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.

Association between birth characteristics and incidence of pituitary adenoma and craniopharyngioma: a registry-based study in California, 2001-2015.

PURPOSE: To evaluate the association between birth characteristics, including parental sociodemographic characteristics, and early-onset pituitary adenoma (PA) and craniopharyngioma. METHODS: Leveraging the population-based California Linkage Study of Early-onset Cancers, we identified the birth characteristics of incident cases with PA (n = 1,749) or craniopharyngioma (n = 227) who were born from 1978 to 2015 and diagnosed 1988-2015, as well as controls in a 50:1 ratio matched on birth year. Adjusted odds ratios (OR) and 95% confidence interval (CI) estimates were computed using unconditional multivariable logistic regression. RESULTS: Males had a lower risk of PA than females (OR = 0.37, 95%CI: 0.34-0.41), and Black (OR = 1.55, 95%CI: 1.30-1.84) or Hispanic (OR = 1.53, 95%CI: 1.34-1.74) individuals had a higher risk compared to non-Hispanic Whites. Older maternal age was positively associated with PA (OR = 1.09, 95%CI: 1.04-1.15 per 5 years, p < 0.01), as was higher maternal education (OR = 1.12, 95%CI: 1.04-1.20 per year, p < 0.01). There were no statistically significant associations between birthweight (OR = 1.04, 95%CI: 0.99-1.09 per 500 g, p = 0.12), birth plurality, or birth order and PA. When stratified by race and ethnicity, the significant association with maternal education was identified only for non-Hispanic White individuals. On multivariable logistic regression, no statistically significant associations were identified between birth characteristics and incidence of craniopharyngioma, except that risk was higher among Hispanic (OR = 1.45, 95%CI: 1.01-2.08) compared to non-Hispanic White individuals. CONCLUSION: In this large, population-based study, female sex, older maternal age, higher maternal education, and Hispanic ethnicity and Black race compared to non-Hispanic White race, were associated with an increased risk of PA in children and young adults.

Birth characteristics and risk of Ewing sarcoma.

PURPOSE: The incidence of Ewing sarcoma varies according to race and ethnicity, and genetic susceptibility is known to affect disease risk. Apart from these factors, the etiology of Ewing sarcoma is largely unknown. METHODS: We compared the birth characteristics of a population-based series of 556 Ewing sarcoma cases born in California in 1978-2015 and diagnosed in 1988-2015 with those of 27,800 controls selected from statewide birth records and frequency-matched to cases on the year of birth, using multivariable logistic regression models. We also assessed whether Ewing sarcoma clustered within families. RESULTS: Compared to non-Hispanic White subjects, Black (odds ratio [OR] = 0.07, 95% confidence interval [CI] 0.03-0.18), Asian (OR = 0.57, 95% CI 0.41-0.80), and Hispanic (OR = 0.73, 95% CI 0.62-0.88) individuals had a significantly lower risk of Ewing sarcoma. Race and ethnicity differences were more profound for metastatic Ewing sarcoma. Birthweight was also identified as a significant risk factor (OR = 1.09, 95% CI 1.00-1.18 for each 500 g increase in birthweight). A separate family-based cancer clustering analysis did not suggest any strong role for familial predisposition alleles. CONCLUSIONS: This population-based study with minimal selection bias provides support for a role of accelerated fetal growth in the etiology of Ewing sarcoma in addition to more precise estimates of racial and ethnic variations in disease risk. This comparatively large analysis of birth characteristics and Ewing sarcoma in a multiethnic population should stimulate further investigations into genetic and environmental causes.

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).

Genetic determinants of childhood and adult height associated with osteosarcoma risk.

BACKGROUND: Although increased height has been associated with osteosarcoma risk in previous epidemiologic studies, to the authors' knowledge the relative contribution of stature during different developmental timepoints remains unclear. Furthermore, the question of how genetic determinants of height impact osteosarcoma etiology remains unexplored. Genetic variants associated with stature in previous genome-wide association studies may be biomarkers of osteosarcoma risk. METHODS: The authors tested the associations between osteosarcoma risk and polygenic scores for adult height (416 variants), childhood height (6 variants), and birth length (5 variants) in 864 osteosarcoma cases and 1879 controls of European ancestry. RESULTS: Each standard deviation increase in the polygenic score for adult height, corresponding to a 1.7-cm increase in stature, was found to be associated with a 1.10-fold increase in the risk of osteosarcoma (95% confidence interval [95% CI], 1.01-1.19; P =.027). Each standard deviation increase in the polygenic score for childhood height, corresponding to a 0.5-cm increase in stature, was associated with a 1.10-fold increase in the risk of osteosarcoma (95% CI, 1.01-1.20; P =.023). The polygenic score for birth length was not found to be associated with osteosarcoma risk (P =.11). When adult and childhood height scores were modeled together, they were found to be independently associated with osteosarcoma risk (P =.037 and P = .043, respectively). An expression quantitative trait locus for cartilage intermediate layer protein 2 (CILP2), rs8103992, was significantly associated with osteosarcoma risk after adjustment for multiple comparisons (odds ratio, 1.35; 95% CI, 1.16-1.56 [P = 7.93×10-5 and Padjusted =.034]). CONCLUSIONS: A genetic propensity for taller adult and childhood height attainments contributed independently to osteosarcoma risk in the current study data. These results suggest that the biological pathways affecting normal bone growth may be involved in osteosarcoma etiology.

Perinatal factors associated with clinical presentation of osteosarcoma in children and adolescents.

BACKGROUND: Osteosarcoma typically develops during puberty with tumors arising at sites of rapid bone growth, suggesting a role for growth-regulating pathways in tumor etiology. Birthweight is one measure of perinatal growth that has been investigated as an osteosarcoma risk factor. Whether birthweight affects clinical features of osteosarcoma remains unexplored. METHOD: Six hundred seventy patients with osteosarcoma, aged 0-19 years, were identified through the California Cancer Registry. We analyzed birth certificate data from the California Department of Public Health vital statistics unit for these patients and 2,860 controls, matched by sex, birth-year, and race/ethnicity. We examined the impact of birthweight on the risk, timing, and clinical presentation of pediatric osteosarcoma including tumor location, size, extension, differentiation, presence of metastasis, and age at onset. Regression models were adjusted for race, sex, gestational age, socioeconomic status, and tumor site. RESULTS: Higher birthweight was associated with more advanced tumor stage (P = 0.017), a trend toward greater tumor extension into surrounding tissues (P = 0.083), and with occurrence of tumors in sites other than the long bones of the arms/legs (P = 9.7 × 10-3 ). Higher birthweight was also associated with an increased likelihood of metastases present at diagnosis (P = 0.047), with each 200 g increase in birthweight associated with a 1.11-fold increase in the odds of having metastatic disease (95% confidence interval: 1.01-1.22). CONCLUSIONS: The association between higher birthweight and more aggressive osteosarcoma, frequently occurring at sites other than the long bones, suggests that growth pathways active during gestation may play an important role in future osteosarcoma progression, especially at anatomic sites with diminished rates of osteoblastic proliferation.

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.

Genetic variation near GRB10 associated with bone growth and osteosarcoma risk in canine and human populations.

BACKGROUND: Canine and human osteosarcoma are similar in clinical presentation and tumor genomics. Giant breed dogs experience elevated osteosarcoma incidence, and taller stature remains a consistent risk factor for human osteosarcoma. Whether evolutionarily conserved genes contribute to both human and canine osteosarcoma predisposition merits evaluation. METHODS: A multi-center sample of childhood osteosarcoma patients and controls underwent genome-wide genotyping and imputation. Ancestry-adjusted SNP associations were calculated within each dataset using logistic regression, then meta-analyzed across the three datasets, totaling 1091 patients and 3026 controls. Ten regions previously associated with canine osteosarcoma risk were mapped to the human genome, spanning ∼6 Mb. We prioritized association testing of 5985 human SNPs mapping to candidate osteosarcoma risk regions detected in Irish wolfhounds, the largest dog breed studied. Secondary analyses explored 6289 additional human SNPs mapping to candidate osteosarcoma risk regions identified in Rottweilers and greyhounds. RESULTS: Fourteen SNPs were associated with human osteosarcoma risk after adjustment for multiple comparisons, all within a 42 kb region of human Chromosome 7p12.1. The lead variant was rs17454681 (OR=1.25, 95 %CI: 1.12-1.39; P=4.1×10-5), and independent risk variants were not observed in conditional analyses. While the associated region spanned 2.1 Mb and contained eight genes in Irish wolfhounds, associations were localized to a 50-fold smaller region of the human genome and strongly implicate GRB10 (growth factor receptor-bound protein 10) in canine and human osteosarcoma predisposition. PheWAS analysis in UK Biobank data identified noteworthy associations of the rs17454681 risk allele with varied measures of height and pubertal timing. CONCLUSIONS: Our comparative oncology analysis identified a novel human osteosarcoma risk allele near GRB10, a growth inhibitor that suppresses activated receptor tyrosine kinases including IGF1R, PDGFRB, and EGFR. Epidemiologists may benefit from leveraging cross-species comparisons to identify haplotypes in highly susceptible but genetically homogenous populations of domesticated animals, then fine-mapping these associations in diverse human populations.

Folate metabolism and risk of childhood acute lymphoblastic leukemia: a genetic pathway analysis from the Childhood Cancer and Leukemia International Consortium.

BACKGROUND: Prenatal folate supplementation has been consistently associated with a reduced risk of childhood lymphoblastic leukemia (ALL). Previous germline genetic studies examining the one carbon (folate) metabolism pathway were limited in sample size, scope, and population diversity, and led to inconclusive results. METHODS: We evaluated whether ~2,900 single nucleotide polymorphisms (SNPs) within 46 candidate genes involved in the folate metabolism pathway influence the risk of childhood ALL, using genome-wide data from nine case-control-studies in the Childhood Cancer and Leukemia International Consortium (n=9,058 cases including 4,510 children of European ancestry, 3,018 Latinx, and 1,406 Asians, and 92,364 controls). Each study followed a standardized protocol for quality control and imputation of genome-wide data, and summary statistics were meta-analyzed for all children combined and by major ancestry group using METAL software. RESULTS: None of the selected SNPs reached statistical significance, overall and for major ancestry groups (using adjusted Bonferroni p-value of 5x10-6 and less stringent p-value of 3.5x10-5 accounting for the number of "independent" SNPs). None of the 10 top (non-significant) SNPs and corresponding genes overlapped across ancestry groups. CONCLUSION: This large meta-analysis of original data does not reveal associations between many common genetic variants in the folate metabolism pathway and childhood ALL in various ancestry groups. IMPACT: Genetic variants in the folate pathway alone do not appear to substantially influence childhood ALL risk. Other mechanisms such as gene-folate interaction, DNA methylation or maternal genetic effects may explain the observed associations with self-reported prenatal folate intake.

Evaluating Genomic Polygenic Risk Scores for Childhood Acute Lymphoblastic Leukemia in Latinos.

The utility of polygenic risk score (PRS) models has not been comprehensively evaluated for childhood acute lymphoblastic leukemia (ALL), the most common type of cancer in children. Previous PRS models for ALL were based on significant loci observed in genome-wide association studies (GWAS), even though genomic PRS models have been shown to improve prediction performance for a number of complex diseases. In the United States, Latino (LAT) children have the highest risk of ALL, but the transferability of PRS models to LAT children has not been studied. In this study we constructed and evaluated genomic PRS models based on either non-Latino white (NLW) GWAS or a multi-ancestry GWAS. We found that the best PRS models performed similarly between held-out NLW and LAT samples (PseudoR 2 = 0.086 ± 0.023 in NLW vs. 0.060 ± 0.020 in LAT), and can be improved for LAT if we performed GWAS in LAT-only (PseudoR 2 = 0.116 ± 0.026) or multi-ancestry samples (PseudoR 2 = 0.131 ± 0.025). However, the best genomic models currently do not have better prediction accuracy than a conventional model using all known ALL-associated loci in the literature (PseudoR 2 = 0.166 ± 0.025), which includes loci from GWAS populations that we could not access to train genomic PRS models. Our results suggest that larger and more inclusive GWAS may be needed for genomic PRS to be useful for ALL. Moreover, the comparable performance between populations may suggest a more oligo-genic architecture for ALL, where some large effect loci may be shared between populations. Future PRS models that move away from the infinite causal loci assumption may further improve PRS for ALL.

Outdoor artificial light at night, air pollution, and risk of childhood acute lymphoblastic leukemia in the California Linkage Study of Early-Onset Cancers.

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.

Evaluating genomic polygenic risk scores for childhood acute lymphoblastic leukemia in Latinos.

The utility of polygenic risk score (PRS) models has not been comprehensively evaluated for childhood acute lymphoblastic leukemia (ALL), the most common type of cancer in children. Previous PRS models for ALL were based on significant loci observed in genome-wide association studies (GWASs), even though genomic PRS models have been shown to improve prediction performance for a number of complex diseases. In the United States, Latino (LAT) children have the highest risk of ALL, but the transferability of PRS models to LAT children has not been studied. In this study, we constructed and evaluated genomic PRS models based on either non-Latino White (NLW) GWAS or a multi-ancestry GWAS. We found that the best PRS models performed similarly between held-out NLW and LAT samples (PseudoR2 = 0.086 ± 0.023 in NLW vs. 0.060 ± 0.020 in LAT), and can be improved for LAT if we performed GWAS in LAT-only (PseudoR2 = 0.116 ± 0.026) or multi-ancestry samples (PseudoR2 = 0.131 ± 0.025). However, the best genomic models currently do not have better prediction accuracy than a conventional model using all known ALL-associated loci in the literature (PseudoR2 = 0.166 ± 0.025), which includes loci from GWAS populations that we could not access to train genomic PRS models. Our results suggest that larger and more inclusive GWASs may be needed for genomic PRS to be useful for ALL. Moreover, the comparable performance between populations may suggest a more oligogenic architecture for ALL, where some large effect loci may be shared between populations. Future PRS models that move away from the infinite causal loci assumption may further improve PRS for ALL.

Gene-Environment Analyses Reveal Novel Genetic Candidates with Prenatal Tobacco Exposure in Relation to Risk for Childhood Acute Lymphoblastic Leukemia.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. IMPACT: Despite the lack of an overall "main effect," tobacco exposure during pregnancy affects childhood ALL risk depending on specific genetic variants.

Birth characteristics and risk of meningioma in a population-based study in California.

Background: We evaluated the potential role of birth characteristics in the etiology of early-onset meningioma. Methods: Leveraging a population-based linkage of California birth records (from 1978 to 2015) and cancer registry data (from 1988 to 2015), we identified 362 nonmalignant meningioma cases aged 0-37 years and selected 18 100 controls matched on year of birth. Cases and controls were compared with regard to birth characteristics, with adjusted odds ratios (ORs) and 95% confidence intervals (CIs) estimated from unconditional multivariable logistic regression models. We also conducted stratified analyses by race/ethnicity and age. Results: Female sex (compared to male: OR = 1.43, 95% CI: 1.16 to 1.79; P < .01) and Black race (compared to White: OR = 1.46, 95% CI: 1.02 to 2.07; P = .04) were associated with higher risk of meningioma. Higher birth order (OR = 0.90, 95% CI: 0.81 to 0.99 per additional birth position; P = .04) was associated with a lower risk. No significant associations were observed between birthweight, gestational age, delivery mode, maternal age, or maternal education and meningioma risk. In the non-Latino White subgroup, higher birthweight was associated with a higher risk of meningioma (OR = 1.20, 95% CI: 1.02 to 1.41 per 500 grams; P = .03), but this was not recapitulated in the Latino subgroup. In age-stratified analyses, female sex was a risk factor for those diagnosed at the age of 20-37 years but not among younger individuals. Conclusions: In this large population-based study less prone to selection and recall bias, higher birth order was associated with a reduced risk of early-onset meningioma, while female sex and Black race were linked to an increased risk. There were also indications of differential associations by race/ethnicity and age of diagnosis.

Hispanic Ethnicity Differences in Birth Characteristics, Maternal Birthplace, and Risk of Early-Onset Hodgkin Lymphoma: A Population-Based Case-Control Study.

BACKGROUND: Hispanic ethnicity differences in the risk of early-onset Hodgkin lymphoma diagnosed at <40 years are understudied. We conducted a population-based case-control study to evaluate associations between birth characteristics and early-onset Hodgkin lymphoma with a focus on potential ethnic differences. METHODS: This study included 1,651 non-Hispanic White and 1,168 Hispanic cases with Hodgkin lymphoma endorsing a range of races diagnosed at the age of 0 to 37 years during 1988-2015 and 140,950 controls without cancer matched on race/ethnicity and year of birth from the California Linkage Study of Early-Onset Cancers. OR and 95% confidence intervals (CI) were estimated from multivariable logistic regression models. RESULTS: Having a foreign-born mother versus a United States-born mother (i.e., the reference group) was associated with an increased risk of early-onset Hodgkin lymphoma among non-Hispanic Whites (OR = 1.52; 95% CI, 1.31-1.76; P < 0.01) and a decreased risk among Hispanics (OR = 0.78; 95% CI, 0.69-0.88; P < 0.01). Among both race groups, risk of early-onset Hodgkin lymphoma increased with birthweight and maternal age (all Ptrends < 0.01). Among non-Hispanic Whites, each 5-year increase in maternal age (OR = 1.11; 95% CI, 1.04-1.18; Ptrend < 0.01) and paternal age (OR = 1.07; 95% CI, 1.02-1.13; Ptrend < 0.01) was associated with increased risk of early-onset Hodgkin lymphoma. Compared with female Hispanics, male Hispanics had an increased risk of early-onset Hodgkin lymphoma (OR = 1.26; 95% CI, 1.12-1.42; P < 0.01). CONCLUSIONS: Maternal birthplace may play a role in risk of early-onset Hodgkin lymphoma that differs by ethnicity. IMPACT: The ethnic differences observed between certain birth characteristics, maternal birthplace, and early-onset Hodgkin lymphoma raise questions about the underlying biological, generational, lifestyle, residential, and genetic contributions to the disease.

Proximity to endocrine-disrupting pesticides and risk of testicular germ cell tumors (TGCT) among adolescents: A population-based case-control study in California.

BACKGROUND: The incidence of testicular germ cell tumors (TGCT) is increasing steadily in the United States, particularly among Latinos. TGCT is thought to be initiated in utero and exposure to endocrine-disrupting chemicals, suspected contributors to TGCT pathogenesis, during this critical developmental period may contribute to the rise. OBJECTIVES: To assess the relationship between fetal exposure to agricultural endocrine-disrupting pesticides (EDPs) and TGCT risk among adolescents in a diverse population in California. METHODS: We conducted a registry-based case-control study of TGCT. Cases, diagnosed between 1997 and 2011, were 15-19 years of age (n = 381). Controls were matched on birth year and race/ethnicity (n = 762). Quantities (kilograms) of 33 pesticides applied within 3 km and 1 km radii of each individual's address before birth were estimated using the Pesticide Use Reporting database. Odds ratios (OR), 95% confidence intervals (CI), and population attributable risk (PAR) were calculated for each EDP (using log-2 transformed values). Risk models considered race/ethnicity, birth year, and neighborhood socioeconomic status. RESULTS: A doubling of nearby acephate applications (3 km and 1 km radii) and malathion applications (1 km radius) was associated with increased risks of TGCT among Latinos only (OR = 1.09; 95% CI:1.01-1.17; 1.30; 95% CI:1.08-1.57, and 1.19; 95% CI:1.01-1.39, respectively), whereas application of carbaryl within a 3 km radius increased TGCT risk in non-Latinos only (OR = 1.14, 95% CI:1.01-1.28). We estimate that acephate was associated with approximately 10% of the TGCT PAR, malathion with 3% and carbaryl with 1%. CONCLUSIONS: TGCT among adolescents in California was associated with prenatal residential proximity to acephate and malathion among Latinos, and with carbaryl among non-Latinos. These results suggest that the rise in TGCT risk among Latinos may be associated with exposure to these pesticides.

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.

Mode of Delivery, Birth Characteristics, and Early-Onset Non-Hodgkin Lymphoma in a Population-Based Case-Control Study.

BACKGROUND: The etiology of non-Hodgkin lymphoma (NHL) in children and in adolescents and young adults (AYA) is not well understood. METHODS: We evaluated potential associations between mode of delivery, birth characteristics, and NHL risk in a population-based case-control study, which included 3,064 cases of NHL [490 with Burkitt lymphoma, 981 with diffuse large B-cell lymphoma (DLBCL), and 978 with T-cell NHL) diagnosed at the age of 0 to 37 years in California during 1988 to 2015 and 153,200 controls frequency matched on year of birth. Odds ratios (OR) and 95% confidence intervals (CI) were estimated from an unconditional multivariable logistic regression model that included year of birth and birth characteristics. RESULTS: Individuals born via cesarean section had a decreased risk of pediatric Burkitt lymphoma (age 0-14 years; OR = 0.71, 95% CI: 0.51-0.99) and pediatric T-cell NHL (OR = 0.73, 95% CI: 0.55-0.97) compared with those born vaginally. Having a birth order of second (OR = 0.73, 95% CI: 0.57-0.93) or third or higher (OR = 0.76, 95% CI: 0.58-0.99) was associated with a lower risk of pediatric T-cell NHL compared with first-borns. AYA (age 15-37 years) with a heavier birthweight had an elevated risk of DLBCL (OR for each kg = 1.16, 95% CI: 1.00-1.35). Associations between other birth characteristics, including plurality, maternal age, maternal education, and NHL risk, also exhibited variations across subgroups based on age of diagnosis and histologic subtype. CONCLUSIONS: These findings support a role of mode of delivery and birth characteristics in the etiology of early-onset NHL. IMPACT: This study underscores the etiologic heterogeneity of early-onset NHL.

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.

A review and meta-analysis of red and processed meat consumption and breast cancer.

The relationship between meat consumption and breast cancer has been the focus of several epidemiological investigations, yet there has been no clear scientific consensus as to whether red or processed meat intake increases the risk of breast cancer. We conducted a comprehensive meta-analysis incorporating data from several recently published prospective studies of red or processed meat intake and breast cancer. In the meta-analysis utilising data from the Pooling Project publication (includes data from eight cohorts) combined with data from nine studies published between 2004 and 2009 and one study published in 1996, the fixed-effect summary relative risk estimate (SRRE) for red meat intake (high v. low) and breast cancer was 1·02 (95 % CI 0·98, 1·07; P value for heterogeneity = 0·001) and the random-effects SRRE was 1·07 (95 % CI 0·98, 1·17). The SRRE for each 100 g increment of red meat was 1·04 (95 % CI 1·00, 1·07), based on a fixed-effects model, and 1·12 (95 % CI 1·03, 1·23) based on a random-effects model. No association was observed for each 100 g increment of red meat among premenopausal women (SRRE 1·01; 95 % CI 0·92, 1·11) but a statistically significant SRRE of 1·22 (95 % CI 1·04, 1·44) was observed among postmenopausal women using a random-effects model. However, the association for postmenopausal women was attenuated and non-significant when using a fixed-effects model (SRRE 1·03; 95 % CI 0·98, 1·08). The fixed- and random-effect SRRE for high (v. low) processed meat intake and breast cancer were 1·00 (95 % CI 0·98, 1·01; P value for heterogeneity = 0·005) and 1·08 (95 % CI 1·01, 1·16), respectively. The fixed- and random-effect SRRE for each 30 g increment of processed meat were 1·03 (95 % CI 1·00, 1·06) and 1·06 (95 % CI 0·99, 1·14), respectively. Overall, weak positive summary associations were observed across all meta-analysis models, with the majority being non-statistically significant. Heterogeneity was evident in most analyses, summary associations were sensitive to the choice of analytical model (fixed v. random effects), and publication bias appeared to have produced slightly elevated summary associations. On the basis of this quantitative assessment, red meat and processed meat intake does not appear to be independently associated with increasing the risk of breast cancer, although further investigations of potential effect modifiers, such as analyses by hormone receptor status, may provide valuable insight to potential patterns of associations.