<p>Background: Hepatoblastoma (HB) is a rare embryonal liver tumor, with a rising global incidence that underscores the need to understand its genetic etiology. Methods: Utilizing the ancestry-matched expression quantitative loci data, we performed a HB transcriptome-wide association study (TWAS) on 4539 Europeans, 1047 Latinos, and 378 African Americans (~1:10 cases control ratio). We conducted a multi-ancestry transcriptome-wide analysis (METRO) meta-analysis followed by METRO-EGGER sensitivity analysis and ancestry-specific gene set enrichment analyses. We further explored genes with additional evidence gathered from independent cohorts and databases. Results: Across the three ancestries, the discovered genes shared the same effect direction across ancestries. A meta-analysis of the three ancestries identified 28 genes significantly associated with HB risk, and 15 were nominally significant for at least two ancestries. Our post-TWAS analyses highlighted eight genes among these 28, including OXER1 (meta-analysis p-value=7.3410-6), FADS1 (p-value=4.0110-6), and UGDH (p-value=5.2910-8), which were expressed in fetal liver hepatoblast cells and were differentially expressed in tumor and normal tissues in an independent Japanese HB study (p-values=2.6110-13, 3.6210-3 , and 1.9510-9, respectively). Conclusions: We pinpoint eight potential genes associated with HB using data from an ongoing multi-ancestry genome-wide association study. Impact: We conducted the largest HB TWAS to date, prompting further exploration of genes.</p>

Southern U.S. communities experience high HIV incidence and substance use prevalence, yet low PrEP uptake. Providers (N = 191) completed a survey about willingness to refer/link clients with HIV risk to PrEP. Through in-depth interviews, 12 directors (5 sexually transmitted infection [STI] clinics; 5 syringe services programs [SSPs]; 2 substance use treatment programs [SUTPs]) described multi-level factors that contextualized provider willingness. Providers were more willing to refer/link clients with unspecified HIV risk and men who have sex with men to PrEP vs. other populations. SUTP (vs. SSP) providers were less willing to refer/link clients with unspecified risk and men who use opioids. Older (vs. younger) providers were less willing, and more (vs. less) experienced providers more willing to refer/link to PrEP. Directors described facilitators (e.g., comprehensive health center partnerships) and barriers (e.g., provider stigma toward people who use drugs) to PrEP implementation. Findings highlight the importance of considering multi-level factors in PrEP implementation.

<p>Disclosure: E.M. Bomberg: Novo Nordisk. L.G. Spector: None. A. Raduski: None. Z. Lu: None. C. Im: None. T.M. Jenkins: None. T.H. Inge: Standard Bariatrics, Teleflex, Medtronic, Mediflix, Independent Medical Expert Consulting Services, Wolters Kluwer (UpToDate). J.R. Ryder: Boehringer Ingelheim, Eli Lilly &amp; Company, Recordati, Calorify.</p>

Background: Momcology is a US-based patient advocacy organization that provides support for families of children with cancer. This study describes Momcology for researchers by detailing the demographic, clinical, and socioeconomic (socioeconomic status [SES]) data within its registry and comparing it to the National Surveillance, Epidemiology, and End Results (SEER) dataset. This study contextualizes differences within the cohort and highlights opportunities for similar organizations to improve research partnerships. Procedure: In 2020, Momcology transitioned its membership registry to Research Electronic Data Capture (REDCap), a secure, web-based platform designed for standardized data collection and research collaboration. Caregivers of children with cancer completed surveys capturing diagnosis, demographics, and socioeconomic information. We compared children aged 0–19 years diagnosed between 2000 and 2020 in the Momcology registry with cases from SEER-22 for demographic and clinical variables and SEER-18 (2006–2018) for SES. Multivariable logistic regression was used to examine associations between registry membership and age, sex, race/ethnicity, cancer subtype, and SES. Results: Among 4,305 Momcology patients and 156,407 SEER cases, Momcology children were younger at diagnosis, more likely to be non-Hispanic White, and from higher SES backgrounds. Momcology showed a substantially greater proportion of leukemias compared to SEER. Additionally, the REDCap database enables efficient data queries and targeted family outreach based on specific circumstances. Conclusion: Momcology's membership is large and includes all pediatric cancer types and demographic backgrounds. Despite representation gaps in certain populations, Momcology maintains a presently characterized and active cohort that facilitates connections between families and researchers for community-based participatory research and caregiver support initiatives within pediatric oncology.

Acute leukemias, mainly consisting of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), comprise a major diagnostic group among hematologic cancers. Due to the early age at onset of ALL, particularly, it has long been suspected that acute leukemias of childhood may have an in utero origin. This supposition has motivated many investigations seeking direct proof of prenatal leukemogenesis, in particular, twin and “backtracking studies”. The suspected in utero origin has also focused on gestation as a critical window of risk, resulting in a rich literature on prenatal risk factors for pediatric acute leukemias. In this narrative review, we recount the circumstantial and direct evidence for an in utero origin of childhood acute leukemias.

<p>Background: We examined association between late stage diagnosis and individual- and community-level characteristics among pediatric Hodgkin lymphoma (HL) and rhabdomyosarcoma (RMS) patients. Methods: We obtained Children’s Oncology Group (COG) data from 1999-2021 including summary stage (local (L), regional (R), distant (D)), tumor subtype, demographics, and ZIP code at diagnosis. We linked ZIP codes to county-level redlining scores (C,D=greatest redlining), Child Opportunity Index (COI), and measures of segregation (racial dissimilarity indices (DI)). Logistic regressions calculated odds ratios for late stage diagnosis, and by race within tumor subtype. Results: 5,933 HL and 2,800 RMS patients were included. Late stage diagnosis of HL was correlated with Black race (ORDistant(D) vs regional/local(R&amp;L)=1.38 [1.13-1.68]), being uninsured (ORD vs R&amp;L=1.38 [1.09-1.75]), and subtype (Nodular sclerosis vs Other HL: ORD vs R&amp;L=1.64 [1.34-2.01], Untyped: ORD vs R&amp;L=1.30 [1.04-1.63]). Late stage rhabdomyosarcoma was correlated with bilingual households (ORDistant/regional(D&amp;R) vs local(L)=2.66 [1.03-6.91]) and tumor type (Alveolar vs Embryonal ORD vs R&amp;L=6.16 [5.00-7.58]. Community-level factors associated with late stage HL were greater Black (OR80-100%=1.83; 95% CI=1.11-3.02) and Hispanic (OR60-79%=1.30; 95%CI=1.05-1.60) DI. Late stage diagnosis for RMS was associated with more redlined census tracts within counties (OR=1.54; 95% CI =1.02-2.35) and low/very low COI (OR=1.21; 95% CI=1.02-1.45). Conclusion: Novel markers of community deprivation, such as redlining and racial segregation, likely affect cancer outcomes for children with HL and RMS in this first disparities study using COG registries. Impact: The interplay of multilevel risk factors provides important consideration for efforts to improve early detection of pediatric cancer diagnosis.</p>

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.

<p>Background: Racial and ethnic disparities in incidence and outcomes for childhood B-cell acute lymphoblastic leukemia (B-ALL) are well established. While genome-wide association studies (GWASs) among children of European (EUR) genetic ancestry have identified robust risk loci, comparable studies in children of African (AFR) genetic ancestry do not exist. Here we report on results from the first GWAS of B-ALL exclusive to AFR children.</p>

<p>The generalizability of clinical trial outcomes hinges upon the equitable access and enrollment of diverse patient populations. Yet, disparities persist that may influence enrollment patterns. In neuroblastoma, the impact of ethnicity, socioeconomic status (SES), distance to care, and age at diagnosis on enrollment in therapeutic trials remains underexplored. We aimed to investigate these factors in neuroblastoma patients to identify potential disparities in clinical trial participation. We utilized the Childhood Cancer Research Network data, selecting neuroblastoma cases from 2008-2015, excluding those &amp;gt;21 years old or with incomplete data. We focused on factors influencing enrollment in therapeutic trials (ANBL0032, ANBL0421, ANBL0531, ANBL0532, ANBL0621, ANBL0931, ANBL1021, ANBL1221, ANBL1232). Key predictors examined were ethnicity, age at diagnosis, SES (via Yost Index), and distance to care from home to treatment hospital. We employed Poisson regression to calculate adjusted risk ratios (aRR) and 95% confidence intervals for trial participation. Analyzing 3,148 neuroblastoma cases from the CCRN registry, the ethnic composition was as follows: 68% were non-Hispanic White, 14% Hispanic, and 10% NH Black and SES distribution was even across quintiles. Age at diagnosis was a significant factor in trial enrollment: children &amp;gt;2 years were 94% more likely to enroll than those under 2 years (p &amp;lt; 0.001). Race, ethnicity, SES, and distance to care showed no significant effect on enrollment, all with non-significant p-values. In CCRN, neuroblastoma patient's age at diagnosis was a determinant in therapeutic trial enrollment, providing insight into design strategies to encourage trial participation. While common barriers like race, ethnicity, SES, and distance to care did not impact enrollment in our cohort, the significant role of age highlights an area where focused efforts can ensure that all age groups have equitable access to the potential benefits of therapeutic trials.</p>

<p>Some evidence suggests that pediatric sarcomas have both shared and distinct genetic profiles; however, large-scale efforts to characterize germline genetic susceptibility across these malignancies are limited by their rarity. We evaluated the role of common and rare variants in the genetic etiology of the more frequent pediatric sarcomas: osteosarcoma (OS); Ewing sarcoma (ES); and rhabdomyosarcoma (RMS), subcategorized into embryonal (ERMS) and alveolar (ARMS).</p>

<p>We evaluated whether socioeconomic status (SES), race/ethnicity, and their interaction were associated with the presentation of advanced stage at diagnosis in embryonal tumors. Children 0 to 19 years of age diagnosed with embryonal tumors between 2006 and 2018 were identified from the US Surveillance, Epidemiology, and End Results program database specialized with Census Tract SES/Rurality. SES quintile was derived from a composite index for census tracts. We performed logistic regression to estimate odds ratios (ORs) and 95% confidence intervals by SES and race/ethnicity, adjusting for sex, age, and diagnosis year. Overall, no significant associations were found between either SES or race/ethnicity and the risk of presenting with advanced stage at diagnosis, although patterns of risk reductions were observed in atypical teratoid/rhabdoid tumors and embryonal rhabdomyosarcoma with increasing SES. In the stratified analysis, decreased odds of presenting with advanced-stage embryonal rhabdomyosarcoma were observed for Hispanics with higher SES (OR: 0.24, 95% Confidence Interval: 0.08-0.75) compared with Hispanics with lower SES. Future studies incorporating individual-level SES, cancer-specific staging information, and potential demographic, clinical, epidemiological, and genetic risk factors are warranted to confirm our findings.</p>

10026Background: Childhood cancer survivors are at high risk for developing subsequent breast cancer with higher mortality than females in the general population wit...

<h2>ABSTRACT</h2><h3>BACKGROUND</h3><p>Regionalization of congenital heart surgery (CHS) has been proposed to improve post-surgical outcomes by increasing experience in the care of high-risk patients. We sought to determine whether procedure-specific center volume was associated with mortality following infantile CHS up to 3 years following surgery.</p><h3>METHODS</h3><p>We analyzed data from 12,263 infants in the Pediatric Cardiac Care Consortium undergoing CHS between 1982 and 2003 at 46 centers within the United States. We used logistic regression to assess the association between procedure-specific center volume and mortality from discharge to 3 years post-procedure, accounting for clustering at the center level and adjusting for patient age and weight at surgery, chromosomal abnormality, and surgical era.</p><h3>RESULTS</h3><p>We found decreased odds for in-hospital mortality for Norwood procedures (OR = 0.955, 95% CI=0.935-0.976), arterial switch operations (OR=0.924, 95% CI=0.889-0.961), tetralogy of Fallot repairs (OR=0.975, 95% CI=0.956-0.995), Glenn shunts (OR=0.971, 95% CI=0.943-1.000) and ventricular septal defect closures (OR=0.974, 95% CI=0.964-0.985). The association persisted up to three years post-surgery for Norwood procedures (OR=0.971, 95% CI=0.955-0.988), arterial switches (OR=0.929, 95% CI=0.890-0.970), and ventricular septal defect closures (OR=0.986, 95% CI=0.977-0.995); however, after excluding deaths which occurred within the first 90 days of following surgery, we observed no association between center volume and mortality for any of the procedures studied.</p><h3>CONCLUSIONS</h3><p>These findings suggest that procedure-specific center volume is inversely associated with early postoperative mortality for infantile CHS across the complexity spectrum but has no measurable effect on later mortality.</p>

<p>OBJECTIVES/GOALS: We leverage the disparate incidence of Ewing sarcoma (ES) between European (EUR) and African (AFR) ancestry to study ES tumorigenesis in iPSC-derived cells from donors with a range of AFR ancestry via functional / molecular profiling. Integrated multi-omics analysis furthers explore local regulatory networks in pursuit of novel drug targets of ES. METHODS/STUDY POPULATION: In our pilot, eight induced pluripotent stem cell lines were obtained, differentiated into neural crest cells, and then transduced with a lentivirus expressing GFP-2A-EWS/FLI1. We compared wild type (WT) to EWS-FLI1-induced cells and then compared cell survival, gene expression, and EWS-FLI1 binding differences at varying levels of EUR / AFR ancestry admixture. We will build on this pilot data by expanding the number of cell lines and measuring chromatin state. Subsequently we will refine our understanding of the relationships between local ancestry, epigenetic and gene expression changes, and phenotype in tumor progression via integration of multi-omics datasets. Our systems genomics approach will utilize directed local regulatory networks in a Bayesian structure learning framework. RESULTS/ANTICIPATED RESULTS: Induction by EWS-FLI1 resulted in gene expression changes enriched in known ES gene sets. Higher %EUR ancestry correlated with prolonged maintenance of EWS-FLI1. We identified thousands of ancestry-linked changes to gene expression and EWS-FLI1 binding. Eighty of these genes are both differentially expressed and differentially bound based on AFR ancestry admixture level and may be some of the early critical targets that initiate the cascade of molecular changes in ES. We will identify novel drug targets, with potential cross functional use of known drugs. Once we have developed directed local regulatory networks, we will use them to test in silico potential perturbations due to small molecules or novel drugs and predict expression changes. DISCUSSION/SIGNIFICANCE: With a limited number of cell lines, we identify 80 ancestry-linked candidate loci for functional validation through genome engineering. As EWS-FLI1 itself has proven elusive to direct targeting, studying its immediate downstream effects has the potential for establishing new druggable biologic pathways for treatment of ES.</p>

<p>Introduction: Prior work indicates that Hispanic and Black children diagnosed with leukemia may experience a higher risk of death in the period shortly after diagnosis, but no work has examined these disparities taking into account leukemia subtypes and the role socioeconomic status (SES) may play. We investigated reported race/ethnicity (RRE), health insurance status, neighborhood SES, and early death among pediatric acute lymphoblastic leukemia (ALL) patients enrolled on clinical trials. Methods: Using data from the Childhood Cancer Research Network as well as Children’s Oncology Group therapeutic trials, we estimated the associations between RRE (Non-Hispanic [NH] White, NH Black, NH Asian/Pacific Islander [PI], or Hispanic/Native American), health insurance status, neighborhood SES using the Yost Index, and death within 60 days of diagnosis using multivariable logistic regression. All analyses were adjusted for age at diagnosis, sex, and ALL subtype (Standard Risk B-Cell, High Risk B-Cell, Infant ALL, T-Cell). We also estimated associations among non-infant patients diagnosed with B-Cell ALL, additionally adjusting for standard or high-risk disease. All associations were estimated as odds ratios (OR) with 95% confidence intervals (CI). Results: Overall, we analyzed data from 8,634 pediatric ALL cases (7,559 B-Cell; 122 Infant ALL; 953 T-Cell) enrolled across 7 clinical trials (AALL0232, AALL0331, AALL0434, AALL0631, AALL0932, AALL1131, AALL1231). In total, there were 29 deaths within 60 days of diagnosis, including 22 among B-Cell, 4 among infant ALL, and 3 among T-Cell patients. In the full analysis, infant ALL subtype was very strongly associated with early death compared to Standard Risk B-Cell patients (OR: 37.8 [95% CI: 9.22, 137]). We also observed a suggestive association between NH Asian/PI RRE and higher odds of early death compared to NH Whites (OR: 3.10 [95% CI: 0.71, 9.63]), which remained after limiting the analysis to B-Cell patients (OR: 5.63 [95% CI: 1.24, 18.7]). No association was apparent between NH Black or Hispanic/Native American RRE and odds of early death. Neighborhood SES was not significantly associated with early death, though point estimates suggested a potential protective effect of increasing SES. Lack of health insurance was also suggestively associated with greater odds of early death (OR: 2.78 [95% CI: 0.60, 9.47]). Conclusion: Unlike prior work, we observed increased odds of death soon after diagnosis for NH Asian/PI children. Future work incorporating more detailed treatment and cytogenetic subtype information is needed to identify the factors contributing to this disparity.</p>

STUDY QUESTION: Which genetic factors regulate female propensity for giving birth to spontaneous dizygotic (DZ) twins? SUMMARY ANSWER: We identified four new loci, GNRH1, FSHR, ZFPM1, and IPO8, in addition to previously identified loci, FSHB and SMAD3.

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.