Background: Taking a family history of cancer (FH) is essential for identifying individuals with heritable cancer predisposition. Project:EveryChild (Children's Oncology Group [COG] trial APEC14B1), the registration and biobanking protocol of the COG, includes suggested questions about FH in first-degree relatives and personal history of genetic syndromes (GS) in pediatric oncology patients. The validity of these items is unclear; therefore, the authors assessed the data quality and face validity of the responses. Methods: The authors analyzed case report forms regarding FH and GS of 30,157 participants (aged birth to 21 years) with newly diagnosed pediatric cancer enrolled in APEC14B1. FH and GS data were manually curated to interpret the responses and group them into categories, followed by face validity assessment—defined as the extent to which the information provided represented what it was intended to capture. Results: Responses were provided for 65.7% of participants (n = 19,810), with 6.1% reporting FH (n = 1204). Of those, 97.9% (n = 1178) included sufficient free-text detail to assess face validity, although 49.4% required manual interpretation. Among FH reports, 48.3% (n = 595) were suggestive of heritable cancer risk. GS was reported in 4.3% of responders (n = 863), with 93.3% (n = 780) showing face validity after curation. Down syndrome (n = 302) and neurofibromatosis type 1 (n = 93) were the most frequently reported syndromes, with neurofibromatosis type 1 most common in patients who had central nervous system tumors. Conclusions: Despite limitations and the need for manual curation, FH and GS data collected by using proposed questions were sufficient to identify known heritable cancer patterns. These findings support questionnaire-based data collection and highlight areas for improvement.

Oil and gas development (OGD) has been linked to increased pediatric cancer risk, but the literature to date is focused on hematologic malignancies and active wells. The emergence of suspected clusters of cancers such as Ewing sarcoma in children living near OGD and widespread presence of abandoned wells warrants investigation. This study included 558 children born in California (1982–2015) reported to the California Cancer Registry with a diagnosis of Ewing sarcoma at 0–19 years (1988–2015), and 27,800 cancer-free controls frequency-matched to cases on birth-year (50:1 ratio). We used birth address to assign prenatal OGD exposure to active (drilled or producing) and plugged/abandoned wells separately with inverse distance-squared weighted well counts at 5 and 10 km buffer sizes from three months before conception to birth. We evaluated potential exposure disparities and estimated odds ratios (OR) and 95% confidence intervals (CI) for the association between prenatal OGD exposure and Ewing sarcoma risk using multivariable logistic regression. Hispanic children were significantly more likely to be exposed to both active and abandoned OGD within 10 km than non-Hispanics (40% vs. 23% and 14% vs. 6%, respectively). There were no associations between prenatal exposure to active OGD within 10 km and Ewing sarcoma risk (OR: 0.88 [95% CI: 0.72–1.08]). However, children within 10 km of abandoned wells were 1.27 [0.96–1.66] times as likely to develop Ewing sarcoma as unexposed children; when stratified by ethnicity, this association appeared in Hispanic children only (1.33 [0.95–1.88]). We did not identify an association between exposure to active OGD and pediatric Ewing sarcoma risk in California. Abandoned wells were associated with a suggestive increase in risk among Hispanic children, who were also more likely to be exposed to any OGD activity than non-Hispanic children. This disparity could have implications for other health outcomes including childhood cancers.

Background Childhood cancers comprise a variety of liquid and solid tumors that display different patterns of incidence than adult cancers. Most have distinct molecular subtypes characterized by specific genomic driver events. The mutational processes that influence the somatic landscape of cancers also generate distinctive mutational signatures (mutSig). While these signatures are often inert, they do represent a fingerprint of the insult(s) present during mutagenesis. Associating mutSig with putatively causal exposures for pediatric cancer could inform future etiologic studies and elucidate the exposure pathways underlying risk. Content Here we review the epidemiology of pediatric cancers. We then summarize the knowledge around mutSig seen in pediatric cancer to date, discuss observed geographic and subtype-related variability, and discuss future efforts to characterize mutSig with unknown etiologies. Summary The diversity of childhood cancers and their molecular subtypes suggest etiologic heterogeneity. Detection of mutSig in childhood cancers has promoted hypothesis generation; e.g., the enrichment of UV-related signatures in aneuploid B-acute lymphoblastic leukemia has inspired new studies. Although the Mutographs projects were developed to investigate geographical variation in incidence, mutational epidemiology studies should also be employed to understand why certain mutSig are enriched in particular childhood cancers or subtypes. As pediatric cancers have lower mutational burdens than adult cancers, studying childhood cancer may also help determine the causes of mutSig with unknown etiologies. Given persistent differences in pediatric cancer risk by ancestry and socioeconomics, as well as the shifting global burden of childhood cancer, there is a need for studies with patients from diverse populations.

<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.

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...

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>

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.

PrEP is an HIV prevention option that could benefit substance-involved women, a high-risk population with low PrEP uptake. Little is known about their interest in PrEP. This qualitative study used in-depth interviews to examine PrEP willingness, barriers, and facilitators among 16 women in outpatient psychosocial substance use treatment, methadone, and/or harm reduction/syringe programs in NYC. All expressed willingness to use PrEP, but only during periods of perceived risk. Women perceived themselves to be at high risk for HIV when engaging in active substance use and/or transactional sex. They perceived themselves to be at low risk and therefore unmotivated to take PrEP when abstinent from these activities. Paradoxically, a major barrier to using PrEP was anticipated interference from substance use and transactional sex, the very same activities that create a perception of risk. Facilitators of PrEP use included perceptions of it as effortless (as opposed to barrier methods during sex) and effective, safe, and accessible. Other barriers included fear of stigma and doubts about adhering daily. Recommendations for best PrEP implementation practices for substance-involved women included tailored and venue-specific PrEP information and messaging, PrEP discussion with trusted medical providers, and on-site PrEP prescription in substance use treatment and harm reduction programs.