Residential proximity to oil and gas developments and childhood cancer survival.

BACKGROUND: Environmental toxicants may impact survival in children with cancer, but the literature investigating these associations remains limited. Because oil and gas developments emit several hazardous air pollutants, the authors evaluated the relationship between residential proximity to oil or gas development and survival across 21 different pediatric cancers. METHODS: The Texas Cancer Registry had 29,730 children (≤19 years old) diagnosed with a primary cancer between 1995 to 2017. Geocoded data were available for 285,266 active oil or gas wells and 109,965 horizontal wells. The authors calculated whether each case lived within 1000 m (yes/no) from each type of oil or gas development. Survival analyses were conducted using Cox regression, adjusting for potential confounders. RESULTS: A total of 14.2% of cases lived within 1000 m of an oil or gas well or horizontal well. Living within 1000 m of an oil or gas well was associated with risk of mortality in cases with acute myeloid leukemia (AML) (adjusted hazard ratio [aHR], 1.36; 95% confidence interval [CI], 1.01-1.84) and hepatoblastoma (aHR, 2.13; 95% CI, 1.03-4.39). An inverse association was observed with Ewing sarcoma (aHR, 0.35; 95% CI, 0.13-0.95). No associations were observed with horizontal well. There was evidence of a dose-response effect in children with AML or hepatoblastoma and residential proximity to oil or gas wells. In general, the magnitude of association increased with decreasing distance and with higher number of wells across the three distances. CONCLUSIONS: Residential proximity to oil or gas wells at diagnosis is associated with the risk of mortality in children with AML or hepatoblastoma.

CancerHERVdb: Human Endogenous Retrovirus (HERV) Expression Database for Human Cancer Accelerates Studies of the Retrovirome and Predictions for HERV-Based Therapies.

In this study, we sought to create a database summarizing the expression of human endogenous retroviruses (HERVs) in various human cancers. HERVs are suitable therapeutic targets due to their abundance in the human genome, overexpression in various malignancies, and involvement in various cancer pathways. We identified articles on HERVs from PubMed and then prescreened and automatically categorized them using the portable document format (PDF) data extractor (PDE) R package. We discovered 196 primary research articles with HERV expression data from cancer tissues or cancer cell lines. HERV RNA and protein expression was reported in brain, breast, cervical, colorectal, endocrine, gastrointestinal, kidney/renal/pelvis, liver, lung, genital, oral cavity, pharynx, ovary, pancreas, prostate, skin, testicular, urinary/bladder, and uterus cancers, leukemias, lymphomas, and myelomas. Additionally, we discovered reports of HERV RNA-only overexpression in soft tissue cancers including heart, thyroid, bone, and joint cancers. The CancerHERVdb database is hosted in the form of interactive visualizations of the expression data and a summary data table at https://erikstricker.shinyapps.io/cancerHERVdb/. The user can filter the findings according to cancer type, HERV family, HERV gene, or a combination thereof and easily export the results with the corresponding reference list. In our report, we provide examples of potential uses of the CancerHERVdb, such as identification of cancers suitable for off-target treatment with the multiple sclerosis-associated retrovirus (MSRV)-Env-targeting antibody GNbAC1 (now named temelimab) currently in phase 2b clinical trials for multiple sclerosis or the discovery of cancers overexpressing HERV-H long terminal repeat-associating 2 (HHLA2), a newly emerging immune checkpoint. In summary, the CancerHERVdb allows cross-study comparisons, encourages data exploration, and informs about potential off-target effects of HERV-targeting treatments. IMPORTANCE Human endogenous retroviruses (HERVs), which in the past have inserted themselves in various regions of the human genome, are to various degrees activated in virtually every cancer type. While a centralized naming system and resources summarizing HERV levels in cancers are lacking, the CancerHERVdb database provides a consolidated resource for cross-study comparisons, data exploration, and targeted searches of HERV activation. The user can access data extracted from hundreds of articles spanning 25 human cancer categories. Therefore, the CancerHERVdb database can aid in the identification of prognostic and risk markers, drivers of cancer, tumor-specific targets, multicancer spanning signals, and targets for immune therapies. Consequently, the CancerHERVdb database is of direct relevance for clinical as well as basic research.

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.

Genetic errors of immunity distinguish pediatric nonmalignant lymphoproliferative disorders.

BACKGROUND: Pediatric nonmalignant lymphoproliferative disorders (PLPDs) are clinically and genetically heterogeneous. Long-standing immune dysregulation and lymphoproliferation in children may be life-threatening, and a paucity of data exists to guide evaluation and treatment of children with PLPD. OBJECTIVE: The primary objective of this study was to ascertain the spectrum of genomic immunologic defects in PLPD. Secondary objectives included characterization of clinical outcomes and associations between genetic diagnoses and those outcomes. METHODS: PLPD was defined by persistent lymphadenopathy, lymph organ involvement, or lymphocytic infiltration for more than 3 months, with or without chronic or significant Epstein-Barr virus (EBV) infection. Fifty-one subjects from 47 different families with PLPD were analyzed using whole exome sequencing. RESULTS: Whole exome sequencing identified likely genetic errors of immunity in 51% to 62% of families (53% to 65% of affected children). Presence of a genetic etiology was associated with younger age and hemophagocytic lymphohistiocytosis. Ten-year survival for the cohort was 72.4%, and patients with viable genetic diagnoses had a higher survival rate (82%) compared to children without a genetic explanation (48%, P = .03). Survival outcomes for individuals with EBV-associated disease and no genetic explanation were particularly worse than outcomes for subjects with EBV-associated disease and a genetic explanation (17% vs 90%; P = .002). Ascertainment of a molecular diagnosis provided targetable treatment options for up to 18 individuals and led to active management changes for 12 patients. CONCLUSIONS: PLPD defines children at high risk for mortality, and whole exome sequencing informs clinical risks and therapeutic opportunities for this diagnosis.

Long-term outcomes for children and adolescents with Kaposi sarcoma.

OBJECTIVES: Kaposi sarcoma (KS) is one of the most common childhood cancers in eastern and central Africa. It has become a treatable disease with increasing availability of antiretroviral therapy (ART) and chemotherapy. We aimed to fill the data gap in establishing whether long-term survival is achievable for children in low-income countries. METHODS: We retrospectively analysed data for children and adolescents aged ≤ 18.9 years diagnosed with HIV-related or endemic KS from 2006 to 2015 who received standardized institutional treatment regimens utilizing chemotherapy plus ART (if HIV-positive) at a tertiary care public hospital in Lilongwe, Malawi. Long-term survival was analysed and mortality was associated with KS for those with refractory/progressive disease at the time of death. RESULTS: There were 207 children/adolescents with KS (90.8% HIV-related); 36.7% were alive, 54.6% had died, and 8.7% had been lost to follow-up. The median follow-up time for survivors was 6.9 years (range 4.2-13.9 years). Death occurred at a median of 5.3 months after KS diagnosis (range 0.1-123 months). KS progression was associated with mortality for most (61%) early deaths (survival time of < 6 months); conversely, KS was associated with a minority (31%) of late-onset deaths (after 24 months). The 7-year overall survival was 37% [95% confidence interval (CI) 30-44%] and was higher for those diagnosed between 2011 and 2015 compared to 2006-2010: 42% (95% CI 33-51%) versus 29% (95% CI 20-39%), respectively (P = 0.01). Among the 66 HIV-positive survivors, 58% were still on first-line ART. CONCLUSIONS: Long-term survival is possible for pediatric KS in low-resource settings. Despite better survival in more recent years, there remains room for improvement.

Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis.

The HLH-2004 criteria are used to diagnose hemophagocytic lymphohistiocytosis (HLH), yet concern exists for their misapplication, resulting in suboptimal treatment of some patients. We sought to define the genomic spectrum and associated outcomes of a diverse cohort of children who met the HLH-2004 criteria. Genetic testing was performed clinically or through research-based whole-exome sequencing. Clinical metrics were analyzed with respect to genomic results. Of 122 subjects enrolled over the course of 17 years, 101 subjects received genetic testing. Biallelic familial HLH (fHLH) gene defects were identified in only 19 (19%) and correlated with presentation at younger than 1 year of age (P < .0001). Digenic fHLH variants were observed but lacked statistical support for disease association. In 28 (58%) of 48 subjects, research whole-exome sequencing analyses successfully identified likely molecular explanations, including underlying primary immunodeficiency diseases, dysregulated immune activation and proliferation disorders, and potentially novel genetic conditions. Two-thirds of patients identified by the HLH-2004 criteria had underlying etiologies for HLH, including genetic defects, autoimmunity, and malignancy. Overall survival was 45%, and increased mortality correlated with HLH triggered by infection or malignancy (P < .05). Differences in survival did not correlate with genetic profile or extent of therapy. HLH should be conceptualized as a phenotype of critical illness characterized by toxic activation of immune cells from different underlying mechanisms. In most patients with HLH, targeted sequencing of fHLH genes remains insufficient for identifying pathogenic mechanisms. Whole-exome sequencing, however, may identify specific therapeutic opportunities and affect hematopoietic stem cell transplantation options for these patients.

Area deprivation is associated with poorer overall survival in children with acute lymphoblastic leukemia.

BACKGROUND: Few studies have evaluated social determinants of outcomes disparities for children with acute lymphoblastic leukemia (ALL). We investigated the association of area deprivation index (ADI), a measure of neighborhood socioeconomic disadvantage, with overall survival (OS) among children and adolescents with ALL. PROCEDURE: We obtained demographic and clinical data, geocoded addresses at diagnosis, and vital status on all Texas children diagnosed with ALL from 1995 to 2011 (N = 4104). Using the US Census Bureau 2010 geography, we computed ADI scores for all census tracts in Texas and grouped the tracts into quartiles: least, third-most, second-most, and most disadvantaged. We mapped children to ADI quartiles based on residence at diagnosis, and estimated OS using Cox regression adjusting for sex, race/ethnicity, age, and metropolitan/nonmetropolitan residence. RESULTS: Five-year OS ranged from 89% (95% confidence interval [CI] 87-91%) for children in the least disadvantaged tracts to 79% (95% CI 76-81%) for children in the most disadvantaged tracts (P = 4E-7). An elevated hazard ratio (HR) for death was observed for children in the most disadvantaged tracts (HR 1.57, 95% CI 1.23-2.00), and trends toward increased mortality were observed in the third-most and second-most disadvantaged tracts (HR 1.23, 95% CI 0.97-1.57 and HR 1.27, 95% CI 0.99-1.62, respectively). In stratified analyses, area disadvantage was more strongly associated with OS in males than females. CONCLUSIONS: Neighborhood socioeconomic disadvantage is associated with inferior OS in this analysis of over 4100 children with ALL, highlighting the substantial contributions of social-environmental factors to childhood cancer survival. This association was stronger in males than females.

Kaposi Sarcoma Herpesvirus Inflammatory Cytokine Syndrome-like Clinical Presentation in Human Immunodeficiency Virus-infected Children in Malawi.

We describe 7 human immunodeficiency virus-infected Malawian children with Kaposi sarcoma who met criteria for Kaposi sarcoma herpesvirus (KSHV) inflammatory cytokine syndrome. Each presented with persistent fevers, bulky lymphadenopathy, massive hepatosplenomegaly, and severe cytopenias. Plasma analyses were performed in 2 patients, both demonstrating extreme elevations of KSHV viral load and interleukin 6.

KSHV viral load and Interleukin-6 in HIV-associated pediatric Kaposi sarcoma-Exploring the role of lytic activation in driving the unique clinical features seen in endemic regions.

Kaposi sarcoma (KS) is among the most common childhood malignancies in central, eastern, and southern Africa. Although its unique clinical features have been established, biological mechanisms related to the causative agent, KS-associated herpes-virus (KSHV), have yet to be explored in children. We performed a prospective observational pilot study to explore associations between KSHV viral load (VL), human interleukin-6 (IL-6) and IL-10 levels, and clinical characteristics of 25 children with KS in Lilongwe, Malawi from June 2013-August 2015. The median age was 6.4 years. Lymphadenopathy was the most common site of KS involvement (64%), followed by skin and oral mucosa (44% each), woody edema (12%), and pulmonary (8%). Baseline samples for plasma KSHV VL, IL-6 and IL-10 analyses were available for 18/25 patients (72%) at time of KS diagnosis. KSHV VL was detectable at baseline in 12/18 (67%) patients, the median baseline IL-6 level was 8.53 pg/mL (range 4.31-28.33), and the median baseline IL-10 level was 19.53 pg/mL (range 6.91-419.69). Seven (39%) patients presented with an IL-6 level > 10 pg/mL (exceeding twice the upper limit of normal). Detectable KSHV VL was significantly associated with lymphadenopathic KS (p = 0.004), while having undetectable KSHV VL was associated with a higher likelihood of presenting with hyperpigmented skin lesions (p = 0.01). Detectable KSHV VL and elevated IL-6 levels are present in a subset of children with KS. Lytic activation of KSHV and associated elevation in KSHV VL may contribute to the unique clinical manifestations of pediatric KS in KSHV-endemic regions of Africa.

Racial/ethnic disparities and incidence of malignant peripheral nerve sheath tumors: results from the Surveillance, Epidemiology, and End Results Program, 2000-2014.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are rare tumors, generally high-grade, and comprise ~ 5-10% of soft tissue sarcomas. Over two-thirds of MPNSTs metastasize, and upwards of 40% clinically recur. Etiologic risk factors for MPNSTs are historically understudied. There is evidence to suggest MPNST incidence differs across racial/ethnic groups in pediatric populations. Therefore, we sought to estimate differences in MPNST incidence by race/ethnicity among all ages in the United States. METHODS: Incidence data were obtained from the Surveillance, Epidemiology, and End Results (SEER-18) Program, 2000-2014. Race/ethnicity was categorized as: White; Black; Asian; Other; and Latino/a ("Spanish-Hispanic-Latino"). Latino/a included all races, while all other categories excluded those identified as Latino/a. Age-adjusted incidence rate ratios (IRR) and 95% confidence intervals (CIs) were generated in SEER-STAT (v8.3.4). We estimated incidence rates among all ages, and among those diagnosed < 25 and ≥ 25 years. RESULTS: MPNST cases were abstracted from SEER-18 (n = 1047). Among all age groups, Blacks experienced an elevated incidence of MPNSTs compared to Whites (IRRBlacks = 1.26, 95% CI 1.04-1.50). Asian and Latinos/as experienced lower incidences compared to Whites (IRRAsians = 0.78, 95% CI 0.61-0.99; IRRLatinos/as = 0.84, 95% CI 0.69-1.02). In subgroup analyses, no statistically significant associations with MPNSTs were identified among cases diagnosed < 25 years of age, whereas the associations observed among all age groups were prominent among those diagnosed ≥ 25 years of age. CONCLUSIONS: Incidence rates of MPNSTs were highest in Blacks compared to Whites and other minority groups. This study suggests specific patterns exist in terms of race/ethnicity and age at diagnosis of MPNSTs.

Evaluation of maternal and perinatal characteristics on childhood lymphoma risk: A population-based case-control study.

BACKGROUND: Lymphoma is one of the most common pediatric malignancies; however, there are few well-established risk factors. Therefore, we investigated if maternal and perinatal characteristics influenced the risk of childhood lymphoma. PROCEDURE: Information on cases (n = 374) diagnosed with lymphoma and born in Texas for the period 1995-2011 was obtained from the Texas Cancer Registry. Birth certificate controls were randomly selected at a ratio of 10 controls per 1 case for the same period of 1995-2011. Unconditional logistic regression was used to generate unadjusted (OR) and adjusted odds ratios (aOR) and 95% confidence intervals (CI) for the following histologic subtypes: Hodgkin (HL), Burkitt (BL), and non-BL non-HLs (non-BL NHLs). RESULTS: Overall, our findings indicate specific maternal and perinatal characteristics influence childhood lymphoma risk. Mexico-born mothers were more likely to have offspring who developed BL compared to mothers born in the United States (U.S.; aOR: 2.15; 95% CI: 1.06-4.36). Further, mothers who resided at time of delivery in a county on the U.S.-Mexico border were more likely to give birth to offspring who developed non-BL NHL (aOR: 1.72; 95% CI: 1.11-2.67) compared to mothers not living on the U.S.-Mexico border at time of infant birth. Last, infants born large-for-gestational-age experienced a twofold increase in BL risk (aOR: 2.00; 95% CI: 1.10-3.65). CONCLUSIONS: In this population-based assessment, we confirmed previously reported risk predictors of childhood lymphoma, including sex of infant, while highlighting novel risk factors that warrant assessment in future studies.

Family-based exome-wide assessment of maternal genetic effects on susceptibility to childhood B-cell acute lymphoblastic leukemia in hispanics.

BACKGROUND: Children of Hispanic ancestry have a higher incidence of acute lymphoblastic leukemia (ALL) compared with other ethnic groups, but to the authors' knowledge, the genetic basis for these racial disparities remain incompletely understood. Genome-wide association studies of childhood ALL to date have focused on inherited genetic effects; however, maternal genetic effects (the role of the maternal genotype on phenotype development in the offspring) also may play a role in ALL susceptibility. METHODS: The authors conducted a family-based exome-wide association study of maternal genetic effects among Hispanics with childhood B-cell ALL using the Illumina Infinium HumanExome BeadChip. A discovery cohort of 312 Guatemalan and Hispanic American families and an independent replication cohort of 152 Hispanic American families were used. RESULTS: Three maternal single-nucleotide polymorphisms (SNPs) approached the study threshold for significance after correction for multiple testing (P<1.0 × 10-6 ): MTL5 rs12365708 (testis expressed metallothionein-like protein [tesmin]) (relative risk [RR], 2.62; 95% confidence interval [95% CI], 1.61-4.27 [P = 1.8 × 10-5 ]); ALKBH1 rs6494 (AlkB homolog 1, histone H2A dioxygenase) (RR, 3.77; 95% CI, 1.84-7.74 [P = 3.7 × 10-5 ]); and NEUROG3 rs4536103 (neurogenin 3) (RR, 1.75; 95% CI, 1.30-2.37 [P = 1.2 × 10-4 ]). Although effect sizes were similar, these SNPs were not nominally significant in the replication cohort in the current study. In a meta-analysis comprised of the discovery cohort and the replication cohort, these SNPs were still not found to be statistically significant after correction for multiple comparisons (rs12365708: pooled RR, 2.27 [95% CI, 1.48-3.50], P = 1.99 × 10-4 ; rs6494: pooled RR, 2.31 [95% CI, 1.38-3.85], P = .001; and rs4536103: pooled RR, 1.67 [95% CI, 1.29-2.16] P = 9.23 × 10-5 ). CONCLUSIONS: In what to the authors' knowledge is the first family-based based exome-wide association study to investigate maternal genotype effects associated with childhood ALL, the results did not implicate a strong role of maternal genotype on disease risk among Hispanics; however, 3 maternal SNPs were identified that may play a modest role in susceptibility. Cancer 2016;122:3697-704. © 2016 American Cancer Society.

Modifiable Lifestyle Risk Factors in Adult Survivors of Childhood Cancer: A Nationally Representative Study.

OBJECTIVES: Given the vulnerable health condition of adult childhood cancer survivors, it is essential that they develop positive health behaviors to minimize controllable health risks. Therefore, we evaluated if adult survivors of non-childhood cancer and childhood cancer differ in the odds of each modifiable risk factor compared with each other and compared with the general population. METHODS: This nationally representative study leveraged the National Health Interview Survey (NHIS) sample from 2000 to 2018 and the Behavioral Risk Factor Surveillance System (BRFSS) sample from 2016 to 2021. Our study population included adults diagnosed with cancer when they were ≤14 years of age. Outcomes included physical activity, body mass index (BMI), current smoking, ever-smoking, alcohol use, and binge drinking. RESULTS: Insufficient physical activity was not statistically significant in the BRFSS, but in the NHIS, childhood cancer survivors had significantly more insufficient physical activity compared with non-childhood cancer survivors (aOR 1.29, P =0.038) and the general population (aOR 1.40, P =0.006). Childhood cancer survivors also had a higher likelihood of being significantly underweight (aOR 1.84, P =0.018) and having ever-smoked (aOR 1.42, P =0.001) compared with the general population in the NHIS. There was a significantly higher likelihood of smoking among childhood cancer survivors in the BRFSS (aOR 2.02, P =0.004). CONCLUSIONS: The likelihoods of many risky behaviors between adult childhood cancer survivors and general population controls were comparable, although rates of physical activity may be decreased, and rates of smoking may be increased among childhood cancer survivors. Targeted interventions are needed to promote healthy behaviors in this vulnerable population.

HERVs and Cancer-A Comprehensive Review of the Relationship of Human Endogenous Retroviruses and Human Cancers.

Genomic instability and genetic mutations can lead to exhibition of several cancer hallmarks in affected cells such as sustained proliferative signaling, evasion of growth suppression, activated invasion, deregulation of cellular energetics, and avoidance of immune destruction. Similar biological changes have been observed to be a result of pathogenic viruses and, in some cases, have been linked to virus-induced cancers. Human endogenous retroviruses (HERVs), once external pathogens, now occupy more than 8% of the human genome, representing the merge of genomic and external factors. In this review, we outline all reported effects of HERVs on cancer development and discuss the HERV targets most suitable for cancer treatments as well as ongoing clinical trials for HERV-targeting drugs. We reviewed all currently available reports of the effects of HERVs on human cancers including solid tumors, lymphomas, and leukemias. Our review highlights the central roles of HERV genes, such as gag, env, pol, np9, and rec in immune regulation, checkpoint blockade, cell differentiation, cell fusion, proliferation, metastasis, and cell transformation. In addition, we summarize the involvement of HERV long terminal repeat (LTR) regions in transcriptional regulation, creation of fusion proteins, expression of long non-coding RNAs (lncRNAs), and promotion of genome instability through recombination.

Pediatric HIV+ Kaposi sarcoma exhibits clinical, virological, and molecular features different from the adult disease.

BACKGROUNDKaposi sarcoma (KS) is among the most common childhood cancers in Eastern and Central Africa. Pediatric KS has a distinctive clinical presentation compared with adult KS, which includes a tendency for primary lymph node involvement, a considerable proportion of patients lacking cutaneous lesions, and a potential for fulminant disease. The molecular mechanisms or correlates for these disease features are unknown.METHODSThis was a cross-sectional study. All cases were confirmed by IHC for KS-associated herpesvirus (KSHV) LANA protein. Baseline blood samples were profiled for HIV and KSHV genome copy numbers by qPCR and secreted cytokines by ELISA. Biopsies were characterized for viral and human transcription, and KSHV genomes were determined when possible.RESULTSSeventy participants with pediatric KS were enrolled between June 2013 and August 2019 in Malawi and compared with adult patients with KS. They exhibited high KSHV genome copy numbers and IL-6/IL-10 levels. Four biopsies (16%) had a viral transcription pattern consistent with lytic viral replication.CONCLUSIONThe unique features of pediatric KS may contribute to the specific clinical manifestations and may direct future treatment options.FUNDINGUS National Institutes of Health U54-CA-254569, PO1-CA019014, U54-CA254564, RO1-CA23958.

Maternal and perinatal factors are associated with risk of pediatric central nervous system tumors and poorer survival after diagnosis.

Central nervous system (CNS) tumors are the most common solid tumors in children. Findings on the role of maternal and perinatal factors on the susceptibility or outcome of these tumors are inconclusive. Therefore, we investigated the association between these early-life factors, risk, and survival of pediatric CNS tumors, using data from one of the world's largest and most diverse cancer registries. Information on pediatric CNS tumor cases (n = 1950) for the period 1995-2011 was obtained from the Texas Cancer Registry. Birth certificate controls were frequency-matched on birth year at a ratio of 10:1 for the same period. Evaluated maternal and perinatal variables were obtained from birth records. Unconditional logistic regression was used to generate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for etiological factors. Additionally, Cox proportional hazards regression was employed to assess adjusted hazard ratios (HRs) and 95% CIs for survival factors. The results indicated that Hispanic and non-Hispanic black mothers were less likely to have children with CNS tumors compared to non-Hispanic white mothers (OR 0.88 [95% CI 0.78-0.98] P-value = 0.019; OR 0.79 [95% CI 0.67-0.93 P-value = 0.004], respectively). Infants born large for gestational age (OR 1.26 [95% CI 1.07-1.47] P-value = 0.004) and those delivered pre-term (OR 1.19 [95% CI 1.04-1.38] P-value = 0.013) showed an increased risk of CNS tumors. Infants born by vaginal forceps or vacuum delivery had a higher risk of CNS tumors compared to those born by spontaneous vaginal delivery (OR 1.35 [95% CI 1.12-1.62] P-value = 0.002). Additionally, offspring of Hispanic and non-Hispanic black mothers showed a higher risk of death (HR 1.45 [95% CI 1.16-1.80] P-value = 0.001; HR 1.53 [95% CI 1.12-2.09] P-value = 0.008, respectively). Infants born by cesarean had a higher risk of death compared to those delivered vaginally (HR 1.28 [95% CI 1.05-1.57] P-value = 0.016). These findings indicate the important role of maternal and perinatal characteristics in the etiology and survival of these clinically significant malignancies.

Residence in a Hispanic Enclave Is Associated with Inferior Overall Survival among Children with Acute Lymphoblastic Leukemia.

Hispanic children with acute lymphoblastic leukemia (ALL) experience poorer overall survival (OS) than non-Hispanic White children; however, few studies have investigated the social determinants of this disparity. In Texas, many Hispanic individuals reside in ethnic enclaves-areas with high concentrations of immigrants, ethnic-specific businesses, and language isolation, which are often socioeconomically deprived. We determined whether enclave residence was associated with ALL survival, overall and among Hispanic children. We computed Hispanic enclave index scores for Texas census tracts, and classified children (N = 4083) as residing in enclaves if their residential tracts scored in the highest statewide quintile. We used Cox regression to evaluate the association between enclave residence and OS. Five-year OS was 78.6% for children in enclaves, and 77.8% for Hispanic children in enclaves, both significantly lower (p < 0.05) than the 85.8% observed among children not in enclaves. Children in enclaves had increased risk of death (hazard ratio (HR) 1.20, 95% confidence interval (CI) 1.01-1.49) after adjustment for sex, age at diagnosis, year of diagnosis, metropolitan residence and neighborhood socioeconomic deprivation and after further adjustment for child race/ethnicity (HR 1.19, 95% CI 0.97-1.45). We observed increased risk of death when analyses were restricted to Hispanic children specifically (HR 1.30, 95% CI 1.03-1.65). Observations suggest that children with ALL residing in Hispanic enclaves experience inferior OS.

Altered mechanisms of genital development identified through integration of DNA methylation and genomic measures in hypospadias.

Hypospadias is a common birth defect where the urethral opening forms on the ventral side of the penis. We performed integrative methylomic, genomic, and transcriptomic analyses to characterize sites of DNA methylation that influence genital development. In case-control and case-only epigenome-wide association studies (EWAS) of preputial tissue we identified 25 CpGs associated with hypospadias characteristics and used one-sample two stage least squares Mendelian randomization (2SLS MR) to show a causal relationship for 21 of the CpGs. The largest difference was 15.7% lower beta-value at cg14436889 among hypospadias cases than controls (EWAS P = 5.4e-7) and is likely causal (2SLS MR P = 9.8e-15). Integrative annotation using two-sample Mendelian randomization of these methylation regions highlight potentially causal roles of genes involved in germ layer differentiation (WDHD1, DNM1L, TULP3), beta-catenin signaling (PKP2, UBE2R2, TNKS), androgens (CYP4A11, CYP4A22, CYP4B1, CYP4X1, CYP4Z2P, EPHX1, CD33/SIGLEC3, SIGLEC5, SIGLEC7, KLK5, KLK7, KLK10, KLK13, KLK14), and reproductive traits (ACAA1, PLCD1, EFCAB4B, GMCL1, MKRN2, DNM1L, TEAD4, TSPAN9, KLK family). This study identified CpGs that remained differentially methylated after urogenital development and used the most relevant tissue sample available to study hypospadias. We identified multiple methylation sites and candidate genes that can be further evaluated for their roles in regulating urogenital development.

Maternal Residential Proximity to Major Roadways and the Risk of Childhood Acute Leukemia: A Population-Based Case-Control Study in Texas, 1995-2011.

Acute leukemia is the most common pediatric malignancy. Some studies suggest early-life exposures to air pollution increase risk of childhood leukemia. Therefore, we explored the association between maternal residential proximity to major roadways and risk of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Information on cases with acute leukemia (n = 2030) was obtained for the period 1995-2011 from the Texas Cancer Registry. Birth certificate controls were frequency matched (10:1) on birth year (n = 20,300). Three residential proximity measures were assessed: (1) distance to nearest major roadway, (2) residence within 500 meters of a major roadway, and (3) roadway density. Multivariate logistic regression was used to generate adjusted odds ratios (aOR) and 95% confidence intervals (CI). Mothers who lived ≤500 meters to a major roadway were not more likely to have a child who developed ALL (OR = 1.03; 95% CI: 0.91-1.16) or AML (OR = 0.84; 95% CI: 0.64-1.11). Mothers who lived in areas characterized by high roadway density were not more likely to have children who developed ALL (OR = 1.06, 95% CI: 0.93-1.20) or AML (OR = 0.83, 95% CI: 0.61-1.13). Our results do not support the hypothesis that maternal proximity to major roadways is strongly associated with childhood acute leukemia. Future assessments evaluating the role of early-life exposure to environmental factors on acute leukemia risk should explore novel methods for directly measuring exposures during relevant periods of development.