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Introduction: Children with congenital heart defects (CHD) have shorter life expectancy than the general population. Previous studies also suggest that patients with CHD have higher risk of cancer. This study aims to describe cancer-related mortality among patients with a history of CHD interventions using the Pediatric Cardiac Care Consortium (PCCC), a large US cohort of such patients., Methods: We performed a retrospective cohort study of individuals (<21 years) who underwent interventions for CHD in the PCCC from 1982 to 2003. Patients surviving their first intervention were linked to the National Death Index through 2020. Multivariable models assessed risk of cancer-related death, adjusting for age, sex, race, and ethnicity. Patients with/without genetic abnormalities (mostly Down syndrome [DS]) were considered separately, due to expected differential risk in cancer., Results: Among the 57,601 eligible patients in this study, cancer was the underlying or contributing cause of death for 208; with 20% among those with DS. Significantly increased risk of cancer-related death was apparent among patients with DS compared to the non-genetic group (aHR: 3.63, 95% confidence interval [CI]: 2.52-5.24, p < .001). For the group with non-genetic abnormalities, the highest association with cancer-related death compared to those with mild CHD was found among those with more severe CHD (severe two-ventricle aHR: 1.82, 95% CI: 1.04-3.20, p = .036, single-ventricle aHR: 4.68, 95% CI: 2.77-7.91, p < .001)., Conclusions: Patients with more severe forms of CHD are at increased risk for cancer-related death. Despite our findings, we are unable to distinguish whether having CHD raises the risk of cancer or reduces survival., (© 2024 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Background: Non-chromosomal birth defects are an important risk factor for several childhood cancers. However, these associations are less clear for Hodgkin lymphoma (HL). Therefore, we sought to more fully elucidate the association between non-chromosomal birth defects and HL risk., Procedure: Information on cases (n = 517) diagnosed with HL (ages of 0-14) at Children's Oncology Group Institutions for the period of 1989-2003 was obtained. Control children without a history of cancer (n = 784) were identified using random digit dialing and individually matched to cases on sex, race/ethnicity, age, and geographic location. Parents completed comprehensive interviews and answered questions including whether their child had been born with a non-chromosomal birth defect. To test the association between birth defects and HL risk, conditional logistic regression was applied to generate adjusted odds ratios (aORs) and 95% confidence intervals (CIs)., Results: Children born with any non-chromosomal birth defect were not more likely to be diagnosed with HL at 0-14 years of age (aOR: 0.91; 95% CI: 0.69-1.21). No associations were detected between major or minor birth defects and HL (aOR: 1.34; 95% CI: 0.67-2.67 and aOR: 0.88; 95% CI: 0.57-1.34, respectively). Similarly, no association was observed for children born with any birth defect and EBV-positive HL (aOR: 0.57; 95% CI: 0.25-1.26)., Conclusions: Previous assessments of HL in children with non-chromosomal birth defects have been limited. Using data from the largest case-control study of HL in those <15 years of age, we did not observe strong associations between being born with a birth defect and HL risk., (© 2023 Wiley Periodicals LLC.)

The Children's Oncology Group (COG) Epidemiology Committee has a primary focus on better understanding the etiologies of childhood cancers. Over the past 10 years, the committee has leveraged the Childhood Cancer Research Network, and now more recently Project:EveryChild (PEC), to conduct epidemiologic assessments of various childhood cancers, including osteosarcoma, neuroblastoma, germ cell tumors, Ewing sarcoma, rhabdomyosarcoma, and Langerhans cell histiocytosis. More recent studies have utilized questionnaire data collected as part of PEC to focus on specific characteristics and/or features, including the presence of congenital disorders and the availability of stored cord blood. Members of the COG Epidemiology Committee have also been involved in other large-scale National Institutes of Health efforts, including the Childhood Cancer Data Initiative and the Gabriella Miller Kids First Pediatric Research Program, which are improving our understanding of the factors associated with childhood cancer risk. Future plans will focus on addressing questions surrounding health disparities, utilizing novel biospecimens in COG epidemiology studies, exploring the role of environmental factors on the etiologies and outcomes of childhood cancer, collaborating with other COG committees to expand the role of epidemiology in childhood cancer research, and building new epidemiologic studies from the Molecular Characterization Initiative-all with the ultimate goal of developing novel prevention and intervention strategies for childhood cancer., (© 2023 Wiley Periodicals LLC.)

Although global differences in the incidence of neuroblastoma have been examined, the underlying mechanism has yet to be elucidated. Previous studies have suggested genetic ancestry and human development index (HDI) as contributing factors, but few studies have been conducted at the international level. Here, we aimed to examine whether the frequency of common genomic variation associated with neuroblastoma can affect its risk at the ecological level with consideration of the HDI. Minor allele frequencies (MAFs) for 22 single-nucleotide polymorphisms (SNPs) were abstracted from the Geography of Genetic Variants Browser. The number of incident neuroblastomas for each population was obtained from the Cancer Incidence in Five Continents series. Further, population pseudo-polygenic risk scores (pp-PRSs) were calculated as a sum of MAFs at the population level, each of which was weighted by effect sizes from prior studies. Negative binomial regression was used to estimate the incidence rate ratios (IRRs) and the 95% confidence intervals (CIs) to examine whether differences in MAFs across the population influence the risk of neuroblastoma, with and without adjustment for HDI and whether pp-PRSs can be a predictor of the risk of neuroblastoma. Overall, our results indicated that the neuroblastoma risk associated with variation in SNP frequency could not be differentiated from that of HDI at the ecological level. Additionally, pp-PRSs were not significantly associated with the risk of neuroblastoma (IRR: 0.99, 95% CI: 0.62-1.60). Further study using individual-level data is warranted to minimize the bias related to the use of population-level data in this study., (© 2022 Wiley Periodicals LLC.)

Background: Despite improvements in overall survival for pediatric cancers, treatment disparities remain for racial/ethnic minorities compared to non-Hispanic Whites; however, the impact of race on treatment outcomes for pediatric brain and central nervous system (CNS) tumors in the United States is not well known., Methods: We included 8713 children aged 0-19 years with newly diagnosed primary brain and CNS tumors between 2000 and 2015 from the Census Tract-level SES and Rurality Database developed by Surveillance, Epidemiology, and End Results (SEER) Program. We used chi-square tests to assess differences in sociodemographic, cancer, and treatment characteristics by race/ethnicity and Kaplan-Meier curves and Cox proportional hazards models to examine differences in 10-year survival, adjusting for these characteristics., Results: Among 8713 patients, 56.75% were non-Hispanic White, 9.59% non-Hispanic Black, 25.46% Hispanic, and 8.19% from "other" racial/ethnic groups. Median unadjusted survival for all pediatric brain tumors was 53 months, but varied significantly by race/ethnicity with a median survival of 62 months for non-Hispanic Whites, 41 months for non-Hispanic Blacks, and 40 months for Hispanic and other. Multivariable analyses demonstrated minority racial groups still had significantly higher hazard of death than non-Hispanic Whites; Hispanic (adjusted hazard ratio [aHR] 1.25 [1.18-1.31]); non-Hispanic Black (aHR 1.12 [1.04-1.21]); other (aHR 1.22 [1.12-1.32]). Results were consistent when stratified by tumor histology., Conclusion: We identified disparities in survival among racial/ethnic minorities with pediatric brain and CNS tumors, with Hispanic patients having the highest risk of mortality. Eliminating these disparities requires commitment toward promoting heath equity and personalized cancer treatment., (© 2020 Wiley Periodicals LLC.)

Background: The etiology of childhood cancers and its social patterning remains largely unknown. Accounting for socioeconomic status (SES) when exploring the association between race/ethnicity and cancer incidence is necessary to better understand such etiology. We aimed to investigate differences in the incidence of embryonal tumors (ETs) by SES and race/ethnicity in the United States using population-based registries of the Surveillance, Epidemiology, and End Results (SEER) Program., Procedure: Children with ETs aged 0-19 years diagnosed between 2000 and 2015 were ascertained from the census tract-level SEER database. SES was measured using a tract-level composite index. Incidence rate ratios (IRRs) with 95% confidence intervals (CIs) by SES quintile and race/ethnicity were estimated using multivariable Poisson regression models., Results: The majority of tumors had lower incidence among nonwhite children compared with non-Hispanic (NH) white children, after controlling for SES. NH blacks had a higher incidence of Wilms tumor than NH whites (IRR: 1.26; 95% CI, 1.13-1.39). There was an increasing linear trend (P = 0.0001) across increasing SES quintile for embryonal rhabdomyosarcoma after controlling for race/ethnicity. Effect modification by race/ethnicity of the relationship between SES and tumor incidence was observed for several groups. Hispanics had a significant, linear trend (P = 0.0005) in the incidence of Wilms tumor, while Asian/Pacific Islanders experienced a significant inverse trend (P = 0.0002)., Conclusions: Results from this study suggest differences in the incidence of several ETs by race/ethnicity and that these differences may be modified by SES. Investigation of potential risk factors that are socially patterned is warranted., (© 2020 Wiley Periodicals LLC.)

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., (© 2019 Wiley Periodicals, Inc.)

Background: Since 1975, childhood cancer incidence rates have gradually increased in the United States; however, few studies have conducted analyses across time to unpack this temporal rise. The aim of this study was to test the hypothesis that increasing cancer incidence rates are due to secular trends in pregnancy characteristics that are established risk factors for childhood cancer incidence including older maternal age, higher birthweight, and lower birth order. We also considered temporal trends in sociodemographic characteristics including race/ethnicity and poverty., Procedure: We conducted a time series county-level ecologic analysis using linked population-based data from Surveillance, Epidemiology, and End Results cancer registries (1975-2013), birth data from the National Center for Health Statistics (1970-2013), and sociodemographic data from the US Census (1970-2010). We estimated unadjusted and adjusted average annual percent changes (AAPCs) in incidence of combined (all diagnoses) and individual types of cancer among children, ages 0-4 years, from Poisson mixed models., Results: There was a statistically significant unadjusted temporal rise in incidence of combined childhood cancers (AAPC = 0.71%; 95% CI = 0.55-0.86), acute lymphoblastic leukemia (0.78%; 0.49-1.07), acute myeloid leukemia (1.86%; 1.13-2.59), central nervous system tumors (1.31%; 0.94-1.67), and hepatoblastoma (2.70%; 1.68-3.72). Adjustment for county-level maternal age reduced estimated AAPCs between 8% (hepatoblastoma) and 55% (combined). However, adjustment for other county characteristics did not attenuate AAPCs, and AAPCs remained significantly above 0% in models fully adjusted for county-level characteristics., Conclusion: Although rising maternal age may account for some of the increase in childhood cancer incidence over time, other factors, not considered in this analysis, may also contribute to temporal trends., (© 2017 Wiley Periodicals, Inc.)

Background: Rhabdomyosarcoma (RMS) is a rare, highly malignant tumor arising from primitive mesenchymal cells that differentiate into skeletal muscle. Relatively little is known about RMS susceptibility. Based on growing evidence regarding the role of early immunologic challenges on RMS development, we evaluated the role of infections and immunizations on this clinically significant pediatric malignancy., Procedure: RMS cases (n = 322) were enrolled from the third trial coordinated by the Intergroup Rhabdomyosarcoma Study Group. Population-based controls (n = 322) were pair matched to cases on race, sex, and age. The following immunizations were assessed: diphtheria, pertussis, and tetanus (DPT); measles, mumps, and rubella; and oral polio vaccine. We also evaluated if immunizations were complete versus incomplete. We examined selected infections including chickenpox, mumps, pneumonia, scarlet fever, rubella, rubeola, pertussis, mononucleosis, and lung infections. Conditional logistic regression models were used to calculate an odds ratio (OR) and 95% confidence interval (CI) for each exposure, adjusted for maternal education and total annual income., Results: Incomplete immunization schedules (OR = 5.30, 95% CI: 2.47-11.33) and incomplete DPT immunization (OR = 1.56, 95% CI: 1.06-2.29) were positively associated with childhood RMS. However, infections did not appear to be associated with childhood RMS., Conclusions: This is the largest study of RMS to date demonstrating a possible protective effect of immunizations against the development of childhood RMS. Further studies are needed to validate our findings. Our findings add to the growing body of literature, suggesting a protective role of routine vaccinations in childhood cancer and specifically in childhood RMS., (© 2016 Wiley Periodicals, Inc.)

Background: Osteosarcoma (OS) is the most common primary malignant bone tumor in many countries, with metastatic disease responsible for most patient deaths. This study compares the prevalence of metastatic OS at diagnosis across countries to inform the critical question of whether diagnostic delay or tumor biology drives metastases development prior to diagnosis., Procedure: A literature search of the PubMed database was conducted to compare the prevalence of metastatic disease at the time of OS diagnosis between countries. A pooled prevalence with 95% confidence intervals was calculated for each study meeting inclusion criteria. Studies were grouped for analysis based on human development index (HDI) scores., Results: Our analysis found an 18% (95% confidence interval [CI]: 15%, 20%) average global pooled proportion of metastasis at OS diagnosis. The average prevalence of metastasis at diagnosis increased as HDI groupings decreased, with very high HDI, high HDI, and medium/low HDI groups found to be 15% (95% CI: 13%, 17%), 20% (95% CI: 14%, 28%), and 31% (95% CI: 15%, 52%), respectively., Conclusions: Our evidence suggests there is a biological baseline for metastatic OS at diagnosis, which is observed in countries with very high HDI. In countries with medium/low HDI, where there are more barriers to accessing healthcare, the higher prevalence of metastasis may result from treatment delay or an artificial prevalence inflation due to patients with less severe symptoms not presenting to clinic. Additional research in countries with medium/low HDI may reveal that earlier detection and treatment could improve patient outcomes in those countries., (© 2016 Wiley Periodicals, Inc.)

Background: Hepatoblastoma is a malignancy of young children. Low birth weight is associated with significantly increased risk of hepatoblastoma and neonatal medical exposures are hypothesized as contributors. This study represents the largest case-control study of hepatoblastoma to date and aimed to define the role of neonatal exposures in hepatoblastoma risk among low birth weight children., Procedure: Incident hepatoblastoma cases who were born <2,500 g (N = 60), diagnosed between 2000 and 2008, were identified through the Children's Oncology Group. Controls were recruited through state birth registries (N = 51). Neonatal medical exposures were abstracted from medical records. Subjects from the Vermont Oxford Network were used for further comparisons, as were existing reports on neonatal medical exposures., Results: Case-control comparisons were hindered by poor matching within birth weight strata. Cases were smaller and received more aggressive neonatal treatment compared to controls, and reflected high correlation levels between birth weight and treatments. Similar difficulty was encountered when comparing cases to Vermont Oxford Network subjects; cases were smaller and required more aggressive neonatal therapy. Furthermore, it appears hepatoblastoma cases were exposed to a greater number of diagnostic X-rays than in case series previously reported in the neonatal literature., Conclusions: This study presents the largest case series of hepatoblastoma in <2,500 g birth weight infants with accompanying neonatal medical exposure data. Findings confirm that birth weight is highly correlated with exposure intensity, and neonatal exposures are themselves highly correlated, which hampers the identification of a causal exposure among hepatoblastoma cases. Experimental models or genetic susceptibility testing may be more revealing of etiology., (© 2014 Wiley Periodicals, Inc.)

Investigators worldwide have for over 40 years conducted case-control studies aimed at determining the causes of childhood cancer. The central challenge to conducting such research is the rarity of childhood cancer, thus many studies aggregate cases through clinical trials organizations such as COG. Rarity also precludes the use of prospective study designs, which are less prone to recall and selection biases. Despite these challenges a substantial literature on childhood cancer etiology has emerged but few strong environmental risk factors have been identified. Genetic studies are thus now coming to the fore with some success. The ultimate aim of epidemiologic studies is to reduce the population burden of childhood cancer by suggesting preventive measures or possibly by enabling early detection. Pediatr Blood Cancer 2013; 60: 1059-1062. © 2012 Wiley Periodicals, Inc., (Copyright © 2012 Wiley Periodicals, Inc.)

Although leukemia is the most common childhood cancer diagnosis, the subtype, acute myeloid leukemia (AML), is less common and fewer etiologic studies exist. This review summarizes the major risk factors for AML. We searched the literature using PubMed for articles on childhood AML and reviewed 180 articles. While few risk factors are definitive, we identified several with consistent evidence of a possible effect. Thorough analysis of genetic and epigenetic factors is missing from this literature and methodological issues are unresolved. Future studies should more closely examine causal mechanisms, improve exposure measurement, and include analysis using genetic and epigenetic factors., (Copyright © 2013 Wiley Periodicals, Inc.)

Background: The mixed lineage leukemia (MLL) gene is commonly rearranged in infant leukemia (IL). Genetic determinants of susceptibility to IL are unknown. Recent genome-wide association studies for childhood acute lymphoblastic leukemia (ALL) have identified susceptibility loci at IKZF1, ARID5B, and CEBPE., Procedure: We genotyped these loci in 171 infants with leukemia and 384 controls and evaluated associations overall, by subtype [ALL, acute myeloid leukemia (AML)], and by presence (+) or absence (-) of MLL rearrangements., Results: Homozygosity for a variant IKZF1 allele (rs11978267) increased risk of infant AML [Odds ratio (OR) = 3.9, 95% confidence interval (CI) = 1.8-8.4]; the increased risk was similar for AML/MLL+ and MLL- cases. In contrast, risk of ALL/MLL- was increased in infants homozygous for the IKZF1 variant (OR = 5.1, 95% CI = 1.8-14.5) but the variant did not modify risk of ALL/MLL+. For ARID5B (rs10821936), homozygosity for the variant allele increased risk for the ALL/MLL- subgroup only (OR = 7.2, 95% CI = 2.5-20.6). There was little evidence of an association with the CEBP variant (rs2239633)., Conclusion: IKZF1 is expressed in early hematopoiesis, including precursor myeloid cells. Our data provide the first evidence that IKZF1 modifies susceptibility to infant AML, irrespective of MLL rearrangements, and could provide important new etiologic insights into this rare and heterogeneous hematopoietic malignancy., (Copyright © 2012 Wiley Periodicals, Inc.)

Few causes of hepatoblastoma have been conclusively identified, mainly due to the extreme rarity of the disease. Inherited conditions including Familial Adenomatous Polyposis and Beckwith-Wiedemann Syndrome dramatically raise risk of hepatoblastoma but account for few cases overall. A small number of case-control studies investigating risk factors for sporadic hepatoblastoma have been conducted to date. Although most of these studies feature fewer than 200 cases, several clues have emerged. Most notably there is a roughly 20-fold increased risk of hepatoblastoma among children with very low birth weight (<1,500 g) and a doubling of risk among those with moderately low birth weight (1,500-2,500 g). A modicum of evidence points to a possible role of parental tobacco use prior to or during pregnancy in the causation of hepatoblastoma as well., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: High birth weight increases the risk of childhood acute lymphoid leukemia (ALL) through unknown mechanisms. Whether this risk is specific to ALL subtypes is unknown, and low case numbers have prevented investigation of the rarer leukemias. Here we address these associations using a large population-based dataset., Procedure: Using the National Registry of Childhood Tumors, birth weights of 7,826 leukemia cases, defined by immunophenotype and cytogenetic subgroup, were compared with those of 10,785 controls born in England and Wales between 1980 and 2007., Results: The risk for overall leukemia increases 7% with each 0.5 kg increase in birth weight (OR 1.07, 95%CI 1.04-1.10). This risk is limited to the lymphoid leukemias (OR 1.08, 95%CI 1.05-1.12) diagnosed between 1 and 9 years of age. Analysis by cytogenetic feature reveals that there appears to be association with specific chromosomal abnormality: the risk of tumors with high hyperdiploid karyotypes increases 12% per 0.5 kg increase in birth weight (OR 1.12, 95%CI 1.05-1.20), and t(1;19) tumors show an increased risk of 41% per 0.5 kg increase (OR 1.41, 95%CI 1.09-1.84). The risk of acute myeloid leukemia is elevated in high and low birth weight babies. There is no significant risk relationship to other leukemias or myeloproliferative diseases., Conclusions: Birth weight is a risk factor for ALL and AML. Other subtypes of the disease are not significantly affected. There appears to be association with specific chromosomal abnormality, which may aid our understanding of the development of childhood leukemia in utero., (Copyright © 2011 Wiley Periodicals, Inc.)

Background: Children with Down syndrome (DS) have about a 20-fold increased risk of developing leukemia. Early childhood infections may protect against acute lymphoid leukemia (ALL) in children with and without DS. We examined whether maternal infections and health conditions during pregnancy were associated with acute leukemia in children with DS., Procedure: We conducted a case-control study of 158 children with DS and leukemia (including 97 cases with acute lymphoblastic leukemia (ALL) and 61 cases with acute myeloid leukemia (AML)) and 173 children with DS during the period 1997-2002. Maternal interview included information about 14 maternal conditions during gestation that are likely to induce an inflammatory response. We evaluated their prevalence in cases and controls. Five of these were common enough to allow analyses by leukemia subtype., Results: Vaginal bleeding was the most frequent (18% cases, 25% controls) and was associated with a reduced risk (odds ratio (OR) = 0.57; 95% confidence interval (CI) = 0.33-0.99) for all cases combined. Other variables, while showing a potential trend toward reduced risk had effect estimates, which were imprecise and not statistically significant. In contrast, amniocentesis was marginally associated with an increased risk of AML (OR = 2.06, 95% CI = 0.90-4.69)., Conclusions: Data from this exploratory investigation suggest that some health conditions during pregnancy may be relevant in childhood leukemogenesis. Larger epidemiological studies and other model systems (animal, clinical studies) may provide a clearer picture of the potential association and mechanisms., ((c) 2009 Wiley-Liss, Inc.)

Studies suggest nearly a 20-fold increased risk of leukemia in individuals with Down syndrome. Most of this increased risk appears in the first few decades of life, with the highest incidence in children less than 5 years of age. It is unknown why children with Down syndrome are at such an increased risk of leukemia. With respect to environmental exposures, it will be important to investigate risk factors associated with childhood leukemia in general (including diagnostic x-rays, pesticides, and other occupational exposures) as well as experiences common to children with Down syndrome (including routine medical screening tests, increased susceptibility to infections, and increased vitamin deficiencies)., ((c) 2004 Wiley-Liss, Inc.)