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Simple Summary: Leukemia is the most frequent cancer in children. While cure rates have improved, many children will not survive, and of those who do, the majority experience lifelong complications. As a result, understanding what increases or decreases the risk of leukemia is important to inform prevention. Following on earlier observations that taking B-vitamins (such as folate) before and during pregnancy reduces the risk of childhood leukemia, we conducted a study to directly measure 11 nutrients in the folate metabolism pathway that is central to DNA integrity. These measurements were done in blood samples collected at birth among 122 children with leukemia and 122 healthy children, using novel laboratory techniques. Our data showed that none of these nutrients measured at birth (therefore representing levels within the last weeks of pregnancy) distinguished children who later contracted childhood leukemia. Whether levels of these nutrients may be important at the time of conception or during the first trimester, which are critical periods for fetal development, should be further investigated. Leukemia is the most common cancer in children in industrialized countries, and its initiation often occurs prenatally. Folic acid is a key vitamin in the production and modification of DNA, and prenatal folic acid intake is known to reduce the risk of childhood leukemia. We characterized the one-carbon (folate) metabolism nutrients that may influence risk of childhood acute lymphoblastic leukemia (ALL) among 122 cases diagnosed at age 0–14 years during 1988–2011 and 122 controls matched on sex, age, and race/ethnicity. Using hydrophilic interaction chromatography (HILIC) applied to neonatal dried blood spots, we evaluated 11 folate pathway metabolites, overall and by sex, race/ethnicity, and age at diagnosis. To conduct the prediction analyses, the 244 samples were separated into learning (75%) and test (25%) sets, maintaining the matched pairings. The learning set was used to train classification methods which were evaluated on the test set. High classification error rates indicate that the folate pathway metabolites measured have little predictive capacity for pediatric ALL. In conclusion, the one-carbon metabolism nutrients measured at birth were unable to predict subsequent leukemia in children. These negative findings are reflective of the last weeks of pregnancy and our study does not address the impact of these nutrients at the time of conception or during the first trimester of pregnancy that are critical for the embryo's DNA methylation programming. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 (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 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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (©2022 American Association for Cancer Research.)

Background: Ependymoma is a histologically defined central nervous system tumor most commonly occurring in childhood. Population-level incidence differences by race/ethnicity are observed, with individuals of European ancestry at highest risk. We aimed to determine whether extent of European genetic ancestry is associated with ependymoma risk in US populations., Methods: In a multi-ethnic study of Californian children (327 cases, 1970 controls), we estimated the proportions of European, African, and Native American ancestry among recently admixed Hispanic and African American subjects and estimated European admixture among non-Hispanic white subjects using genome-wide data. We tested whether genome-wide ancestry differences were associated with ependymoma risk and performed admixture mapping to identify associations with local ancestry. We also evaluated race/ethnicity-stratified ependymoma incidence data from the Central Brain Tumor Registry of the United States (CBTRUS)., Results: CBTRUS data revealed that African American and Native American children have 33% and 36%, respectively, reduced incidence of ependymoma compared with non-Hispanic whites. In genetic analyses, a 20% increase in European ancestry was associated with a 1.31-fold higher odds of ependymoma among self-reported Hispanics and African Americans (95% CI: 1.08-1.59, Pmeta = 6.7 × 10-3). Additionally, eastern European ancestral substructure was associated with increased ependymoma risk in non-Hispanic whites (P = 0.030) and in Hispanics (P = 0.043). Admixture mapping revealed a peak at 20p13 associated with increased local European ancestry, and targeted fine-mapping identified a lead variant at rs6039499 near RSPO4 (odds ratio = 1.99; 95% CI: 1.45-2.73; P = 2.2 × 10-5) but which was not validated in an independent set of posterior fossa type A patients., Conclusions: Interethnic differences in ependymoma risk are recapitulated in the genomic ancestry of ependymoma patients, implicating regions to target in future association studies., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Testicular germ cell tumor (TGCT) incidence has increased over the last 40 years in the United States. In contrast to TGCT among infants, it is hypothesized that TGCT in adolescents and young men is the result of sex steroid hormone imbalance during early fetal development. However, little is known about the neonatal period when abrupt hormonal changes occur, and direct supporting evidence is scarce due to the difficulties in obtaining prediagnostic specimens. Methods: We conducted a population-based case-control study examining hormone levels at birth among 91 infants (0-4 years) and 276 adolescents (15-19 years) diagnosed with TGCT, and 344 matched controls. Estrogen and androgen levels were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) from archived newborn dried blood spots. Logistic regression models were used to estimate the association between each hormone level and TGCT risk. Results: Higher levels of androstenedione were associated with increased TGCT risk among adolescents [odds ratio (OR): 2.33, 95% confidence interval (CI): 1.37-3.97 for highest vs. lowest quartile; P trend = 0.003] but not among infants (OR: 0.70, 95% CI: 0.28-1.77). A similar pattern was observed for testosterone (OR: 1.73, 95% CI: 1.00-3.00,) although the trend was not significant ( P trend = 0.12). Associations were stronger among non-Hispanic white subjects, relative to Hispanics. There was no difference by tumor histologic subtype. Estriol (the only detectable estrogen) was not associated with TGCT risk in either age group. Conclusions: Higher levels of neonatal androgens were associated with increased risk of TGCT among adolescents, suggesting that early life hormone levels are related to the later development of TGCT. Impact: This is the first study with direct measures of sex steroid hormones to examine the relationship between estrogens and androgens at birth and risk of adolescent TGCT. Cancer Epidemiol Biomarkers Prev; 27(4); 488-95. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Objective: To utilize Mendelian randomization to estimate the causal association between low serum vitamin D concentrations, increased body mass index (BMI), and pediatric-onset multiple sclerosis (MS) using genetic risk scores (GRS)., Methods: We constructed an instrumental variable for vitamin D (vitD GRS) by computing a GRS for 3 genetic variants associated with levels of 25(OH)D in serum using the estimated effect of each risk variant. A BMI GRS was also created that incorporates the cumulative effect of 97 variants associated with BMI. Participants included non-Hispanic white individuals recruited from over 15 sites across the United States (n = 394 cases, 10,875 controls) and Sweden (n = 175 cases, 5,376 controls; total n = 16,820)., Results: Meta-analysis findings demonstrated that a vitD GRS associated with increasing levels of 25(OH)D in serum decreased the odds of pediatric-onset MS (odds ratio [OR] 0.72, 95% confidence interval [CI] 0.55, 0.94; p = 0.02) after controlling for sex, genetic ancestry, HLA-DRB1*15:01 , and over 100 non-human leukocyte antigen MS risk variants. A significant association between BMI GRS and pediatric disease onset was also demonstrated (OR 1.17, 95% CI 1.05, 1.30; p = 0.01) after adjusting for covariates. Estimates for each GRS were unchanged when considered together in a multivariable model., Conclusions: We provide evidence supporting independent and causal effects of decreased vitamin D levels and increased BMI on susceptibility to pediatric-onset MS., (© 2017 American Academy of Neurology.)

Incidence rates of childhood leukemia in the United States have steadily increased over the last several decades, but only recently have disparities in the increase in incidence been recognized. In the current analysis, Surveillance, Epidemiology and End Results (SEER) data were used to evaluate recent trends in the incidence of childhood leukemia diagnosed at age 0-19 years from 1992 to 2013, overall and by age, race/ethnicity, gender and histologic subtype. Hispanic White children were more likely than non-Hispanic White, non-Hispanic Black or non-Hispanic Asian children to be diagnosed with acute lymphocytic leukemia (ALL) from 2009 to 2013. From 1992 to 2013, a significant increase in ALL incidence was observed for Hispanic White children [annual percent change (APC) Hispanic  = 1.08, 95% CI: 0.59, 1.58]; no significant increase was observed for non-Hispanic White, Black or Asian children. ALL incidence increased by about 3% per year from 1992 to 2013 for Hispanic White children diagnosed from 15 to 19 years (APC = 2.67; 95% CI: 0.88, 4.49) and by 2% for those 10-14 years (APC = 2.09; 95% CI: 0.57, 3.63), while no significant increases in incidence were observed in non-Hispanic White, Black, or Asian children of the same age. Acute myeloid leukemia (AML) incidence increased among non-Hispanic White children under 1 year at diagnosis, and among Hispanic White children diagnosed at age 1-4. The increase in incidence rates of childhood ALL appears to be driven by rising rates in older Hispanic children (10-14, and 15-19 years). Future studies are needed to evaluate reasons for the increase in ALL among older Hispanic children., (© 2016 UICC.)

Hispanic children have a higher incidence of acute lymphoblastic leukemia (ALL) than non-Hispanic whites but tend to be diagnosed at older ages. In genome-wide association studies, Native American ancestry and polymorphisms in six genes have been associated with ALL risk. In multivariable regression models, we investigated whether genomic ancestry, inherited risk SNPs, or acquired somatic alterations were associated with differences in age at diagnosis in Hispanic children with B-cell ALL. Genome-wide array data were used to estimate each participant's percent membership in the three Hispanic ancestral populations: Native American, African, and European. Each 20% increase in European ancestry was associated with a six month younger age at diagnosis (95% CI = 0.36-11.6 months, P = 0.037). Correspondingly, each 20% increase in Native American ancestry was associated with a six-month older age at diagnosis (P = 0.037). Both the TEL-AML1 translocation and high-hyperdiploidy were associated with younger age at diagnosis (24.4 months, P = 2.0 x 10(-4) and 12.4 months, P = 0.011, respectively), while CDKN2A and IKZF1 deletions were associated with older age at diagnosis (19.7 months, P = 7.0 x 10(-4) and 18.1 months, P = 0.012, respectively). No associations with age at diagnosis were observed for RAS mutation, PAX5 deletion or for known heritable risk alleles in IKZF1, CDKN2A, PIP4K2A, GATA3, ARID5B, or CEBPE. Because younger age at diagnosis is associated with improved treatment outcomes for children with ALL, the effect of European ancestry on ALL survival may be mediated by its effect on age at diagnosis, or by proxy, its association with more treatable molecular subtypes of ALL., (© 2014 Wiley Periodicals, Inc.)

Background: Home and garden pesticide use has been linked to cancer and other health outcomes in numerous epidemiological studies. Exposure has generally been self-reported, so the assessment is potentially limited by recall bias and lack of information on specific chemicals., Objectives: As part of an integrated assessment of residential pesticide exposure, we identified active ingredients and described patterns of storage and use., Methods: During a home interview of 500 residentially stable households enrolled in the Northern California Childhood Leukemia Study during 2001-2006, trained interviewers inventoried residential pesticide products and queried participants about their storage and use. U.S. Environmental Protection Agency registration numbers, recorded from pesticide product labels, and pesticide chemical codes were matched to public databases to obtain information on active ingredients and chemical class. Poisson regression was used to identify independent predictors of pesticide storage. Analyses were restricted to 259 participating control households., Results: Ninety-five percent (246 of 259) of the control households stored at least one pesticide product (median, 4). Indicators of higher sociodemographic status predicted more products in storage. We identified the most common characteristics: storage areas (garage, 40%; kitchen, 20%), pests treated (ants, 33%; weeds, 20%), pesticide types (insecticides, 46%; herbicides, 24%), chemical classes (pyrethroids, 77%; botanicals, 50%), active ingredients (pyrethrins, 43%) and synergists (piperonyl butoxide, 42%). Products could contain multiple active ingredients., Conclusions: Our data on specific active ingredients and patterns of storage and use will inform future etiologic analyses of residential pesticide exposures from self-reported data, particularly among households with young children.