The Effect of Socioeconomic Status and Race/Ethnicity on the Risk of Presenting With Advanced Stage at Diagnosis in Embryonal Tumors.

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.

Sex differences in osteosarcoma survival across the age spectrum: A National Cancer Database analysis (2004-2016).

BACKGROUND: Osteosarcoma displays a bimodal peak in incidence in adolescence and later adulthood. Males are more frequently diagnosed with osteosarcoma in both periods. Males have worse survival than females, which is generally poor at 30-70% 5-years post diagnosis, depending on age, but treatment received is often unaccounted for in survival analyses. METHODS: Therefore, we estimated sex differences in survival for children and adults stratifying by treatment received and other disease characteristics using the National Cancer Database (2004-2016, n=9017). We estimated sex differences in long-term survival using Kaplan Meier survival curves and Log-Rank p-values. We also estimated hazard ratios (HR) and 95% confidence intervals (CIs) as the measure of association between sex and death using Cox regression. RESULTS: In all age groups, cases were predominantly male (52-58%). In Kaplan-Meier analyses, males had worse overall survival than females for 0-19, 20-39, and ≥60-year-olds (Log-Rank p<0.05). Females had higher 5- and 10-year survival percentages in all age groups. In adjusted Cox models, males had a higher risk of death among 0-19-year-olds (HRoverall: 1.24, 95% CI: 1.06-1.44; HRnon-metastatic disease: 1.35, 95% CI: 1.12, 1.63, HRlower limb tumors: 1.31, 95% CI: 1.09-1.59). Among 20-39-year-olds, males had an increased risk of death when receiving surgery only (HR: 4.67, 95% CI: 1.44, 15.09). Among those ≥60-year-olds, males had a suggestive increased risk of death overall (HR: 1.17, 95% CI: 0.99-1.39) and a higher risk of death based on some tumor locations, (HRupper limb: 2.52, 95% CI: 1.24, 5.11; HRmidline: 1.36, 95% CI: 1.02, 1.82). CONCLUSIONS: Our findings suggest that the worse survival among young males compared to females with osteosarcoma persisted after accounting for many major disease characteristics, including treatment received. Collectively, our work points toward other unexplored mechanisms beyond treatment, potentially biologic or otherwise, which may be driving the observed sex differences in long-term survival.

Subset scanning for multi-trait analysis using GWAS summary statistics.

MOTIVATION: Multi-trait analysis has been shown to have greater statistical power than single-trait analysis. Most of the existing multi-trait analysis methods only work with a limited number of traits and usually prioritize high statistical power over identifying relevant traits, which heavily rely on domain knowledge. RESULTS: To handle diseases and traits with obscure etiology, we developed TraitScan, a powerful and fast algorithm that identifies potential pleiotropic traits from a moderate or large number of traits (e.g. dozens to thousands) and tests the association between one genetic variant and the selected traits. TraitScan can handle either individual-level or summary-level GWAS data. We evaluated TraitScan using extensive simulations and found that it outperformed existing methods in terms of both testing power and trait selection when sparsity was low or modest. We then applied it to search for traits associated with Ewing Sarcoma, a rare bone tumor with peak onset in adolescence, among 754 traits in UK Biobank. Our analysis revealed a few promising traits worthy of further investigation, highlighting the use of TraitScan for more effective multi-trait analysis as biobanks emerge. We also extended TraitScan to search and test association with a polygenic risk score and genetically imputed gene expression. AVAILABILITY AND IMPLEMENTATION: Our algorithm is implemented in an R package "TraitScan" available at https://github.com/RuiCao34/TraitScan.

In Utero Origins of Acute Leukemia in Children.

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.

Genetic analyses identify evidence for a causal relationship between Ewing sarcoma and hernias.

Knowledge of Ewing sarcoma (EWS) risk factors is exceedingly limited; however, multiple small, independent studies have suggested a possible connection between hernia and EWS. By leveraging hernia summary statistics from the UK Biobank and a recently published genome-wide association study of EWS (733 EWS cases and 1,346 controls), we conducted a genetic investigation of the relationship of 5 hernia types (diaphragmatic, inguinal, umbilical, femoral, and ventral) and EWS. We discovered a positive causal relationship between inguinal hernia and EWS (OR 1.27, 95% confidence interval [CI] 1.01-1.59, and p = 0.041) through Mendelian randomization analysis. Further analyses suggested shared pathways through three genes: HMGA2, LOX, and FBXW7. Diaphragmatic hernia showed a stronger causal relationship with EWS among all of the hernia types (OR 2.26, 95% CI 1.30-3.95, p = 0.004), but no statistically significant local correlation pattern was observed. No evidence of a causal or genetic relationship was observed between EWS and the other three hernia types, including umbilical hernia, despite a previous report indicating an OR as high as 3.3. The finding of our genetic analysis provided additional support to the hypothesis that EWS and hernias may share a common origin.

Nonchromosomal birth defects and risk of childhood acute leukemia: An assessment in 15 000 leukemia cases and 46 000 controls from the Childhood Cancer and Leukemia International Consortium.

Although recent studies have demonstrated associations between nonchromosomal birth defects and several pediatric cancers, less is known about their role on childhood leukemia susceptibility. Using data from the Childhood Cancer and Leukemia International Consortium, we evaluated associations between nonchromosomal birth defects and childhood leukemia. Pooling consortium data from 18 questionnaire-based and three registry-based case-control studies across 13 countries, we used multivariable logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between a spectrum of birth defects and leukemia. Our analyses included acute lymphoblastic leukemia (ALL, n = 13 115) and acute myeloid leukemia (AML, n = 2120) cases, along with 46 172 controls. We used the false discovery rate to account for multiple comparisons. In the questionnaire-based studies, the prevalence of birth defects was 5% among cases vs 4% in controls, whereas, in the registry-based studies, the prevalence was 11% among cases vs 7% in controls. In pooled adjusted analyses, there were several notable associations, including (1) digestive system defects and ALL (OR = 2.70, 95% CI: 1.46-4.98); (2) congenital anomalies of the heart and circulatory system and AML (OR = 2.86, 95% CI: 1.81-4.52) and (3) nervous system defects and AML (OR = 4.23, 95% CI: 1.50-11.89). Effect sizes were generally larger in registry-based studies. Overall, our results could point to novel genetic and environmental factors associated with birth defects that could also increase leukemia susceptibility. Additionally, differences between questionnaire- and registry-based studies point to the importance of complementary sources of birth defect phenotype data when exploring these associations.

Role of non-chromosomal birth defects on the risk of developing childhood Hodgkin lymphoma: A Children's Oncology Group study.

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.

Genetically inferred birthweight, height, and puberty timing and risk of osteosarcoma.

INTRODUCTION: Several studies have linked increased risk of osteosarcoma with tall stature, high birthweight, and early puberty, although evidence is inconsistent. We used genetic risk scores (GRS) based on established genetic loci for these traits and evaluated associations between genetically inferred birthweight, height, and puberty timing with osteosarcoma. METHODS: Using genotype data from two genome-wide association studies, totaling 1039 cases and 2923 controls of European ancestry, association analyses were conducted using logistic regression for each study and meta-analyzed to estimate pooled odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup analyses were conducted by case diagnosis age, metastasis status, tumor location, tumor histology, and presence of a known pathogenic variant in a cancer susceptibility gene. RESULTS: Genetically inferred higher birthweight was associated with an increased risk of osteosarcoma (OR =1.59, 95% CI 1.07-2.38, P = 0.02). This association was strongest in cases without metastatic disease (OR =2.46, 95% CI 1.44-4.19, P = 9.5 ×10-04). Although there was no overall association between osteosarcoma and genetically inferred taller stature (OR=1.06, 95% CI 0.96-1.17, P = 0.28), the GRS for taller stature was associated with an increased risk of osteosarcoma in 154 cases with a known pathogenic cancer susceptibility gene variant (OR=1.29, 95% CI 1.03-1.63, P = 0.03). There were no significant associations between the GRS for puberty timing and osteosarcoma. CONCLUSION: A genetic propensity to higher birthweight was associated with increased osteosarcoma risk, suggesting that shared genetic factors or biological pathways that affect birthweight may contribute to osteosarcoma pathogenesis.

Identifying childhood leukemia with an excess of hematological malignancies in first-degree relatives in Brazil.

Background: Familial aggregation in childhood leukemia is associated with epidemiological and genomic factors. Albeit epidemiological studies on the familial history of hematological malignancies (FHHMs) are scarce, genome-wide studies have identified inherited gene variants associated with leukemia risk. We revisited a dataset of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) patients to explore the familial aggregation of malignancies among their relatives. Methods: A series of 5,878 childhood leukemia (≤21 years of age) from the EMiLI study (2000-2019) were assessed. Lack of well-documented familial history of cancer (FHC) and 670 cases associated with genetic phenotypic syndromes were excluded. Leukemia subtypes were established according to World Health Organization recommendations. Logistic regression-derived odds ratios (ORs) and 95% confidence intervals (CIs) were performed and adjusted by age as a continuous variable, where ALL was the reference group for AML and conversely. The pedigree of 18 families with excess hematological malignancy was constructed. Results: FHC was identified in 472 of 3,618 eligible cases (13%). Ninety-six of the 472 patients (20.3%) had an occurrence of FHHMs among relatives. Overall, FHC was significantly associated with AML (OR, 1.36; 95% CI, 1.01-1.82; p = 0.040). Regarding the first-degree relatives, the OR, 2.92 95% CI,1.57-5.42 and the adjOR, 1.16 (1.03-1.30; p0.001) were found for FHC and FHHM, respectively. Conclusion: Our findings confirmed that AML subtypes presented a significant association with hematological malignancies in first-degree relatives. Genomic studies are needed to identify germline mutations that significantly increase the risk of developing myeloid malignancies in Brazil.

Children's Oncology Group's 2023 blueprint for research: Epidemiology.

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.

Polygenic Risk and Chemotherapy-Related Subsequent Malignancies in Childhood Cancer Survivors: A Childhood Cancer Survivor Study and St Jude Lifetime Cohort Study Report.

PURPOSE: Chemotherapeutic exposures are associated with subsequent malignant neoplasm (SMN) risk. The role of genetic susceptibility in chemotherapy-related SMNs should be defined as use of radiation therapy (RT) decreases. PATIENTS AND METHODS: SMNs among long-term childhood cancer survivors of European (EUR; N = 9,895) and African (AFR; N = 718) genetic ancestry from the Childhood Cancer Survivor Study and St Jude Lifetime Cohort Study were evaluated. An externally validated 179-variant polygenic risk score (PRS) associated with pleiotropic adult cancer risk from the UK Biobank Study (N > 400,000) was computed for each survivor. SMN cumulative incidence comparing top and bottom PRS quintiles was estimated, along with hazard ratios (HRs) from proportional hazards models. RESULTS: A total of 1,594 survivors developed SMNs, with basal cell carcinomas (n = 822), breast cancers (n = 235), and thyroid cancers (n = 221) being the most frequent. Although SMN risk associations with the PRS were extremely modest in RT-exposed EUR survivors (HR, 1.22; P = .048; n = 4,630), the increase in 30-year SMN cumulative incidence and HRs comparing top and bottom PRS quintiles was statistically significant among nonirradiated EUR survivors (n = 4,322) treated with alkylating agents (17% v 6%; HR, 2.46; P < .01), anthracyclines (20% v 8%; HR, 2.86; P < .001), epipodophyllotoxins (23% v 1%; HR, 12.20; P < .001), or platinums (46% v 7%; HR, 8.58; P < .01). This PRS also significantly modified epipodophyllotoxin-related SMN risk among nonirradiated AFR survivors (n = 414; P < .01). Improvements in prediction attributable to the PRS were greatest for epipodophyllotoxin-exposed (AUC, 0.71 v 0.63) and platinum-exposed (AUC,0.68 v 0.58) survivors. CONCLUSION: A pleiotropic cancer PRS has strong potential for improving SMN clinical risk stratification among nonirradiated survivors treated with specific chemotherapies. A polygenic risk screening approach may be a valuable complement to an early screening strategy on the basis of treatments and rare cancer-susceptibility mutations.

Distinct mechanisms of PTEN inactivation in dogs and humans highlight convergent molecular events that drive cell division in the pathogenesis of osteosarcoma.

A hallmark of osteosarcoma in both human and canine tumors is somatic fragmentation and rearrangement of chromosome structure which leads to recurrent increases and decreases in DNA copy number. The PTEN gene has been implicated as an important tumor suppressor in osteosarcoma via forward genetic screens. Here, we analyzed copy number changes, promoter methylation and transcriptomes to better understand the role of PTEN in canine and human osteosarcoma. Reduction in PTEN copy number was observed in 23 of 95 (25%) of the canine tumors examined leading to corresponding decreases in PTEN transcript levels from RNA-Seq samples. Unexpectedly, canine tumors with an intact PTEN locus had higher levels of PTEN transcripts than human tumors. This variation in transcript abundance was used to evaluate the role of PTEN in osteosarcoma biology. Decreased PTEN copy number and transcript level was observed in - and likely an important driver of - increases in cell cycle transcripts in four independent canine transcriptional datasets. In human osteosarcoma, homozygous copy number loss was not observed, instead increased methylation of the PTEN promoter was associated with increased cell cycle transcripts. Somatic modification of PTEN, either by homozygous deletion in dogs or by promoter methylation in humans, is clinically relevant to osteosarcoma, because the cell cycle related transcripts are associated with patient outcomes. The PTEN gene is part of a syntenic rearrangement unique to the canine genome, making it susceptible to somatic loss of both copies of distal chromosome 26 which also includes the FAS death receptor. SIGNIFICANCE STATEMENT: PTEN function is abrogated by different mechanisms in canine and human osteosarcoma tumors leading to uncontrolled cell cycling. Somatic loss of this canine specific syntenic region may help explain why the canine genome appears to be uniquely susceptible to osteosarcoma. Syntenic arrangement, in the context of copy number change, may lead to synergistic interactions that in turn modify species specific cancer risk. Comparative models of tumorigenesis may utilize different driver mechanisms.

The association between maternal nutrient intake during pregnancy and the risk of sporadic unilateral retinoblastoma among offspring.

Previous studies have associated maternal diet during pregnancy with the development of sporadic unilateral retinoblastoma (RB), but few studies have focused on the role of individual nutrients. The aim of this study is to investigate the association between maternal nutrient intake during pregnancy and the development of sporadic unilateral RB in the offspring. A modified food frequency questionnaire, with additional questions on supplement use, was completed via a phone interview. Cases were recruited from hospitals and controls were comprised of friends and relatives of the patient without a history of cancer. Overall, 168 sporadic unilateral RB cases and 145 controls were included in case-control study. We performed logistic regression to estimate odds ratios (ORs) and 95 % confidence intervals (CI), adjusting for child's age, child's sex, parental race/ethnicity, maternal education, total calorie intake during pregnancy, maternal age at birth, maternal smoking during pregnancy, pre-pregnancy body mass index, maternal weight gain during pregnancy, paternal age at birth, and maternal multivitamin use in the year before pregnancy. In the adjusted model, the interquartile (IQR) increase in vitamin A intake, which was measured in retinol activity equivalent (RAE; OR: 0.64, 95 % CI: 0.46-0.90), and vitamin D intake (OR: 0.62, 95 % CI: 0.42-0.91) significantly reduced the risk of sporadic unilateral RB. These findings suggest that a higher intake of vitamins A and D can be a protective factor for sporadic unilateral RB. Further analyses in consideration of multi-exposures such as parental occupational exposures are warranted to discover the complex etiology of sporadic unilateral RB. In addition, the role of nutritional epigenetics for how maternal nutrient intake influences the risk of sporadic unilateral RB in the offspring still needs to be explored.

Sex differences in methylation profiles are apparent in medulloblastoma, particularly among SHH tumors.

Background: Medulloblastoma, the most common malignant pediatric brain tumor, displays marked sex differences in prevalence of the four main molecular subgroups: SHH, WNT, Group 3 and Group 4. Males are more frequently diagnosed with SHH, Group 3 and 4 tumors, which have worse prognoses than WNT tumors. Little is known about sex differences in methylation profiles within subgroups. Methods: Using publicly available methylation data (Illumina HumanMethylation450K array), we compared beta values for males versus females. Differentially methylated positions (DMP) by sex within medulloblastoma subgroups were identified on the autosomes. DMPs were mapped to genes and Reactome pathway analysis was run by subgroup. Kaplan-Meier survival curves (Log-Rank p-values) were assessed for each sex within subgroup. MethylCIBERSORT was used to investigate the tumor microenvironment using deconvolution to estimate the abundances of immune cell types using DNA methylation data. Results: There were statistically significant differences in sex by medulloblastoma subgroups (chi-squared p-value=0.00004): Group 3 (n=144; 65% male), Group 4 (n=326; 67% male), SHH (n=223; 57% male) and WNT (n=70; 41% male). Females had worse survival than males for SHH (p-value=0.02). DMPs by sex were identified within subgroups: SHH (n=131), Group 4 (n=29), Group 3 (n=19), and WNT (n=16) and validated in an independent dataset. Unsupervised hierarchical clustering showed that sex-DMPs in SHH did not correlate with other tumor attributes. Ten genes with sex DMPs (RFTN1, C1orf103, FKBP1B, COL25A1, NPDC1, B3GNT1, FOXN3, RNASEH2C, TLE1, and PHF17) were shared across subgroups. Significant pathways (p<0.05) associated with DMPs were identified for SHH (n=22) and Group 4 (n=4) and included signaling pathways for RET proto-oncogene, advanced glycosylation end product receptor, regulation of KIT, neurotrophic receptors, NOTCH, and TGF-ß. In SHH, we identified DMPs in four genes (CDK6, COL25A1, MMP16, PRIM2) that encode proteins which are the target of therapies in clinical trials for other cancers. There were few sex differences in immune cell composition within tumor subgroups. Conclusion: There are sexually dimorphic methylation profiles for SHH medulloblastoma where survival differences were observed. Sex-specific therapies in medulloblastoma may impact outcomes.

Procedure-Specific Center Volume and Mortality After Infantile Congenital Heart Surgery.

BACKGROUND: Regionalization of congenital heart surgery (CHS) has been proposed to improve postsurgical outcomes by increasing experience in the care of high-risk patients. We sought to determine whether procedure-specific center volume was associated with mortality after infantile CHS up to 3 years post-procedure. METHODS: 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. RESULTS: We found decreased odds for in-hospital mortality for Norwood procedures (odds ratio [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 3 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 that occurred within the first 90 days of following surgery, we observed no association between center volume and mortality for any of the procedures studied. CONCLUSIONS: 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.

Evaluation of the Association Between Congenital Cytomegalovirus Infection and Pediatric Acute Lymphoblastic Leukemia.

Importance: Acute lymphoblastic leukemia (ALL) is the most common form of pediatric cancer, and a leading cause of death in children. Understanding the causes of pediatric ALL is necessary to enable early detection and prevention; congenital cytomegalovirus (cCMV) has recently been identified as a potential moderate-to-strong factor associated with risk for ALL. Objective: To compare the prevalence of cCMV infection between ALL cases and matched controls. Design, Setting, and Participants: In this population-based case-control study of ALL cases and matched controls, cases consisted of children aged 0 to 14 years between 1987 and 2014 with an ALL diagnosis identified through the Michigan Cancer Surveillance Program and born in Michigan on or after October 1, 1987. Cancer-free controls were identified by the Michigan BioTrust for Health and matched on age, sex, and mother's race and ethnicity. Data were analyzed from November to May 2022. Exposures: cCMV infection measured by quantitative polymerase chain reaction in newborn dried blood spots. Main Outcomes and Measures: ALL diagnosed in children aged 0 to 14 years. Results: A total of 1189 ALL cases and 4756 matched controls were included in the study. Bloodspots were collected from participants at birth, and 3425 (57.6%) participants were male. cCMV was detected in 6 ALL cases (0.5%) and 21 controls (0.4%). There was no difference in the odds of cCMV infection comparing ALL cases with controls (odds ratio, 1.30; 95% CI, 0.52-3.24). Immunophenotype was available for 536 cases (45.1%) and cytogenetic data for 127 (27%). When stratified by subtype characteristics, hyperdiploid ALL (74 cases) was associated with 6.26 times greater odds of cCMV infection compared with unmatched controls (95% CI, 1.44-27.19). Conclusions and Relevance: In this case-control study of cCMV and pediatric ALL, cCMV was associated with increased risk of hyperdiploid ALL. These findings encourage continued research.

Genetic ancestry, differential gene expression, and survival in pediatric B-cell acute lymphoblastic leukemia.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 (padjusted  <0.05) associated with AFR, AMR, and EUR ancestry proportion, respectively. We found AMR and AFR ancestry were statistically significantly associated with death (AMR each 10% HR: 1.05, 95% CI: 1.03-1.17, AFR each 10% increase HR: 1.03, 95% CI:1.01-1.19). RRE differences in the risk of death were larger in magnitude upon adjustment for genes associated with genetic ancestry for RRE-Black, but not RRE-Latinx children (RRE-Black HR: 3.35, 95% CI: 1.31, 8.53; RRE-Latinx HR: 1.47, 0.88-2.45). CONCLUSIONS: Our work highlights B-ALL survival differences by RRE after adjusting for ancestry differentially expressed genes suggesting other factors impacting survival are important.

Nutritional Status at Diagnosis as Predictor of Survival from Childhood Cancer: A Review of the Literature.

Few studies so far have examined the impact of nutritional status on the survival of children with cancer, with the majority of them focusing on hematological malignancies. We summarized published evidence reporting the association of nutritional status at diagnosis with overall survival (OS), event-free survival (EFS), relapse, and treatment-related toxicity (TRT) in children with cancer. Published studies on children with leukemia, lymphoma, and other solid tumors have shown that both under-nourished and over-nourished children at cancer diagnosis had worse OS and EFS. Particularly, the risk of death and relapse increased by 30-50% among children with leukemia with increased body mass index at diagnosis. Likewise, the risk of TRT was higher among malnourished children with osteosarcoma and Ewing sarcoma. Nutritional status seems to play a crucial role in clinical outcomes of children with cancer, thus providing a significant modifiable prognostic tool in childhood cancer management. Future studies with adequate power and longitudinal design are needed to further evaluate the association of nutritional status with childhood cancer outcomes using a more standardized definition to measure nutritional status in this population. The use of new technologies is expected to shed further light on this understudied area and give room to person-targeted intervention strategies.