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PDF file - 43K, Analysis of Birth Month in a Study of Leukemia Risk Among California Children Diagnosed Between 1988 and 2007.

PDF file - 222K, Analysis of age at First Exposure to an RSV Season in a Study of Leukemia Risk Among California Children Diagnosed Between 1999 and 2007.

Background: Epidemiologic studies indicate that infections in early childhood may protect against pediatric acute lymphoblastic leukemia (ALL).Methods: We identified 3,402 ALL cases among children 0 to 5 years of age using the California Cancer Registry. From California birth records we randomly selected controls in a 20:1 ratio and frequency matched them to cases by birth year. We investigated markers of exposure to infections, including month of birth, timing of birth in relation to influenza and respiratory syncytial virus (RSV) seasons, and birth order based on data from California birth certificates and national infection surveillance systems.Results: We observed an increased risk of ALL for spring and summer births, and for those first exposed to an influenza or RSV season at nine to twelve months of age compared with those exposed during the first three months of life, and this association was stronger among first born children [odds ratios (OR), 1.44 and 95% confidence intervals (CI), 1.13–1.82, for influenza exposure at nine to twelve months of age]. Decreased risk was observed with increasing birth order among non-Hispanic whites but not Hispanics (OR, 0.76 and 95% CI, 0.59–096, for fourth or higher birth order among whites).Conclusion: Our results support the hypothesis that infections in early childhood decrease risk of ALL.Impact: Our findings implicate early life exposure to infections as protective factors for ALL in young children. Cancer Epidemiol Biomarkers Prev; 23(7); 1195–203. ©2014 AACR.

The KMT2 family of genes is essential epigenetic regulators promoting gene expression. The gene family contains three subgroups, each with two paralogues: KMT2A and KMT2B; KMT2C and KMT2D; KMT2F and KMT2G. KMT2A-D are among the most frequent somatically altered genes in several different cancer types. Somatic KMT2A rearrangements are well-characterized in infant leukemia (IL), and growing evidence supports the role of additional family members (KMT2B, KMT2C, and KMT2D) in leukemogenesis. Enrichment of rare heterozygous frameshift variants in KMT2A and C has been reported in acute myeloid leukemia (AML), IL, and solid tumors. Currently, the non-synonymous variation, prevalence, and penetrance of these four genes are unknown.This study determined the prevalence of pathogenic/likely pathogenic (P/LP) germline KMT2A-D variants in a cancer-free adult population from the Genome Aggregation Database (gnomAD). Two methods of variant interpretation were utilized: a manual genomic variant interpretation and an automated ACMG pipeline.The ACMG pipeline identified considerably fewer P/LP variants (n = 89) compared to the manual method (n = 660) in all 4 genes. Consequently, the total P/LP prevalence and allele frequency (AF) were higher in the manual method (1:112, AF = 4.46E-03) than in ACMG (1:832, AF = 6.01E-04). Multiple ancestry-exclusive P/LP variants were identified along with an increased frequency in males compared to females. Many of these variants identified in this population database are also associated with severe juvenile conditions.These data demonstrate that putatively functional germline variation in these developmentally important genes is more common than previously appreciated and identification in cancer-free adults may indicate incomplete penetrance for many of these variants. Future research should examine a genetic predisposing role in IL and other pediatric cancers.

Black children have lower incidence yet worse survival than White and Latinx children with B-cell acute lymphoblastic leukemia (B-ALL). It is unclear how reported race/ethnicity (RRE) is associated with death in B-ALL after accounting for differentially expressed genes associated with genetic ancestry.Using Phase 1 and 2 NCI TARGET B-ALL cases (N = 273; RRE-Black = 21, RRE-White = 162, RRE-Latinx = 69, RRE-Other = 9, RRE-Unknown = 12), we estimated proportions of African (AFR), European (EUR), and Amerindian (AMR) genetic ancestry. We estimated hazard ratios (HR) and 95% confidence intervals (95% CI) between ancestry and death while adjusting for RRE and clinical measures. We identified genes associated with genetic ancestry and adjusted for them in RRE and death associations.Genetic ancestry varied within RRE (RRE-Black, AFR proportion: Mean: 78.5%, Range: 38.2%-93.6%; RRE-White, EUR proportion: Mean: 94%, Range: 1.6%-99.9%; RRE-Latinx, AMR proportion: Mean: 52.0%, Range: 1.2%-98.7%). We identified 10, 1, and 6 differentially expressed genes (pOur work highlights B-ALL survival differences by RRE after adjusting for ancestry differentially expressed genes suggesting other factors impacting survival are important.

Background Although advanced parental age has been definitively linked to pediatric acute lymphoblastic leukemia, studies of parental age and pediatric solid tumors have not reached firm conclusions. This analysis aimed to elucidate the relationship between parental age and pediatric solid tumors through meta-analysis of existing studies based in population registries. Methods We searched Medline (PubMed) and Embase for registry-based studies of parental age and solid tumors through March 2022. We performed random-effects meta-analysis to estimate pooled effects and 95% confidence intervals (CIs). All statistical tests were 2-sided. Results A total of 15 studies covering 10 childhood solid tumor types (30 323 cases and 3 499 934 controls) were included in this analysis. A 5-year increase in maternal age was associated with an increased risk of combined central nervous system tumors (odds ratio [OR] = 1.07, 95% CI = 1.04 to 1.10), ependymoma (OR = 1.19, 95% CI = 1.09 to 1.31), astrocytoma (OR = 1.10, 95% CI = 1.05 to 1.15), rhabdomyosarcoma (OR = 1.14, 95% CI = 1.03 to 1.25), and germ cell tumors (OR = 1.06, 95% CI = 1.00 to 1.12). A 5-year increase in paternal age was associated with an increased risk of non-Hodgkin lymphoma (OR = 1.06, 95% CI = 1.00 to 1.12). Conclusions This meta-analysis of registry-based analyses of parental age and childhood cancer supports the association between older maternal age and certain childhood solid cancers. There is also some evidence that paternal age may be associated with certain cancers such as non-Hodgkin lymphoma. However, as maternal and paternal age are highly correlated, disentangling potential independent causal effects of either factor will require large studies with extensive data on potential confounders.

Background: Recent investigations of malignant peripheral nerve sheath tumor (MPNST) survival have reported higher mortality among non-White individuals. However, previous analyses have not examined the impact of socioeconomic status (SES) on these observations. This study aims to characterize factors associated with cause-specific MPNST survival, including information related to census-tract-level SES (CT-SES). Methods: We identified 2,432 primary MPNSTs using the Surveillance, Epidemiology, and End Results (SEER) 18 (2000–2016) database. We used Cox proportional hazards modeling to estimate the effects of sex, race/ethnicity, CT-SES quintile, metastasis at diagnosis, tumor site, age at diagnosis, and treatment by surgery on survival. Models were fit in both the full population and, separately, stratified by race/ethnicity and age at diagnosis ( Results: In adjusted models, age at diagnosis, CT-SES, and metastasis at diagnosis were associated with mortality. In race/ethnicity-stratified analysis, higher CT-SES was found to improve survival only in the White population. Among those diagnosed before age 40, metastasis at diagnosis and American Indian/Alaska Native race/ethnicity were associated with mortality, and both Hispanic ethnicity and Asian/Pacific Islander race were suggestive for increased mortality. Among cases, diagnoses at age 40 and above, age at diagnosis, male sex, and CT-SES were associated with mortality. Conclusions: This analysis provides evidence that among pediatric and young adult patients, non-White populations experience inferior survival compared with Whites, independent of CT-SES. Our findings also suggest that the effect of CT-SES on MPNST survival may differ by racial/ethnic group. Impact: These findings suggest that barriers to healthcare for certain racial/ethnic groups extend beyond SES.

Background Incidence rates of pediatric cancers in the United States are typically reported in 5-year age groups, obscuring variation by single year of age. Additionally, racial and ethnic variation in incidence is typically presented in broad categories rather than by narrow age ranges. Methods The Surveillance, Epidemiology, and End Results (SEER) 18 data (2000-2017) were examined to calculate frequencies and age-adjusted incidence rates among individuals aged birth to 39 years. Incidence rate ratios (IRRs) and 95% confidence intervals (95% CIs) were estimated as the measure of association for rate comparisons by race and Hispanic origin overall and by single year of age. Results Several histologic types showed substantial variation in race/ethnicity-specific and overall rates by single year of age. Overall, Black children and young adults experienced substantially decreased incidence of acute lymphoid leukemia (IRR, 0.52; 95% CI, 0.49-0.55) compared to Whites, and this decreased incidence was strongest at ages 1 through 7 years and 16 through 20 years. Hispanic individuals experienced decreased overall incidence of Hodgkin lymphoma (IRR, 0.50; 95% CI, 0.48-0.52) and astrocytoma (IRR, 0.54; 95% CI, 0.52-0.56) and increased risk of acute lymphoblastic leukemia (IRR, 1.46; 95% CI, 1.42-1.51) compared to non-Hispanic Whites, and the increased risk was strongest at ages 10 through 23 years. Substantial decreased risk across many tumor types was also observed for Asian/Pacific Islanders and American Indian/Alaska Natives. Conclusions Examination of incidence rates for pediatric cancers by narrow age groups may provide insights regarding etiological differences in subgroups. Additionally, variation in age-specific incidence rates by race and ethnicity may enable hypothesis generation on drivers of disparities observed.

Fibrolamellar Carcinoma (FLC), a rare liver cancer, has yet no specific tools to evaluate its prognosis. This study aims, in partnership with the patient community, to search for associations between various demographic and clinical factors and overall survival of patients, to assess prognostic factors. We performed a retrospective analysis on a community-based patient registry (The Fibrolamellar Registry http://fibroregistry.org) to examine relations between survival and different variables. The variables examined were demographic (gender), clinical (age at diagnosis, tumor size, number of tumors inside the liver, presence of positive lymph nodes or distant metastasis) as well as treatment modalities (surgery or systemic therapy). Kaplan-Meier survival plots were created for the overall research population and for stratifying by unadjusted variables. Cox proportional hazards model was used for multivariable analysis of hazard ratio (HR) for death at any time among groups, adjusting for variables found significant in the univariate analysis. Among 150 patients, (89 females and 61 males), median overall survival time from diagnosis to death or loss of follow-up was 8 years and 2 months. Features with independent positive effect on survival were female gender, as well as being treated with surgery alone. In contrast, having 10 or more tumors inside the liver had a negative effect on survival. Positive lymph nodes at diagnosis, and distant metastasis at diagnosis, were both associated with poorer prognosis, though did not remain independent when adjusting for covariables. We could not find an effect of age at diagnosis or tumor size at its largest measurement, on survival. In conclusion, our study suggests gender is a significant prognostic factor for FLC patients, with females having a better outcome than males. Surgical removal of the tumor, without additional systemic therapy is a positive prognostic factor as well. Having a large number of tumors of 10 and above, despite all being inside the liver, is a negative prognostic factor. Citation Format: Amichai Berkovitz, Rachael D. Migler, Adam Qureshi, Roger Vaughan, Erin L. Marcotte, Sanford M. Simon. Clinical and demographic predictors of survival for fibrolamellar hepatocellular carcinoma patients - A patient-community registry-based study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2495.

Background: In recent decades, Cesarean section (C-section) rates have increased. C-section is hypothesized to negatively impact the developing immune system by altering activation of the hypothalamic–pituitary–adrenal axis and the infant microbiome, among other mechanisms, thereby potentially modulating childhood cancer risk. Methods: Using linked birth and cancer registry data from Minnesota (1976–2014), we included individuals ages 0–14 at diagnosis with one of 19 cancers. Cases and controls were frequency matched by birth year. We used logistic regression to estimate ORs and 95% confidence intervals (95% CI) as the measure of association between C-section and cancer. We assessed sex–C-section interactions for each cancer and conducted stratified analyses in acute lymphoblastic leukemia (ALL) for birth year, age at diagnosis, and maternal race. Results: There were 3,166 cases and 20,589 controls. One third (n = 1,174) of controls born during 2004–2014 were delivered via C-section compared with 42.2% of cases (n = 285). C-section was associated with ALL (n = 819; OR: 1.20; 95% CI: 1.01–1.43) and hepatoblastoma (n = 50; OR: 1.89; 95% CI: 1.03–3.48), particularly among females (ALL OR: 1.34; 95% CI: 1.04–1.72; hepatoblastoma OR: 3.87; 95% CI: 1.30–11.57). The risk of ALL was highest during 2005–2014 (OR: 1.62; 95% CI: 1.11–2.34) and among children ages 1–5 years (OR: 1.28; 95% CI: 1.02–1.61). Conclusions: C-section was associated with an increased risk of ALL and hepatoblastoma. Impact: These associations require investigation to determine causality and rule out confounding by indication or reverse causality. The mechanisms underlying these associations may depend on neonatal immune system processes altered during C-section deliveries.

Background There is a persistent, unexplained disparity in sex ratio among childhood cancer cases, whereby males are more likely to develop most cancers. This male predominance is also seen for most birth defects, which are strongly associated with risk of childhood cancer. We conducted mediation analysis to estimate whether the increased risk of cancer among males is partially explained by birth defect status. Methods We used a population-based birth cohort with linked data from birth certificates, birth defects registries, and cancer registries from Arkansas, Michigan, North Carolina, and Texas. We conducted counterfactual mediation analysis to estimate the natural direct and indirect effects of sex on cancer risk, modeling birth defect status as mediator. State; birth year; plurality; and maternal race and ethnicity, age, and education were considered confounders. We conducted separate analyses limited to cancers diagnosed younger than 1 year of age. Results Our dataset included 10 181 074 children: 15 110 diagnosed with cancer, 539 567 diagnosed with birth defects, and 2124 co-occurring cases. Birth defect status mediated 38% of the association between sex and cancer overall. The proportion mediated varied by cancer type, including acute myeloid leukemia (93%), neuroblastoma (35%), and non-Hodgkin lymphoma (6%). Among children younger than 1 year of age at cancer diagnosis, the proportion mediated was substantially higher (82%). Conclusions Our results suggest that birth defects mediate a statistically significant proportion of the relationship between sex and childhood cancer. The proportion mediated varied by cancer type and diagnosis age. These findings improve our understanding of the causal pathway underlying male sex as a risk factor for childhood cancer.

BACKGROUND: The incidence of malignant peripheral nerve sheath tumors (MPNSTs) is low in the general population, although individuals with Neurofibromatosis Type I (NF1) are particularly susceptible. These tumors generally have a high probability of metastasis. The rate and types of second malignancies (SMNs) after a primary diagnosis of MPNST are not well characterized. We aimed to quantify the rate of SMNs among individuals with a first primary MPNST using population-based data. METHODS: We estimated age-standardized incidence rates (SIRs) for SMNs among 1,579 primary MPNST cases between ages 0-85+ using SEER 18 (2000-2015). We estimated incidence rate ratios (IRRs) and 95% confidence intervals (95% CI) for SMNs in MPNST cases compared with general population rates. We conducted sex-stratified and age-restricted analyses (

Germ cell tumors (GCT) are a rare form of childhood cancer that originate from the primordial germ cell. Recent genome-wide association studies (GWAS) have identified susceptibility alleles for adult testicular GCT (TGCT). We test whether these SNPs are associated with GCT in pediatric and adolescent populations. This case-parent triad study includes individuals with GCT diagnosed between ages 0 and 19. We evaluated 26 SNPs from GWAS of adult TGCT and estimated main effects for pediatric GCT within complete trios (N = 366) using the transmission disequilibrium test. We used Estimation of Maternal, Imprinting and interaction effects using Multinomial modelling to evaluate maternal effects in non-Hispanic white trios and dyads (N = 244). We accounted for multiple comparisons using a Bonferroni correction. A variant in SPRY4 (rs4624820) was associated with reduced risk of GCT (OR [95% CI]: 0.70 [0.57, 0.86]). A variant in BAK1 (rs210138) was positively associated with GCT (OR [95% CI]: 1.70 [1.32, 2.18]), with a strong estimated effect for testis tumors (OR [95% CI]: 3.31 [1.89, 5.79]). Finally, a SNP in GAB2 (rs948662) was associated with increased risk for GCT (OR [95% CI]: 1.56 [1.20, 2.03]). Nominal associations (P

Studies of environmental exposures and childhood cancers that rely on records often only use maternal address at birth or address at cancer diagnosis to assess exposures in early childhood, possibly leading to exposure misclassification and questionable validity due to residential mobility during early childhood. Our objective was to assess patterns and identify factors that may predict residential mobility in early childhood, and examine the impact of mobility on early childhood exposure assessment for agriculturally applied pesticides and childhood cancers in California. We obtained the addresses at diagnosis of all childhood cancer cases born in 1998-2011 and diagnosed at 0-5 years of age (n = 6478) from the California Cancer Registry (CCR), and their birth addresses from linked birth certificates. Controls were randomly selected from California birth records and frequency matched (20:1) to all cases by year of birth. We obtained residential histories from a public-record database LexisNexis for both case (n = 3877 with age at diagnosis 1-5 years) and control (n = 99,262) families. Logistic regression analyses were conducted to assess the socio-demographic factors in relation to residential mobility in early childhood. We employed a Geographic Information System (GIS)-based system to estimate children's first year of life exposures to agriculturally applied pesticides based on birth vs diagnosis address or residential histories based upon Lexis-Nexis Public Records and assessed agreement between exposure measures using Spearman correlations and kappa statistics. Over 20% of case and control children moved in their first year of life, and 55% of children with cancer moved between birth and diagnosis. Older age at diagnosis, younger maternal age, lower maternal education, not having a Hispanic ethnic background, use of public health insurance, and non-metropolitan residence at birth were predictors of higher residential mobility. There was moderate to strong correlation (Spearman correlation = 0.76-0.83) and good agreement (kappa = 0.75-0.81) between the first year of life exposure estimates for agricultural pesticides applied within 2 km of a residence relying on an address at birth or at diagnosis or LexisNexis addresses; this did not differ by outcome status, but agreement decreased with decreasing buffer size, and increasing distance moved or age at diagnosis. These findings suggest that residential addresses collected at one point in time may represent residential history in early childhood to a reasonable extent; nevertheless, they exposure misclassification in the first year of life remains an issue. Also, the highest proportion of women not captured by LexisNexis were Hispanic women born in Mexico and those living in the lowest SES neighborhoods, i.e. possibly those with the higher environmental exposures, as well as younger women and those with less than high school education. Though LexisNexis only captures a sub-population, its data may be useful for augmenting address information and assessing the extent of exposure misclassification when estimating environmental exposures in large record linkage studies. Future research should investigate how to correct for exposure misclassification introduced by residential mobility that is not being captured by records.

BackgroundPediatric cancer incidence has been steadily increasing over the last several decades with the largest increases reported in infants. Few evaluations have looked at international pediatric cancer incidence trends in the youngest children. The aim of this analysis was to evaluate trends in cancer incidence in children under 5 years of age, overall and by type, using data from Cancer Incidence in 5 Continents (CI5) from 1988 to 2012 (CI5 volumes VII–XI).MethodsRates of cancers in children ages 0–4 years were extracted from registries available in CI5 from 1988 to 2012. To overcome small numbers in individual registries, numerators and denominators were aggregated within regions corresponding to the United Nations’ geoscheme. Average annual percent change (AAPC) was estimated using Poisson regression. Robust standard errors were used in all models to correct for overdispersion in some regions, and 95% Wald confidence intervals and P values were reported. The top five cancers by increasing AAPC were ranked within each region.ResultsOverall, in children under 5 years, increasing incidence was seen in multiple regions for acute lymphoblastic leukemia, acute myeloid leukemia, ependymal tumors, neuroblastoma, and hepatoblastoma. Hepatoblastoma had the largest AAPC in 11 out of 15 regions and showed an increase in all regions except southern Asia. Astrocytic tumors were the only cancer that decreased over the time period.ConclusionsWe evaluated 25 years of cancer incidence in children ages 0–4 years and observed increases in incidence for hepatoblastoma, leukemia, neuroblastoma, and ependymal tumors. Further etiologic evaluation will be required to explain these increases in incidence.

BACKGROUND: Parental age has been associated with several childhood cancers, albeit the evidence is still inconsistent. AIM: To examine the associations of parental age at birth with acute myeloid leukemia (AML) among children aged 0-14 years using individual-level data from the Childhood Leukemia International Consortium (CLIC) and non-CLIC studies. MATERIAL/METHODS: We analyzed data of 3182 incident AML cases and 8377 controls from 17 studies [seven registry-based case-control (RCC) studies and ten questionnaire-based case-control (QCC) studies]. AML risk in association with parental age was calculated using multiple logistic regression, meta-analyses, and pooled-effect estimates. Models were stratified by age at diagnosis (infants

Although substantial advances in the identification of cytogenomic subtypes of childhood acute lymphoblastic leukemia (ALL) have been made in recent decades, epidemiologic research characterizing the etiologic heterogeneity of ALL by subtype has not kept pace. The purpose of this review is to summarize the current literature concerning subtype-specific epidemiologic risk factor associations with ALL subtype defined by immunophenotype (e.g., B-cell vs. T-cell) and cytogenomics (including gross chromosomal events characterized by recurring numerical and structural abnormalities, along with cryptic balanced rearrangements, and focal gene deletions). In case–control analyses investigating nongenetic risk factors, home paint exposure is associated with hyperdiploid, MLL-rearranged, and ETV6-RUNX1 subtypes, yet there are few differences in risk factor associations between T- and B-ALL. Although the association between maternal smoking and ALL overall has been null, maternal smoking is associated with an increasing number of gene deletions among cases. GWAS-identified variants in ARID5B have been the most extensively studied and are strongly associated with hyperdiploid B-ALL. GATA3 single nucleotide variant rs3824662 shows a strong association with Ph-like ALL (OR = 3.14). However, there have been relatively few population-based studies of adequate sample size to uncover risk factors that may define etiologic heterogeneity between and within the currently defined cytogenomic ALL subtypes.

It is estimated that 300,000 children 0-14 years of age are diagnosed with cancer worldwide each year. While the absolute risk of cancer in children is low, it is the leading cause of death due to disease in children in high-income countries. In spite of this, the etiologies of pediatric cancer are largely unknown. Environmental exposures have long been thought to play an etiologic role. However, to date, there are few well-established environmental risk factors for pediatric malignancies, likely due to technical barriers in collecting biological samples prospectively in pediatric populations for direct measurements. In this review, we propose the use of novel or underutilized biospecimens (dried blood spots and teeth) and molecular approaches for exposure assessment (epigenetics, metabolomics, and somatic mutational profiles). Future epidemiologic studies of pediatric cancer should incorporate novel exposure assessment methodologies, data on molecular features of tumors, and a more complete assessment of gene-environment interactions.

Background: There is a persistent yet unexplained disparity in the sex ratio among childhood cancer cases, whereby males are more likely to develop several cancers. These patterns are also seen for most birth defects, which are strongly associated with the risk of childhood cancer. We conducted a mediation analysis to estimate whether birth defect status mediates the association between sex and childhood cancer risk. Methods: We linked data from birth, birth defects, and cancer registries to obtain a population-based birth cohort including births from 1992-2013 in Arkansas, Michigan, North Carolina, and Texas. We obtained birth defects diagnoses, including chromosomal and nonchromosomal defects, from statewide, population-based birth defects registries. We focused on “major” defects as defined by the National Birth Defects Prevention Network and the National Birth Defects Prevention Study. Cancer diagnoses that occurred prior to age 18 years were obtained from state cancer registries. We obtained data on child’s sex, birth weight, gestational age, maternal race/ethnicity, maternal age, and plurality from birth records. We conducted counterfactual mediation analysis to estimate the direct and indirect effects of sex on risk of childhood cancer, modeling sex as the exposure, birth defect status as the mediator, and cancer type as the outcome. State, maternal race/ethnicity (white, black, other), maternal age (continuous), and plurality (singleton vs. multiple) were considered potential mediator-outcome confounders. Due to lower success rates of linkage to birth records among adolescent cancer cases, we conducted a sensitivity analysis limiting to cancers diagnosed at age < 5 years. Results: Our dataset included 10,181,074 children (5,208,379 males; 4,972,695 females), including 15,110 with cancer diagnoses (8044 males; 7066 females), 539,567 children with birth defects diagnoses (320,666 males; 218,901 females), and 2,124 co-occurring cases (children with both cancer and one or more birth defect diagnosis: 1,186 males; 938 females). We observed mediation of the association between sex and childhood cancer overall by birth defect status (proportion mediated [PM]: 38%). In analyses of specific cancer types, we observed variation of the estimated proportion mediated among several cancers, including hepatoblastoma (PM: 33%), neuroblastoma (PM: 35%), non-Hodgkin lymphoma (PM: 6%), and soft tissue sarcomas (PM: 25%). In analysis of children age < 5 years at cancer diagnosis, we observed similar results. Conclusions: Our results suggest that birth defects mediate a significant proportion of the overall relationship between sex and childhood cancer. While approximately 60% of the male excess in childhood cancer cases remains unexplained, these findings add to our understanding of the causal pathway of male sex as a risk factor for childhood cancer. Additional studies are under way to characterize the biology underlying these observations. This abstract is also being presented as Poster A66. Citation Format: Erin L. Marcotte, Jeremy M. Schraw, Tania A. Desrosiers, Wendy N. Nembhard, Peter H. Langlois, Mark A. Canfield, Robert E. Meyer, Sharon E. Plon, Philip Lupo. Sex ratio disparities and the risk of childhood cancer: Evaluating the mediating effect of birth defects among 15,000 childhood cancer cases [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr PR03.

The causes of childhood cancer have been systematically studied for several decades, but apart from high-dose radiation and prior chemotherapy there are few or no strong external risk factors. On the other hand, inherent risk factors including birth weight, parental age, and congenital anomalies are consistently associated with most types of pediatric cancer. Rare, highly-penetrant syndromes have long been known to cause a small proportion of cancers but recently the contribution of common genetic variation to etiology has come into focus through genome wide association studies. These have highlighted genes not previously implicated in childhood cancers and, surprisingly, have suggested that common variation explains a larger proportion of childhood cancers than adult. Rare variation and non-Mendelian inheritance, such as through maternal genetic effects or de novo germline mutations, may also contribute to childhood cancer risk but have not been widely examined to date.

BACKGROUND Infant leukaemia (IL) is extremely rare with fewer than 150 cases occurring each year in the United States. Little is known about its causes. However, recent evidence supports a role of de novo mutations in IL aetiology. Parental age has been associated with several adverse outcomes in offspring, including childhood cancers. Given the role of older parental age in de novo mutations in offspring, we carried out an analysis of parental age and IL. METHODS We evaluated the relationship between parental age and IL in a case-control study using registry data from New York, Minnesota, California, Texas, and Washington. Records from 402 cases [219 acute lymphoblastic leukaemia (ALL), 131 acute myeloid leukaemia (AML), and 52 other] and 45 392 controls born during 1981-2004 were analysed. Odds ratios (OR) and 95% confidence intervals (CI) were calculated by logistic regression. Estimates were adjusted for infant sex, birth year category, maternal race, state, and mutually adjusted for paternal or maternal age, respectively. RESULTS Infants with mothers' age ≥40 years had an increased risk of developing AML (OR 4.80, 95% CI 1.80, 12.76). In contrast, paternal age

Background: Studies have reported increased risks of pediatric acute lymphoblastic leukemia (ALL) among children born by cesarean delivery (CD). However, no previous study has examined the impact of CD on risk of infant leukemia specifically. Methods: In this study, 443 infants diagnosed with acute leukemia, including both ALL and acute myelogenous leukemia (AML), were identified at Children's Oncology Group institutions between January 1996 and December 2006; 324 controls frequency matched by year of birth were identified though random digit dialing and random selection from U.S. birth registries. Using interview data and, for a subset of participants, medical record data, we analyzed CD overall and by indications that likely resulted in pre-labor CD (PLCD) or emergency CD (ECD). Odds ratios (ORs) and 95% confidence intervals (CIs) for risk of ALL and AML were estimated using multivariable unconditional logistic regression models, adjusted for year of birth, birth weight, and maternal race. Results: We observed an increased point estimate for the association between CD and ALL (OR, 1.52 and 95% CI, 1.02–2.25). We did not observe an association between CD and AML (OR, 1.02 and 95% CI, 0.64–1.62). In analyses of indication for CD, we observed elevated effect estimates for the associations of both PLCD and ECD and infant ALL. Conclusions: Our analysis suggests an increased risk of infant ALL following CD, including both PLCD and ECD. Altered microbiota colonization may be involved in development of leukemia in infants, but clear biological mechanisms have yet to be determined. Impact: This study provides the first in-depth examination of CD and infant leukemia. Cancer Epidemiol Biomarkers Prev; 27(4); 473–8. ©2018 AACR.

Background: Epidemiologic studies indicate that infections in early childhood may protect against pediatric acute lymphoblastic leukemia (ALL). Methods: We identified 3,402 ALL cases among children 0 to 5 years of age using the California Cancer Registry. From California birth records we randomly selected controls in a 20:1 ratio and frequency matched them to cases by birth year. We investigated markers of exposure to infections, including month of birth, timing of birth in relation to influenza and respiratory syncytial virus (RSV) seasons, and birth order based on data from California birth certificates and national infection surveillance systems. Results: We observed an increased risk of ALL for spring and summer births, and for those first exposed to an influenza or RSV season at nine to twelve months of age compared with those exposed during the first three months of life, and this association was stronger among first born children [odds ratios (OR), 1.44 and 95% confidence intervals (CI), 1.13–1.82, for influenza exposure at nine to twelve months of age]. Decreased risk was observed with increasing birth order among non-Hispanic whites but not Hispanics (OR, 0.76 and 95% CI, 0.59–096, for fourth or higher birth order among whites). Conclusion: Our results support the hypothesis that infections in early childhood decrease risk of ALL. Impact: Our findings implicate early life exposure to infections as protective factors for ALL in young children. Cancer Epidemiol Biomarkers Prev; 23(7); 1195–203. ©2014 AACR.

BackgroundLymphoma is the third most common childhood malignancy and comprises two types, Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). The etiology of pediatric lymphomas is largely unknown, but has been suggested to have prenatal origins.MethodsIn this population-based study, California birth certificates were identified for 478 lymphoma cases diagnosed in children 0-5 years of age between 1988 and 2007; 208,015 controls frequency-matched by birth year were randomly selected from California birth records.ResultsCompared to non-Hispanic whites, Hispanic children had an increased risk of HL (odds ratio (OR) and 95% confidence interval (CI) 2.43 [1.14, 5.17]), and in particular, were diagnosed more often with the mixed cellularity subtype. For all types of lymphoma, we observed an about twofold risk increase with indicators for high risk pregnancies including tocolysis, fetopelvic disproportion and previous preterm birth. NHL risk doubled with the complication premature rupture of membranes (OR and 95% CI 2.18 [1.12, 4.25]) and HL with meconium staining of amniotic fluids (OR and 95% CI 2.55 [1.01, 6.43]).ConclusionThese data support previously reported associations between Hispanic ethnicity and HL and suggest that pregnancy related factors, such as intra-uterine infections and factors associated with preterm labor, may be involved in lymphoma pathogenesis.

Background The male excess in childhood cancer incidence is well-established; however, the underlying biologic mechanisms remain unknown. Examining the association between male sex and childhood cancer by single year of age and tumor type may highlight important periods of risk such as variation in growth and hormonal changes, which will inform etiologic hypotheses. Methods Using data from the Surveillance, Epidemiology, and End Results (SEER) 18 registries (2000-2015), incidence rate ratios (IRR) and 95% confidence intervals (95% CI) were estimated as the measure of association between male sex and childhood cancer by single year of age (0-19). Results The IRR for male cancer overall was 1.19 (95% CI, 1.18-1.20) and was similar in magnitude at nearly every year of age. Burkitt lymphoma was strongly associated with male sex (IRRs ≥2 at each year of age). Increased incidence was observed among males for acute lymphoblastic leukemia, Hodgkin and non-Hodgkin lymphomas for nearly all years of age. Medulloblastoma was the only central nervous system tumor with a significant male predominance at nearly every age. Male sex displayed a consistent inverse association with nephroblastoma and thyroid carcinoma over the ages studied. Conclusions Male sex was positively associated with most cancers. The higher incidence rates observed in males remained consistent over the childhood and adolescent periods, suggesting that childhood and adolescent hormonal fluctuations may not be the primary driving factor for the sex disparities in childhood cancer. The observed incidence disparities may be due to sex differences in exposures, genetics, or immune responses.

Germ cell tumors (GCT) are a rare form of childhood cancer that originate from the primordial germ cell. Recent genome-wide association studies (GWAS) have identified susceptibility alleles for adult testicular GCT (TGCT). We test whether these SNPs are associated with GCT in pediatric and adolescent populations. This case-parent triad study includes individuals with GCT diagnosed between ages 0 and 19. We evaluated 26 SNPs from GWAS of adult TGCT and estimated main effects for pediatric GCT within complete trios (N = 366) using the transmission disequilibrium test. We used Estimation of Maternal, Imprinting and interaction effects using Multinomial modelling to evaluate maternal effects in non-Hispanic white trios and dyads (N = 244). We accounted for multiple comparisons using a Bonferroni correction. A variant in SPRY4 (rs4624820) was associated with reduced risk of GCT (OR [95% CI]: 0.70 [0.57, 0.86]). A variant in BAK1 (rs210138) was positively associated with GCT (OR [95% CI]: 1.70 [1.32, 2.18]), with a strong estimated effect for testis tumors (OR [95% CI]: 3.31 [1.89, 5.79]). Finally, a SNP in GAB2 (rs948662) was associated with increased risk for GCT (OR [95% CI]: 1.56 [1.20, 2.03]). Nominal associations (P 0.05) were noted for eight additional loci. A maternal effect was observed for KITLG SNP rs4474514 (OR [95% CI]: 1.66 [1.21, 2.28]) and a paternal parent-of-origin effect was observed for rs7221274 (P = 0.00007), near TEX14, RAD51C, and PPM1E. We observed associations between SNPs in SPRY4, BAK1, and GAB2 and GCTs. This analysis suggests there may be common genetic risk factors for GCT in all age groups.

Background and purpose Non-motor symptoms including depression are important features of Parkinson's disease (PD). We aim to address the relationship between major life events and depression amongst PD patients free of depressive symptoms at baseline. Methods New-onset PD patients from California were recruited in 2001–2007 and followed up for 3–4 years. The participants (n = 221) were examined by neurologists and responded to comprehensive interviews that included major life events, social support, and coping measures from validated scales. Major depression was assessed using the Structured Clinical Interview for the DSM-IV depression module (SCID). Results More than half of all patients had experienced major life events since diagnosed with PD, and 22 patients developed a major depression. The number of life events was associated with risk of depression in an exposure-dependent manner, with each additional event being associated with a 56% higher risk of depression (95% CI: 1.23–1.98). Most individual life events were associated with a two- to eight-fold higher risk of depression. Patients with low social support or coping capacities seemed to be particularly susceptible to developing depression after experiencing major life events. Conclusions Life events play an important role for onset of depression in patients with PD; an effect that seems to be modulated by social support and coping capacities and these factors may therefore be important to assess in order to identify patients with PD at high risk of depression and provide effective interventions.

Introduction. Hepatoblastoma (HB) accounts for over 80% of all liver cancer diagnosed in children under 15 years of age in the United States. Aberrant DNA methylation has been implicated in the pathogenesis of multiple types of cancer, including HB. Global hypomethylation and DNA methylation in the promoter region of selected tumor suppressor genes, including RASSF1A, p16, SOCS1, CASP8, and MT1G, has been observed in previous studies of HB. Methods. A total of 47 flash-frozen samples of HB tumors were available for analysis. These tumors include 26 tumors from cases enrolled in Children's Oncology Group study AEPI04C1 (the HOPE study) and 21 tumors obtained as part of the Children's Oncology Group P9346 HB biology protocol. The Cooperative Human Tissue Network Pediatric Division (CHTN; Columbus, OH) provided 23 normal liver tissue samples from children ages 0—6 to serve as controls in this analysis. Initial multi-dimensional scaling (MDS) plots showed that 8 samples, 2 control and 6 patients, did not cluster with the other samples of the same group and were considered outliers. These 8 samples were removed from the study leaving a total of 62 samples, 21 control and 41 patients, remaining. Differentially methylated regions (DMR) were identified between control and patient samples using the bumphunter algorithm included in the minfi package. We used Ingenuity Pathway Analysis (IPA) to identify pathways that were enriched in the group of CpG with a change in methylation beta value of ≥39% between patients and controls. Results. We found 4833 DMR, which are associated with 3543 genes, when comparing HB patients and controls. Pathway analysis revealed 76 pathways enriched among the DMR. Conclusions. Identification of methylation patterns may elucidate the developmental stage at which HB arose and the at-risk period when environmental exposures could be most harmful. Further, understanding the relevant genetic pathways could lead to the development of new targets for therapy. Citation Format: Erin Marcotte, Logan G. Spector, Heather Nelson, Gail Tomlinson, Mark Krailo, Lauren Mills, Jenny Poynter. Methylation patterns in hepatoblastoma: A report from the Children's Oncology Group [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5336.

Results from case-control studies have shown an increased risk of acute lymphoblastic leukaemia (ALL) in young children born by caesarean delivery, and prelabour caesarean delivery in particular; however, an association of method of delivery with childhood leukaemia subtypes has yet to be established. We therefore did a pooled analysis of data to investigate the association between childhood leukaemia and caesarean delivery. Methods: We pooled data from 13 case-control studies from the Childhood Leukemia International Consortium done in nine countries (Canada, Costa Rica, Egypt, France, Germany, Greece, Italy, New Zealand, and the USA) for births from 1970-2013. We analysed caesarean delivery overall and by indications that probably resulted in prelabour caesarean delivery or emergency caesarean delivery. We used multivariable logistic regression models, adjusted for child's birthweight, sex, age, ethnic origin, parental education, maternal age, and study, to estimate odds ratios (ORs) and 95% CIs for the risk of ALL and acute myeloid leukaemia (AML) in children aged 0-14 years at diagnosis. Findings: The studies provided data for 8780 ALL cases, 1332 AML cases, and 23 459 controls, of which the birth delivery method was known for 8655 (99%) ALL cases, 1292 (97%) AML cases, and 23 351 (>99%) controls. Indications for caesarean delivery were available in four studies (there were caesarean deliveries for 1061 of 4313 ALL cases, 138 of 664 AML cases, and 1401 of 5884 controls). The OR for all indications of caesarean delivery and ALL was 1·06 (95% CI 0·99-1·13), and was significant for prelabour caesarean delivery and ALL (1·23 [1·04-1·47]; p=0·018). Emergency caesarean delivery was not associated with ALL (OR 1·02 [95% CI 0·81-1·30]). AML was not associated with caesarean delivery (all indications OR 0·99 [95% CI 0·84-1·17]; prelabour caesarean delivery 0·83 [0·54-1·26]; and emergency caesarean delivery 1·05 [0·63-1·77]). Interpretation: Our results suggest an increased risk of childhood ALL after prelabour caesarean delivery. If this association is causal, maladaptive immune activation due to an absence of stress response before birth in children born by prelabour caesarean delivery could be considered as a potential mechanism. Funding: National Cancer Institute. © 2016 Elsevier Ltd. Los resultados de los estudios de casos y controles han mostrado un mayor riesgo de leucemia linfoblástica aguda (LLA) en los niños pequeños nacidos por cesárea, y en particular el parto por cesárea antes del trabajo de parto; sin embargo, aún no se ha establecido una asociación del método de parto con los subtipos de leucemia infantil. Por lo tanto, hicimos un análisis combinado de datos para investigar la asociación entre la leucemia infantil y el parto por cesárea. Métodos: reunimos datos de 13 estudios de casos y controles del Consorcio Internacional de Leucemia Infantil realizados en nueve países (Canadá, Costa Rica, Egipto, Francia, Alemania, Grecia, Italia, Nueva Zelanda y los EE. UU.) Para los nacimientos de 1970 a 2013. . Analizamos el parto por cesárea en general y por indicaciones que probablemente dieron como resultado un parto por cesárea antes del trabajo de parto o un parto por cesárea de emergencia. Usamos modelos de regresión logística multivariable, ajustados por el peso al nacer, el sexo, la edad, el origen étnico, la educación de los padres, la edad materna y el estudio, para estimar los odds ratios (OR) y los IC del 95% para el riesgo de LLA y leucemia mieloide aguda (AML ) en niños de 0 a 14 años en el momento del diagnóstico. Hallazgos: Los estudios proporcionaron datos para 8780 casos de LLA, 1332 casos de LMA y 23459 controles, de los cuales se conocía el método de parto para 8655 (99%) casos de LLA, 1292 (97%) casos de LMA y 23351 (> 99%) controles. Las indicaciones para el parto por cesárea estaban disponibles en cuatro estudios (hubo partos por cesárea para 1061 de 4313 casos de LLA, 138 de 664 casos de LMA y 1401 de 5884 controles). El OR para todas las indicaciones de parto por cesárea y LLA fue 1 · 06 (IC 95% 0 · 99-1 · 13), y fue significativo para el parto por cesárea antes del trabajo de parto y LLA (1 · 23 [1 · 04-1 · 47]; p = 0 · 018). El parto por cesárea de emergencia no se asoció con la LLA (OR 1 · 02 [IC 95% 0 · 81-1 · 30]). La LMA no se asoció con el parto por cesárea (todas las indicaciones OR 0 · 99 [IC 95% 0 · 84-1 · 17]; parto por cesárea antes del trabajo de parto 0 · 83 [0 · 54-1 · 26]; y parto por cesárea de emergencia 1 · 05 [0 · 63-1 · 77]). Interpretación: Nuestros resultados sugieren un mayor riesgo de LLA infantil después del parto por cesárea antes del trabajo de parto. Si esta asociación es causal, la activación inmune desadaptativa debida a una ausencia de respuesta al estrés antes del nacimiento en los niños nacidos por cesárea antes del trabajo de parto podría considerarse como un mecanismo potencial. Financiamiento: Instituto Nacional del Cáncer.  © 2016 Elsevier Ltd. University of Minnesota, USA University of Athens, Greece McGill University, Canada Epidemiology of Childhood and Adolescent Cancers Team, France International Agency for Research on Cancer, France Menoufia University, Egypt University of Otago, New Zealand University of California, USA Università del Piemonte Orientale, Italy Baylor College of Medicine, USA Texas Children’s Cancer Center, USA University of Washington School of Public Health, USA Universidad Nacional, Costa Rica Boston University, USA Akademiska Sjukhuset, Sweden Children’s Cancer Hospital Egypt, Egypt University of California, USA Instituto Regional de Estudios en Sustancias Tóxicas

Background Betel quid is chewed by 600 million people worldwide and it has been linked to obesity and cardiovascular disease. The purpose of our study was to examine the prevalence and predictors of betel quid chewing in a rural area of Bangladesh, and determine its effects on body mass index (BMI) and blood pressure. Methods In this population-based prospective study, we analysed data on 19 934 Bangladeshi adults. Linear and multivariate logistic regression was used to determine the socio-demographic predictors of betel quid chewing and the effect of betel quid on change in BMI and on systolic and diastolic blood pressure, pulse pressure, arterial pressure, overweight or obesity, and hypertension. Results At baseline, betel quid was chewed by 33.2% of the cohort (35.5% of men, 31.6% of women). In a subsample in which we collected methods of use, 17.5% chewed it without tobacco and 82.5% chewed it with tobacco. In multivariate analysis, betel quid chewing was associated with female sex, older age, tobacco smoking and lower socio-economic status, as measured by fewer years of formal education and not owning land. Betel quid was chewed more times per day among women and older persons. At follow-up, persons who chewed betel quid without tobacco had higher systolic blood pressure, diastolic blood pressure and arterial pressure in comparison with never users. After controlling for other explanatory variables, chewing betel quid without tobacco was associated with general hypertension [odds ratio (OR) 1.48, 95% confidence interval (CI) 1.04–2.10] and systolic hypertension (OR 1.55, 95% CI 1.01–2.37). We did not observe associations of betel quid chewing with BMI or overweight. Conclusions Betel quid chewing is likely contributing to high blood pressure in Bangladesh, particularly among women.