 (median follow-up time of 13.2 years overall). We obtained data on tobacco smoking (before conception, during pregnancy, after birth), parental education and income, clinical features, and vital status through 2020. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for mortality associated with smoking, adjusting for sociodemographic characteristics and risk group (ALL only). RESULTS: About 23% of mothers and 39% of fathers reported smoking and 130 children with ALL and 52 with AML died within 5 years. For AML, increased risks of death were observed among children whose fathers smoked before conception compared with nonsmoking fathers [HR = 1.41; 95% confidence interval (CI), 0.95-3.44 and 3.47; 95% CI, 1.37-8.81, respectively for <20 vs. ≥20 cigarettes per day; Ptrend = 0.01]. HR for child's passive smoking was 1.74, 95% CI, 0.81-3.73. Paternal preconception smoking may also reduce 5-year survival among ALL with favorable prognostic molecular subtypes (high hyperdiploidy and absence of IKZF1 gene deletion), although the associations did not reach statistical significance (Pheterogeneity = 0.07). CONCLUSIONS: Paternal preconception smoking decreased 5-year survival of childhood AML. IMPACT: Knowledge of exposure to tobacco smoking should be integrated in the treatment plan of childhood leukemias.

Nonchromosomal birth defects and risk of childhood acute leukemia: An assessment in 15 000 leukemia cases and 46 000 controls from the Childhood Cancer and Leukemia International Consortium.

Although recent studies have demonstrated associations between nonchromosomal birth defects and several pediatric cancers, less is known about their role on childhood leukemia susceptibility. Using data from the Childhood Cancer and Leukemia International Consortium, we evaluated associations between nonchromosomal birth defects and childhood leukemia. Pooling consortium data from 18 questionnaire-based and three registry-based case-control studies across 13 countries, we used multivariable logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between a spectrum of birth defects and leukemia. Our analyses included acute lymphoblastic leukemia (ALL, n = 13 115) and acute myeloid leukemia (AML, n = 2120) cases, along with 46 172 controls. We used the false discovery rate to account for multiple comparisons. In the questionnaire-based studies, the prevalence of birth defects was 5% among cases vs 4% in controls, whereas, in the registry-based studies, the prevalence was 11% among cases vs 7% in controls. In pooled adjusted analyses, there were several notable associations, including (1) digestive system defects and ALL (OR = 2.70, 95% CI: 1.46-4.98); (2) congenital anomalies of the heart and circulatory system and AML (OR = 2.86, 95% CI: 1.81-4.52) and (3) nervous system defects and AML (OR = 4.23, 95% CI: 1.50-11.89). Effect sizes were generally larger in registry-based studies. Overall, our results could point to novel genetic and environmental factors associated with birth defects that could also increase leukemia susceptibility. Additionally, differences between questionnaire- and registry-based studies point to the importance of complementary sources of birth defect phenotype data when exploring these associations.

Shingles Vaccine Uptake Among Older Adults: Identifying Early, Later, and Nonadopters.

Introduction: There is growing interest in accelerating adoptions of vaccines. This study examined factors that differentiate the acceptance and timing of uptake of the first shingles vaccine, Zostavax, among older adults in the U.S. Methods: Data from Health and Retirement Study respondents who were aged ≥62 years in 2008 were analyzed to determine whether they received a shingles vaccination from 2006 to 2016. Multinomial logistic regression was used to examine the characteristics associated with vaccine uptake and timing. Results: Of those eligible, 15.2% were vaccinated early (between 2006 and 2010), 20.2% were vaccinated later, and 64.6% remained unvaccinated 10 years after the shingles vaccine was introduced. Respondents more likely to be vaccinated were those who had higher education and income, experience with influenza vaccination, more frequent social interaction with friends, or were residing in an area with higher shingles vaccination rates. Conclusions: Shingles vaccination rates vary by social and geographic characteristics. Efforts to improve and expedite vaccination and other new preventive measures should target specific populations and geographic areas.

Associations between early-life and in utero infections and cytomegalovirus-positive acute lymphoblastic leukemia in children.

Childhood infections and cytomegalovirus (CMV) are associated with pediatric acute lymphoblastic leukemia (ALL). CMV dysregulates the host immune system and alters the immune response to subsequent antigenic exposures. We suspect that this immune dysregulation contributes to increased numbers of symptomatic infections in childhood allowing for expansion of pre-leukemic clones. We explored the association between childhood infections, maternal infections during pregnancy and CMV-positive ALL. Using a droplet digital PCR assay, we screened diagnostic ALL bone marrow samples from the California Childhood Leukemia Study (1995-2015) for the presence of CMV DNA identifying CMV-positive and CMV-negative cases. We performed a case-only analysis (n = 524) comparing the number and types of childhood infections and maternal infections during pregnancy between CMV-positive and CMV-negative ALL cases using logistic regression. With increasing numbers of infections in the first 12 months of life, children were more likely to classify to the highest tertile of CMV DNA in the bone marrow at diagnosis (OR: 1.04, 95% CI: 1.01-1.08). Specifically, those reporting cough or flu in the first 12 months were more likely to be CMV-positive at ALL diagnosis (OR: 2.15, 95% CI: 1.06-4.37 and OR: 2.06, 95% CI: 1.17-3.63 respectively). Furthermore, those with a history of maternal infection during pregnancy were more likely to be CMV-positive (OR: 2.12, 95% CI: 1.24-3.62). We hypothesize that children with underlying immune dysregulation develop more symptomatic infections in childhood and ultimately CMV-positive ALL; this underlying immune dysregulation may be due to early immune system alterations via CMV exposure (in utero or early infancy) proposing a potential link between CMV and ALL etiology.

Periconceptional folate intake influences DNA methylation at birth based on dietary source in an analysis of pediatric acute lymphoblastic leukemia cases and controls.

BACKGROUND: Periconceptional folate intake is associated with the establishment of DNA methylation in offspring; however, variations in this relation by food sources compared with folic acid supplements are not described. Also, maternal folate intake is associated with decreased risk of pediatric acute lymphoblastic leukemia (ALL), but the mechanism is not known. OBJECTIVES: We evaluated the relation between periconceptional folate intake by source and DNA methylation at birth in a cohort of pediatric ALL cases and controls in an epigenome-wide association study. METHODS: Genome-wide DNA methylation status obtained from archived neonatal blood spots from pediatric ALL cases (n = 189) and controls (n = 205) in the California Childhood Leukemia Study (CCLS) from 1995-2008 was compared with periconceptional folate from total, food, and supplemental sources using multivariable linear regression. Further stratification was performed by income, education, ethnicity, and total folate intake. We evaluated variable DNA methylation response to periconceptional folate by ALL case status through an interaction term. RESULTS: Two significant differentially methylated probes (DMPs) were associated with food and supplemental periconceptional folate intake in all subjects (n = 394). The top differentially methylated region at the promoter region of DUSP22(dual specificity phosphatase 22) demonstrated DNA hypermethylation in ALL cases but not in controls in response to total and food folate intake. We further identified 8 interaction term DMPs with variable DNA methylation response to folate intake by ALL case status. Further stratification of the cohort by education and ethnicity revealed a substantially higher number of DMPs associated with supplemental folic acid intake in Hispanic subjects with lower income and educational level. CONCLUSIONS: We identified modest associations between periconceptional folate intake and DNA methylation differing by source, including variation by ALL case status. Hispanic subjects of lower income and education appear uniquely responsive to periconceptional folate supplementation.

Investigating DNA methylation as a mediator of genetic risk in childhood acute lymphoblastic leukemia.

Genome-wide association studies have identified a growing number of single nucleotide polymorphisms (SNPs) associated with childhood acute lymphoblastic leukemia (ALL), yet the functional roles of most SNPs are unclear. Multiple lines of evidence suggest that epigenetic mechanisms may mediate the impact of heritable genetic variation on phenotypes. Here, we investigated whether DNA methylation mediates the effect of genetic risk loci for childhood ALL. We performed an epigenome-wide association study (EWAS) including 808 childhood ALL cases and 919 controls from California-based studies using neonatal blood DNA. For differentially methylated CpG positions (DMPs), we next conducted association analysis with 23 known ALL risk SNPs followed by causal mediation analyses addressing the significant SNP-DMP pairs. DNA methylation at CpG cg01139861, in the promoter region of IKZF1, mediated the effects of the intronic IKZF1 risk SNP rs78396808, with the average causal mediation effect (ACME) explaining ~30% of the total effect (ACME P = 0.0031). In analyses stratified by self-reported race/ethnicity, the mediation effect was only significant in Latinos, explaining ~41% of the total effect of rs78396808 on ALL risk (ACME P = 0.0037). Conditional analyses confirmed the presence of at least three independent genetic risk loci for childhood ALL at IKZF1, with rs78396808 unique to non-European populations. We also demonstrated that the most significant DMP in the EWAS, CpG cg13344587 at gene ARID5B (P = 8.61 × 10-10), was entirely confounded by the ARID5B ALL risk SNP rs7090445. Our findings provide new insights into the functional pathways of ALL risk SNPs and the DNA methylation differences associated with risk of childhood ALL.

Accelerated epigenetic aging in newborns with Down syndrome.

Accelerated aging is a hallmark of Down syndrome (DS), with adults experiencing early-onset Alzheimer's disease and premature aging of the skin, hair, and immune and endocrine systems. Accelerated epigenetic aging has been found in the blood and brain tissue of adults with DS but when premature aging in DS begins remains unknown. We investigated whether accelerated aging in DS is already detectable in blood at birth. We assessed the association between age acceleration and DS using five epigenetic clocks in 346 newborns with DS and 567 newborns without DS using Illumina MethylationEPIC DNA methylation array data. We compared two epigenetic aging clocks (DNAmSkinBloodClock and pan-tissue DNAmAge) and three epigenetic gestational age clocks (Haftorn, Knight, and Bohlin) between DS and non-DS newborns using linear regression adjusting for observed age, sex, batch, deconvoluted blood cell proportions, and genetic ancestry. Targeted sequencing of GATA1 was performed in a subset of 184 newborns with DS to identify somatic mutations associated with transient abnormal myelopoiesis. DS was significantly associated with increased DNAmSkinBloodClock (effect estimate = 0.2442, p < 0.0001), with an epigenetic age acceleration of 244 days in newborns with DS after adjusting for potential confounding factors (95% confidence interval: 196-292 days). We also found evidence of epigenetic age acceleration associated with somatic GATA1 mutations among newborns with DS (p = 0.015). DS was not associated with epigenetic gestational age acceleration. We demonstrate that accelerated epigenetic aging in the blood of DS patients begins prenatally, with implications for the pathophysiology of immunosenescence and other aging-related traits in DS.

Interaction between maternal killer immunoglobulin-like receptors and offspring HLAs and susceptibility of childhood ALL.

Acute lymphoblastic leukemia (ALL) in children is associated with a distinct neonatal cytokine profile. The basis of this neonatal immune phenotype is unknown but potentially related to maternal-fetal immune receptor interactions. We conducted a case-control study of 226 case child-mother pairs and 404 control child-mother pairs to evaluate the role of interaction between HLA genotypes in the offspring and maternal killer immunoglobulin-like receptor (KIR) genotypes in the etiology of childhood ALL, while considering potential mediation by neonatal cytokines and the immune-modulating enzyme arginase-II (ARG-II). We observed different associations between offspring HLA-maternal KIR activating profiles and the risk of ALL in different predicted genetic ancestry groups. For instance, in Latino subjects who experience the highest risk of childhood leukemia, activating profiles were significantly associated with a lower risk of childhood ALL (odds ratio [OR] = 0.59; 95% confidence interval [CI], 0.49-0.71) and a higher level of ARG-II at birth (coefficient = 0.13; 95% CI, 0.04-0.22). HLA-KIR activating profiles were also associated with a lower risk of ALL in non-Latino Asians (OR = 0.63; 95% CI, 0.38-1.01), although they had a lower tumor necrosis factor-α level (coefficient = -0.27; 95% CI, -0.49 to -0.06). Among non-Latino White subjects, no significant association was observed between offspring HLA-maternal KIR interaction and ALL risk or cytokine levels. The current study reports the association between offspring HLA-maternal KIR interaction and the development of childhood ALL with variation by predicted genetic ancestry. We also observed some associations between activating profiles and immune factors related to cytokine control; however, cytokines did not demonstrate causal mediation of the activating profiles on ALL risk.

Infant feeding practices and childhood acute leukemia: Findings from the Childhood Cancer & Leukemia International Consortium.

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

Cytokine Levels at Birth in Children Who Developed Acute Lymphoblastic Leukemia.

BACKGROUND: Prenatal immune development may play an important role in the etiology of childhood acute lymphoblastic leukemia (ALL). METHODS: Seven cytokines, IL1ß, IL4, IL6, IL8, GM-CSF, TNFα, and VEGF, were analyzed in blood spots collected at birth from 1,020 ALL cases and 1,003 controls participating in the California Childhood Leukemia Study. ORs and 95% confidence intervals (95% CI) associated with an interquartile range increment in cytokine levels were calculated using logistic regression, adjusting for sociodemographic and birth characteristics. RESULTS: We found that patients with ALL were born with higher levels of a group of correlated cytokines than controls [IL1ß: OR of 1.18 (95% confidence interval [CI], 1.03-1.35); IL8: 1.19 (1.03-1.38); TNFα: 1.15 (1.01-1.30); VEGF: 1.16 (1.01-1.33)], especially among children of Latina mothers (ORs from 1.31 to 1.40) and for ALL with high hyperdiploidy (ORs as high as 1.27). We found that neonatal cytokine levels were correlated with neonatal levels of endogenous metabolites which had been previously associated with ALL risk; however, there was no evidence that the cytokines were mediating the relationship between these metabolites and ALL risk. CONCLUSIONS: We posit that children born with altered cytokine levels are set on a trajectory towards an increased risk for subsequent aberrant immune reactions that can initiate ALL. IMPACT: This is the first study to evaluate the interplay between levels of immunomodulatory cytokines at birth, prenatal exposures, and the risk of childhood ALL.

Epigenetic Biomarkers of Prenatal Tobacco Smoke Exposure Are Associated with Gene Deletions in Childhood Acute Lymphoblastic Leukemia.

BACKGROUND: Parental smoking is implicated in the etiology of acute lymphoblastic leukemia (ALL), the most common childhood cancer. We recently reported an association between an epigenetic biomarker of early-life tobacco smoke exposure at the AHRR gene and increased frequency of somatic gene deletions among ALL cases. METHODS: Here, we further assess this association using two epigenetic biomarkers for maternal smoking during pregnancy-DNA methylation at AHRR CpG cg05575921 and a recently established polyepigenetic smoking score-in an expanded set of 482 B-cell ALL (B-ALL) cases in the California Childhood Leukemia Study with available Illumina 450K or MethylationEPIC array data. Multivariable Poisson regression models were used to test the associations between the epigenetic biomarkers and gene deletion numbers. RESULTS: We found an association between DNA methylation at AHRR CpG cg05575921 and deletion number among 284 childhood B-ALL cases with MethylationEPIC array data, with a ratio of means (RM) of 1.31 [95% confidence interval (CI), 1.02-1.69] for each 0.1 ß value reduction in DNA methylation, an effect size similar to our previous report in an independent set of 198 B-ALL cases with 450K array data [meta-analysis summary RM (sRM) = 1.32; 95% CI, 1.10-1.57]. The polyepigenetic smoking score was positively associated with gene deletion frequency among all 482 B-ALL cases (sRM = 1.31 for each 4-unit increase in score; 95% CI, 1.09-1.57). CONCLUSIONS: We provide further evidence that prenatal tobacco-smoke exposure may influence the generation of somatic copy-number deletions in childhood B-ALL. IMPACT: Analyses of deletion breakpoint sequences are required to further understand the mutagenic effects of tobacco smoke in childhood ALL.

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

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).

Age-, sex- and disease subtype-related foetal growth differentials in childhood acute myeloid leukaemia risk: A Childhood Leukemia International Consortium analysis.

AIM: Evidence for an association of foetal growth with acute myeloid leukaemia (AML) is inconclusive. AML is a rare childhood cancer, relatively more frequent in girls, with distinct features in infancy. In the context of the Childhood Leukemia International Consortium (CLIC), we examined the hypothesis that the association may vary by age, sex and disease subtype using data from 22 studies and a total of 3564 AML cases. METHODS: Pooled estimates by age, sex and overall for harmonised foetal growth markers in association with AML were calculated using the International Fetal and Newborn Growth Consortium for the 21st Century Project for 17 studies contributing individual-level data; meta-analyses were, thereafter, conducted with estimates provided ad hoc by five more studies because of administrative constraints. Subanalyses by AML subtype were also performed. RESULTS: A nearly 50% increased risk was observed among large-for-gestational-age infant boys (odds ratio [OR]: 1.49, 95% confidence interval [CI]: 1.03-2.14), reduced to 34% in boys aged <2 years (OR: 1.34, 95% CI: 1.05-1.71) and 25% in boys aged 0-14 years (OR: 1.25, 95% CI: 1.06-1.46). The association of large for gestational age became stronger in boys with M0/M1subtype (OR: 1.80, 95% CI: 1.15-2.83). Large birth length for gestational age was also positively associated with AML (OR: 1.38, 95% CI: 1.00-1.92) in boys. By contrast, there were null associations in girls, as well as with respect to associations of decelerated foetal growth markers. CONCLUSIONS: Accelerated foetal growth was associated with AML, especially in infant boys and those with minimally differentiated leukaemia. Further cytogenetic research would shed light into the underlying mechanisms.

Coffee and tea consumption during pregnancy and risk of childhood acute myeloid leukemia: A Childhood Leukemia International Consortium (CLIC) study.

BACKGROUND: Dietary habits during pregnancy have been inconsistently linked to childhood acute myeloid leukemia (AML), given the putative intrauterine onset of the disease as a result of triggering events during the critical period of fetal hematopoiesis. We investigated the potential association of maternal coffee and tea consumption during pregnancy with childhood AML risk, pooling primary data from eight case-control studies participating in the Childhood Leukemia International Consortium. METHODS: Information on coffee and/or tea consumption was available for 444 cases and 1255 age- and sex-matched controls, on coffee consumption for 318 cases and 971 controls and on tea consumption for 388 cases and 932 controls. Categories for cups of daily coffee/tea consumption were created in order to explore potential dose-response associations. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression. RESULTS: Associations were found neither in the analysis on coffee or tea nor in the analysis on coffee only consumption (any versus no). A positive association with increasing coffee intake was observed (>1 cup per day; OR: 1.40, 95% CI: 1.03-1.92, increment of one cup per day; OR: 1.18, 95% CI: 1.01-1.39). No associations were observed with tea consumption. Interaction analyses showed non-significant associations between coffee/tea and smoking. Hyperdiploidy was inversely associated with tea consumption, with other cytogenetic markers having no association with coffee/tea. CONCLUSION: Given the widespread consumption of caffeinated beverages among pregnant women, our finding is of important public health relevance, suggesting adverse effects of maternal coffee consumption during pregnancy in the offspring.

Inherited genetic susceptibility to acute lymphoblastic leukemia in Down syndrome.

Children with Down syndrome (DS) have a 20-fold increased risk of acute lymphoblastic leukemia (ALL) and distinct somatic features, including CRLF2 rearrangement in ∼50% of cases; however, the role of inherited genetic variation in DS-ALL susceptibility is unknown. We report the first genome-wide association study of DS-ALL, comprising a meta-analysis of 4 independent studies, with 542 DS-ALL cases and 1192 DS controls. We identified 4 susceptibility loci at genome-wide significance: rs58923657 near IKZF1 (odds ratio [OR], 2.02; Pmeta = 5.32 × 10-15), rs3731249 in CDKN2A (OR, 3.63; Pmeta = 3.91 × 10-10), rs7090445 in ARID5B (OR, 1.60; Pmeta = 8.44 × 10-9), and rs3781093 in GATA3 (OR, 1.73; Pmeta = 2.89 × 10-8). We performed DS-ALL vs non-DS ALL case-case analyses, comparing risk allele frequencies at these and other established susceptibility loci (BMI1, PIP4K2A, and CEBPE) and found significant association with DS status for CDKN2A (OR, 1.58; Pmeta = 4.1 × 10-4). This association was maintained in separate regression models, both adjusting for and stratifying on CRLF2 overexpression and other molecular subgroups, indicating an increased penetrance of CDKN2A risk alleles in children with DS. Finally, we investigated functional significance of the IKZF1 risk locus, and demonstrated mapping to a B-cell super-enhancer, and risk allele association with decreased enhancer activity and differential protein binding. IKZF1 knockdown resulted in significantly higher proliferation in DS than non-DS lymphoblastoid cell lines. Our findings demonstrate a higher penetrance of the CDKN2A risk locus in DS and serve as a basis for further biological insights into DS-ALL etiology.

Parental occupational exposure to low-frequency magnetic fields and risk of leukaemia in the offspring: findings from the Childhood Leukaemia International Consortium (CLIC).

OBJECTIVES: Previously published studies on parental occupational exposure to extremely low-frequency magnetic fields (ELF-MF) and risk of acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) in their offspring were inconsistent. We therefore evaluated this question within the Childhood Leukemia International Consortium. METHODS: We pooled 11 case-control studies including 9723 childhood leukaemia cases and 17 099 controls. Parental occupational ELF-MF exposure was estimated by linking jobs to an ELF-MF job-exposure matrix (JEM). Logistic regression models were used to estimate ORs and 95% CIs in pooled analyses and meta-analyses. RESULTS: ORs from pooled analyses for paternal ELF-MF exposure >0.2 microtesla (µT) at conception were 1.04 (95% CI 0.95 to 1.13) for ALL and 1.06 (95% CI 0.87 to 1.29) for AML, compared with ≤0.2 µT. Corresponding ORs for maternal ELF-MF exposure during pregnancy were 1.00 (95% CI 0.89 to 1.12) for ALL and 0.85 (95% CI 0.61 to 1.16) for AML. No trends of increasing ORs with increasing exposure level were evident. Furthermore, no associations were observed in the meta-analyses. CONCLUSIONS: In this large international dataset applying a comprehensive quantitative JEM, we did not find any associations between parental occupational ELF-MF exposure and childhood leukaemia.

Predisposing germline mutations in high hyperdiploid acute lymphoblastic leukemia in children.

High hyperdiploidy (HD) is the most common cytogenetic subtype of childhood acute lymphoblastic leukemia (ALL), and a higher incidence of HD has been reported in ALL patients with congenital cancer syndromes. We assessed the frequency of predisposing germline mutations in 57 HD-ALL patients from the California Childhood Leukemia Study via targeted sequencing of cancer-relevant genes. Three out of 57 patients (5.3%) harbored confirmed germline mutations that were likely causal, in NBN, ETV6, and FLT3, with an additional six patients (10.5%) harboring putative predisposing mutations that were rare in unselected individuals (<0.01% allele frequency in the Exome Aggregation Consortium, ExAC) and predicted functional (scaled CADD score ≥ 20) in known or potential ALL predisposition genes (SH2B3, CREBBP, PMS2, MLL, ABL1, and MYH9). Three additional patients carried rare and predicted damaging germline mutations in GAB2, a known activator of the ERK/MAPK and PI3K/AKT pathways and binding partner of PTPN11-encoded SHP2. The frequency of rare and predicted functional germline GAB2 mutations was significantly higher in our patients (2.6%) than in ExAC (0.28%, P = 4.4 × 10-3 ), an observation that was replicated in ALL patients from the TARGET project (P = .034). We cloned patient GAB2 mutations and expressed mutant proteins in HEK293 cells and found that frameshift mutation P621fs led to reduced SHP2 binding and ERK1/2 phosphorylation but significantly increased AKT phosphorylation, suggesting possible RAS-independent leukemogenic effects. Our results support a significant contribution of rare, high penetrance germline mutations to HD-ALL etiology, and pinpoint GAB2 as a putative novel ALL predisposition gene.