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Purpose To evaluate the association between birth characteristics, including parental sociodemographic characteristics, and early-onset pituitary adenoma (PA) and craniopharyngioma. Methods Leveraging the population-based California Linkage Study of Early-onset Cancers, we identified the birth characteristics of incident cases with PA (n = 1,749) or craniopharyngioma (n = 227) who were born from 1978 to 2015 and diagnosed 1988–2015, as well as controls in a 50:1 ratio matched on birth year. Adjusted odds ratios (OR) and 95% confidence interval (CI) estimates were computed using unconditional multivariable logistic regression. Results Males had a lower risk of PA than females (OR = 0.37, 95%CI: 0.34–0.41), and Black (OR = 1.55, 95%CI: 1.30–1.84) or Hispanic (OR = 1.53, 95%CI: 1.34–1.74) individuals had a higher risk compared to non-Hispanic Whites. Older maternal age was positively associated with PA (OR = 1.09, 95%CI: 1.04–1.15 per 5 years, p Conclusion In this large, population-based study, female sex, older maternal age, higher maternal education, and Hispanic ethnicity and Black race compared to non-Hispanic White race, were associated with an increased risk of PA in children and young adults.

Genome-wide association studies have identified a growing number of single nucleotide polymorphisms (SNPs) associated with childhood acute lymphoblastic leukemia (ALL), yet the functional roles of most SNPs are unclear. Multiple lines of evidence suggest that epigenetic mechanisms may mediate the impact of heritable genetic variation on phenotypes. Here, we investigated whether DNA methylation mediates the effect of genetic risk loci for childhood ALL. We performed an epigenome-wide association study (EWAS) including 808 childhood ALL cases and 919 controls from California-based studies using neonatal blood DNA. For differentially methylated CpG positions (DMPs), we next conducted association analysis with 23 known ALL risk SNPs followed by causal mediation analyses addressing the significant SNP-DMP pairs. DNA methylation at CpG cg01139861, in the promoter region of IKZF1, mediated the effects of the intronic IKZF1 risk SNP rs78396808, with the average causal mediation effect (ACME) explaining ~30% of the total effect (ACME P = 0.0031). In analyses stratified by self-reported race/ethnicity, the mediation effect was only significant in Latinos, explaining ~41% of the total effect of rs78396808 on ALL risk (ACME P = 0.0037). Conditional analyses confirmed the presence of at least three independent genetic risk loci for childhood ALL at IKZF1, with rs78396808 unique to non-European populations. We also demonstrated that the most significant DMP in the EWAS, CpG cg13344587 at gene ARID5B (P = 8.61 × 10−10), was entirely confounded by the ARID5B ALL risk SNP rs7090445. Our findings provide new insights into the functional pathways of ALL risk SNPs and the DNA methylation differences associated with risk of childhood ALL.

Background: Hispanic ethnicity differences in the risk of early-onset Hodgkin lymphoma diagnosed at Methods: This study included 1,651 non-Hispanic White and 1,168 Hispanic cases with Hodgkin lymphoma endorsing a range of races diagnosed at the age of 0 to 37 years during 1988–2015 and 140,950 controls without cancer matched on race/ethnicity and year of birth from the California Linkage Study of Early-Onset Cancers. OR and 95% confidence intervals (CI) were estimated from multivariable logistic regression models. Results: Having a foreign-born mother versus a United States–born mother (i.e., the reference group) was associated with an increased risk of early-onset Hodgkin lymphoma among non-Hispanic Whites (OR = 1.52; 95% CI, 1.31–1.76; P < 0.01) and a decreased risk among Hispanics (OR = 0.78; 95% CI, 0.69–0.88; P < 0.01). Among both race groups, risk of early-onset Hodgkin lymphoma increased with birthweight and maternal age (all Ptrends < 0.01). Among non-Hispanic Whites, each 5-year increase in maternal age (OR = 1.11; 95% CI, 1.04–1.18; Ptrend < 0.01) and paternal age (OR = 1.07; 95% CI, 1.02–1.13; Ptrend < 0.01) was associated with increased risk of early-onset Hodgkin lymphoma. Compared with female Hispanics, male Hispanics had an increased risk of early-onset Hodgkin lymphoma (OR = 1.26; 95% CI, 1.12–1.42; P < 0.01). Conclusions: Maternal birthplace may play a role in risk of early-onset Hodgkin lymphoma that differs by ethnicity. Impact: The ethnic differences observed between certain birth characteristics, maternal birthplace, and early-onset Hodgkin lymphoma raise questions about the underlying biological, generational, lifestyle, residential, and genetic contributions to the disease.

Purpose: The incidence of Ewing sarcoma varies according to race and ethnicity, and genetic susceptibility is known to affect disease risk. Apart from these factors, the etiology of Ewing sarcoma is largely undescribed. Methods: We compared a population-based series of 556 Ewing sarcoma cases diagnosed in California in 1988-2015 with 50 controls per case frequency matched on the year of birth. Results: Compared to non-Latino Whites, Blacks (odds ratio [OR] = 0.07, 95% confidence interval [CI]:0.03-0.18), Asians (OR = 0.57, 95%CI: 0.41-0.80), and Latinos (OR = 0.73, 95% CI: 0.62-0.88) have a significantly lower risk of Ewing sarcoma. In a multivariable analysis controlling for race/ethnicity and other birth characteristics (e.g., gestational age, mode of delivery, birth order, maternal age), birthweight was also identified as a significant risk factor (OR = 1.09, 95%CI: 1.00-1.18 for each 500 g increase in birthweight). A separate family-based cancer clustering analysis did not suggest any strong role for familial predisposition alleles, despite evidence for such a role in other childhood sarcomas (rhabdomyosarcoma and osteosarcoma). Conclusions: In sum, this population-based study with minimal selection and no recruitment bias provides support for a role of accelerated fetal growth in the etiology of Ewing sarcoma in addition to more precise estimates of racial/ethnic variation in disease risk. This comparatively large analysis of birth characteristics and Ewing sarcoma in a multiethnic population should stimulate further investigations into genetic and environmental causes.

Background: Parental smoking is implicated in the etiology of acute lymphoblastic leukemia (ALL), the most common childhood cancer. We recently reported an association between an epigenetic biomarker of early-life tobacco smoke exposure at the AHRR gene and increased frequency of somatic gene deletions among ALL cases. Methods: Here, we further assess this association using two epigenetic biomarkers for maternal smoking during pregnancy—DNA methylation at AHRR CpG cg05575921 and a recently established polyepigenetic smoking score—in an expanded set of 482 B-cell ALL (B-ALL) cases in the California Childhood Leukemia Study with available Illumina 450K or MethylationEPIC array data. Multivariable Poisson regression models were used to test the associations between the epigenetic biomarkers and gene deletion numbers. Results: We found an association between DNA methylation at AHRR CpG cg05575921 and deletion number among 284 childhood B-ALL cases with MethylationEPIC array data, with a ratio of means (RM) of 1.31 [95% confidence interval (CI), 1.02–1.69] for each 0.1 β value reduction in DNA methylation, an effect size similar to our previous report in an independent set of 198 B-ALL cases with 450K array data [meta-analysis summary RM (sRM) = 1.32; 95% CI, 1.10–1.57]. The polyepigenetic smoking score was positively associated with gene deletion frequency among all 482 B-ALL cases (sRM = 1.31 for each 4-unit increase in score; 95% CI, 1.09–1.57). Conclusions: We provide further evidence that prenatal tobacco-smoke exposure may influence the generation of somatic copy-number deletions in childhood B-ALL. Impact: Analyses of deletion breakpoint sequences are required to further understand the mutagenic effects of tobacco smoke in childhood ALL.

Accelerated aging is a hallmark of Down syndrome (DS), with adults experiencing early-onset Alzheimer's disease and premature aging of the skin, hair, and immune and endocrine systems. Accelerated epigenetic aging has been found in the blood and brain tissue of adults with DS but when premature aging in DS begins remains unknown. We investigated whether accelerated aging in DS is already detectable in blood at birth. We assessed the association between age acceleration and DS using five epigenetic clocks in 346 newborns with DS and 567 newborns without DS using Illumina MethylationEPIC DNA methylation array data. We compared two epigenetic aging clocks (DNAmSkinBloodClock and pan-tissue DNAmAge) and three epigenetic gestational age clocks (Haftorn, Knight, and Bohlin) between DS and non-DS newborns using linear regression adjusting for observed age, sex, batch, deconvoluted blood cell proportions, and genetic ancestry. Targeted sequencing of GATA1 was performed in a subset of 184 newborns with DS to identify somatic mutations associated with transient abnormal myelopoiesis. DS was significantly associated with increased DNAmSkinBloodClock (effect estimate=0.2442, p

Ependymoma is the third most common brain tumor in children, with well-described molecular characterization but poorly understood underlying germline risk factors. To investigate whether genetic predisposition to longer telomere length influences ependymoma risk, we utilized case–control data from three studies: a population-based pediatric and adolescent ependymoma case–control sample from California (153 cases, 696 controls), a hospital-based pediatric posterior fossa type A (EPN-PF-A) ependymoma case–control study from Toronto’s Hospital for Sick Children and the Children’s Hospital of Philadelphia (83 cases, 332 controls), and a multicenter adult-onset ependymoma case–control dataset nested within the Glioma International Case-Control Consortium (GICC) (103 cases, 3287 controls). In the California case–control sample, a polygenic score for longer telomere length was significantly associated with increased risk of ependymoma diagnosed at ages 12–19 (P = 4.0 × 10−3), but not with ependymoma in children under 12 years of age (P = 0.94). Mendelian randomization supported this observation, identifying a significant association between genetic predisposition to longer telomere length and increased risk of adolescent-onset ependymoma (ORPRS = 1.67; 95% CI 1.18–2.37; P = 3.97 × 10−3) and adult-onset ependymoma (PMR-Egger = 0.042), but not with risk of ependymoma diagnosed before age 12 (OR = 1.12; 95% CI 0.94–1.34; P = 0.21), nor with EPN-PF-A (PMR-Egger = 0.59). These findings complement emerging literature suggesting that augmented telomere maintenance is important in ependymoma pathogenesis and progression, and that longer telomere length is a risk factor for diverse nervous system malignancies.

BackgroundEpendymoma is a histologically defined central nervous system tumor most commonly occurring in childhood. Population-level incidence differences by race/ethnicity are observed, with individuals of European ancestry at highest risk. We aimed to determine whether extent of European genetic ancestry is associated with ependymoma risk in US populations.MethodsIn a multi-ethnic study of Californian children (327 cases, 1970 controls), we estimated the proportions of European, African, and Native American ancestry among recently admixed Hispanic and African American subjects and estimated European admixture among non-Hispanic white subjects using genome-wide data. We tested whether genome-wide ancestry differences were associated with ependymoma risk and performed admixture mapping to identify associations with local ancestry. We also evaluated race/ethnicity-stratified ependymoma incidence data from the Central Brain Tumor Registry of the United States (CBTRUS).ResultsCBTRUS data revealed that African American and Native American children have 33% and 36%, respectively, reduced incidence of ependymoma compared with non-Hispanic whites. In genetic analyses, a 20% increase in European ancestry was associated with a 1.31-fold higher odds of ependymoma among self-reported Hispanics and African Americans (95% CI: 1.08–1.59, Pmeta = 6.7 × 10−3). Additionally, eastern European ancestral substructure was associated with increased ependymoma risk in non-Hispanic whites (P = 0.030) and in Hispanics (P = 0.043). Admixture mapping revealed a peak at 20p13 associated with increased local European ancestry, and targeted fine-mapping identified a lead variant at rs6039499 near RSPO4 (odds ratio = 1.99; 95% CI: 1.45–2.73; P = 2.2 × 10−5) but which was not validated in an independent set of posterior fossa type A patients.ConclusionsInterethnic differences in ependymoma risk are recapitulated in the genomic ancestry of ependymoma patients, implicating regions to target in future association studies.

Background Pediatric astrocytoma constitutes a majority of malignant pediatric brain tumors. Previous studies that investigated pediatric cancer predisposition have primarily been conducted in tertiary referral centers and focused on cancer predisposition genes. In this study, we investigated the contribution of rare germline variants to risk of malignant pediatric astrocytoma on a population level. Methods DNA samples were extracted from neonatal dried bloodspots from 280 pediatric astrocytoma patients (predominantly high grade) born and diagnosed in California and were subjected to whole-exome sequencing. Sequencing data were analyzed using agnostic exome-wide gene-burden testing and variant identification for putatively pathogenic variants in 175 a priori candidate cancer-predisposition genes. Results We identified 33 putatively pathogenic germline variants among 31 patients (11.1%) which were located in 24 genes largely involved in DNA repair and cell cycle control. Patients with pediatric glioblastoma were most likely to harbor putatively pathogenic germline variants (14.3%, N = 9/63). Five variants were located in tumor protein 53 (TP53), of which 4 were identified among patients with glioblastoma (6.3%, N = 4/63). The next most frequently mutated gene was neurofibromatosis 1 (NF1), in which putatively pathogenic variants were identified in 4 patients with astrocytoma not otherwise specified. Gene-burden testing also revealed that putatively pathogenic variants in TP53 were significantly associated with pediatric glioblastoma on an exome-wide level (odds ratio, 32.8, P = 8.04 × 10−7). Conclusion A considerable fraction of pediatric glioma patients, especially those of higher grade, harbor a putatively pathogenic variant in a cancer predisposition gene. Some of these variants may be clinically actionable or may warrant genetic counseling.

Background We evaluated the potential role of birth characteristics in the etiology of early-onset meningioma. Methods Leveraging a population-based linkage of California birth records (from 1978 to 2015) and cancer registry data (from 1988 to 2015), we identified 362 nonmalignant meningioma cases aged 0–37 years and selected 18 100 controls matched on year of birth. Cases and controls were compared with regard to birth characteristics, with adjusted odds ratios (ORs) and 95% confidence intervals (CIs) estimated from unconditional multivariable logistic regression models. We also conducted stratified analyses by race/ethnicity and age. Results Female sex (compared to male: OR = 1.43, 95% CI: 1.16 to 1.79; P Conclusions In this large population-based study less prone to selection and recall bias, higher birth order was associated with a reduced risk of early-onset meningioma, while female sex and Black race were linked to an increased risk. There were also indications of differential associations by race/ethnicity and age of diagnosis.

BACKGROUND AND AIM: Acute lymphoblastic leukemia (ALL) is the most common form of cancer in children. An environmental exposure that has been previously associated with childhood ALL is air polluti...

The risk of childhood acute lymphoblastic leukemia (ALL) differs across ethnic groups and there exist gaps in our understanding of the genetic risk of ALL as most studies took place in populations of predominantly European ancestries. In an effort to address these limitations, we performed a genetic meta-analysis of ALL in 76,317 participants across four ethnic groups, including 17,814 non-European individuals and 3,482 total cases. We replicated 15 out of 16 previously identified loci associated with ALL in our trans-ethnic analysis. We further identified five novel associations at genome-wide significance, including three novel loci and two secondary associations at previously known loci (17q12 and near CEBPE). The three putatively novel loci (rs9376090 near MYB/HBS1L, rs10998283 near TET1, and rs9415680 near JMJD1C/NRBF2) were previously shown to be associated with multiple blood cell traits and other hematopoietic cancers. Polygenic risk scores constructed from our trans-ethnic meta-analysis showed similar efficacy in independent Latino (LAT) and non-Latino white (NLW) ALL cohorts (AUC ∼ 0.67-0.68) and could partly explain the increased risk of ALL in LAT compared to NLW. Cross-population analysis also showed high but significantly less than 100% genetic correlation between LAT and NLW, suggesting potential differences in the underlying genetic architecture between ethnic groups. In summary, our findings enhance the understanding of genetic contribution to ALL risk across diverse populations and highlight the importance to include multiple ethnic groups in GWAS.Key PointsWe identified three novel loci on childhood acute lymphoblastic leukemia near genes previously associated with multiple blood cell traitsPolygenic risk scores using known and novel risk variants showed similar efficacy in Latino and non-Latino white Americans

Children with Down syndrome (DS) have a 20-fold increased risk of acute lymphoblastic leukemia (ALL) and distinct somatic features, including CRLF2 rearrangement in ∼50% of cases; however, the role of inherited genetic variation in DS-ALL susceptibility is unknown. We report the first genome-wide association study of DS-ALL, comprising a meta-analysis of 4 independent studies, with 542 DS-ALL cases and 1192 DS controls. We identified 4 susceptibility loci at genome-wide significance: rs58923657 near IKZF1 (odds ratio [OR], 2.02; Pmeta = 5.32 × 10-15), rs3731249 in CDKN2A (OR, 3.63; Pmeta = 3.91 × 10-10), rs7090445 in ARID5B (OR, 1.60; Pmeta = 8.44 × 10-9), and rs3781093 in GATA3 (OR, 1.73; Pmeta = 2.89 × 10-8). We performed DS-ALL vs non-DS ALL case-case analyses, comparing risk allele frequencies at these and other established susceptibility loci (BMI1, PIP4K2A, and CEBPE) and found significant association with DS status for CDKN2A (OR, 1.58; Pmeta = 4.1 × 10-4). This association was maintained in separate regression models, both adjusting for and stratifying on CRLF2 overexpression and other molecular subgroups, indicating an increased penetrance of CDKN2A risk alleles in children with DS. Finally, we investigated functional significance of the IKZF1 risk locus, and demonstrated mapping to a B-cell super-enhancer, and risk allele association with decreased enhancer activity and differential protein binding. IKZF1 knockdown resulted in significantly higher proliferation in DS than non-DS lymphoblastoid cell lines. Our findings demonstrate a higher penetrance of the CDKN2A risk locus in DS and serve as a basis for further biological insights into DS-ALL etiology.

Background: Philadelphia chromosome negative myeloproliferative neoplasms (MPN) have driver mutations that are acquired early in life, but median age at diagnosis for MPN is 65-69 years and they are infrequent among children, adolescents, and young adults. No epidemiological studies have examined the risk factors for early-onset MPN (EO-MPN), likely due to its rarity, and the etiology remains unclear. Methods: We evaluated associations between birth characteristics and EO-MPN risk in a population-based case-control study nested within a California birth cohort. The study included 219 cases of MPN (75 with polycythemia vera [PV], 114 with essential thrombocythemia [ET], and 30 with primary myelofibrosis) diagnosed at the age of 0-37 years in California during 1988-2015, as well as 10,950 controls randomly selected from the statewide birth cohort and frequency-matched on year of birth. Data on birth characteristics including gestational age, sex, birthweight, birth order, pregnancy complications (e.g., eclampsia, toxemia, diabetes), mode of delivery, and parental ages were retrieved from birth records maintained by the California Department of Public Health. Odds ratios (OR) and 95% confidence intervals (CI) were estimated from an unconditional multivariable logistic regression model that included year of birth and birth characteristics. Results: A higher birthweight was associated with a significantly lower risk of EO-MPN (age at diagnosis: 0-37 years), and the OR for the birthweight z-score was 0.87 (95% CI: 0.78-0.98). Individuals whose mothers experienced complications during pregnancy had a higher EO-MPN risk (OR=1.54, 95% CI: 1.08-2.19). Compared to individuals born to mothers at the age of 25-29 years, those born to mothers ≥35 years had a significantly increased risk of EO-MPN (OR=1.64, 95% CI: 1.09-2.47). Stratified analyses by MPN subtype identified male sex and pre-term birth as risk factors for PV, and lower birthweight, complications during pregnancy, and older paternal age as risk factors for ET. Associations between birth characteristics and risk of EO-MPN also exhibited variations based on age of diagnosis, with lower birthweight being a risk factor for those diagnosed at 0-19 years (n=71 cases) and pregnancy complications being a risk factor for those diagnosed at 20-37 years (n=148 cases). Conclusion: In this first-ever population-based study that examined EO-MPN, our findings support a role of birth characteristics in the etiology of this rare phenotype and underscore etiological heterogeneity by MPN subtype and age of diagnosis. Citation Format: Nikolai A. Podoltsev, Rong Wang, Joseph L. Wiemels, Libby M. Morimoto, Catherine Metayer, Xiaomei Ma. Birth characteristics and risk of early-onset myeloproliferative neoplasms in a population-based case-control study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5882.

BackgroundIL-6 contributes significantly to the chronic inflammatory process of rheumatoid arthritis (RA) and is elevated in serum and synovial fluid of RA patients.Sarilumab (SRL), a human anti-human IL-6 receptor alpha monoclonal antibody that blocks the signaling originated by the IL-6/IL-6R complex like tocilizumab (TCZ),is an effective treatment. Recently, an association between the therapeutic effect of TCZ and neutropenia after TCZ initiation was reported[1]. Neutropenia is a common adverse event of SRL in patients with RA, but the relationship between reduced neutrophil count and clinical response to SRL is still inconclusive. In EULAR 2020, we reported the association between serum soluble gp130 levels before SRL treatment and the efficacy of SRL[2]. It is also unclear whether there is a relationship between IL-6 axis cytokines and SRL-induced neutropenia.ObjectivesThe purpose of this study was to determine whether neutropenia at 1 month by SRL predicts clinical remission within 3 months and whether there is an association between IL-6 axis cytokines levels and SRL-induced neutropenia.MethodsThis research is a retrospective study. We reviewed medical records of RA patients initiating SRL between February 2018 and August 2021 in our hospital. The Clinical Disease Activity Index (CDAI) was evaluated at baseline (before initiating SRL) and 3 months after administration. Clinical remission was defined when CDAI decreased ≤ 2.8. Of the 66 patients treated with SRL, 42 patients with 3 months follow-up, valid CDAI and serum available were enrolled. The ratio of neutrophil counts 1 month after initiating SRL to those at baseline (neutrophil ratio) was also calculated. Serum samples were tested for IL-6 (Human IL-6 Quantikine ELISA Kit, R&D systems), sIL-6R (Human soluble IL-6R alpha Quantikine ELISA Kit, R&D systems) and sgp130 (Human soluble gp130 Quantikine ELISA Kit, R&D systems) using specific ELISAs according to the manufacturer’s instructions. The statistical analyses were performed with EZR 1.55, and p values less than 0.05 were considered significant.ResultsThe median age of patients was 69.0 (IQR: 59.3 - 73.8) years and the median of disease duration was 9.0 (3.0 - 16.0) years. Eighteen (42.9%) patients were biologics and Jakinibs naive. The baseline CDAI was median 16.7 (11.5 - 25.8). When comparing CDAI-remission group (clinical remission: CR) and non-CR group, Patients in the CR group had significantly shorter disease duration, were more Biologic and JAKinib naive, and had greater neutropenia 1 month after starting SRL (0.71 vs 0.94, P=0.0252). There was no significant difference in the baseline serum levels of IL-6, sIL-6R between the CR and non-CR groups, but baseline serum sgp130 levels in the CR group tended to be higher than in the non-CR group (264.9 vs 234.2 ng/mL, P=0.0592). Univariate logistic regression analysis suggested Biologics and JAKinibs naive (odds ratio (OR) 6.68, p = 0.0317), baseline serum sgp130 levels (OR 8.608, P=0.0312) as predictors of CDAI remission treated with SRL at 3 months. Although not significant, neutrophil ratio ≤ 0.8 was associated with achieving remission (OR 6.67, P=0.0537). Univariate logistic regression for neutrophil ratio ≤ 0.8 did not show any relevant factors, including higher baseline serum sgp130 levels (OR 1.25, P=0.782).ConclusionA 20% or greater decrease in neutrophil count after 1 month of SRL treatment and a high baseline serum sgp130 level independently predict clinical remission within 3 months.References[1]Nakajima T, Watanabe R, Hashimoto M, Murata K, Murakami K, Tanaka M, et al. Neutrophil count reduction 1 month after initiating tocilizumab can predict clinical remission within 1 year in rheumatoid arthritis patients. Rheumatol Int. 2021;1rin[2]Yoshikawa T, Furukawa T, Tamura M, Hashimoto T, Morimoto M, Azuma N, et al. FRI0113 THE BASELINE SOLUBLE GP130 IS ASSOCIATED WITH THE RESPONSE OF RHEUMATOID ARTHRITIS PATIENTS TO SARILUMAB. Ann Rheum Dis. 2020;79(Suppl 1):637.1-637.Disclosure of InterestsNone declared

BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disease that primarily affects the multiple joints.The elucidation of the pathogenesis of RA has progressed dramatically in recent decades, and among the many cytokines involved in the pathogenesis of RA, interleukin (IL)-6 and TNF-α are known to be the major pro-inflammatory cytokines that are abundant in the bloodstream and synovial tissue. JAK inhibitors (JAKinibs) such as tofacitinib and baricitinib are used in the treatment of RA by inhibiting JAK, which in turn inhibits the signaling of various cytokines including IL-6. However, predictors of the response to JAKinibs are still required.ObjectivesWe aimed to combine soluble TNF receptor (sTNFR) I, sTNFR II, IL-6, soluble IL-6R (sIL-6R) and soluble gp130 (sgp130) levels to identify groups of JAKinibs responses in RA patients.MethodsThis research is a retrospective study. We reviewed medical records of RA patients initiating JAKinibs between July 2013 and July 2021 in our hospital. The Simplified Disease Activity Index (SDAI) was evaluated at baseline and 3, 6 months after JAKinibs administration. Clinical remission was defined when SDAI decreased ≤ 3.3. Of the 125 patients treated with JAKinibs, 89 patients with 6 months follow-up, valid SDAI and serum available were enrolled. Serum samples were tested for IL-6 (Human IL-6 Quantikine ELISA Kit, R&D systems), sIL-6R (Human soluble IL-6R alpha Quantikine ELISA Kit, R&D systems) and sgp130 (Human soluble gp130 Quantikine ELISA Kit, R&D systems), sTNFR I (Human TNF RI/TNFRSF1A Quantikine ELISA Kit DRT100) and sTNFR II (Human sTNF RII/TNFRSF1B Quantikine ELISA Kit DRT200) using specific ELISAs according to the manufacturer’s instructions. The statistical analyses were performed with EZR 1.55, and p values less than 0.05 were considered significant.ResultsThe median age of patients was 62 (IQR: 51 - 72) years and the median of disease duration was 6.0 (2.0 - 16.0) years. Twenty-seven (30.3%) patients were biologics and Jakinibs naive. The baseline SDAI was median 18.9 (12.7 - 27.9). When comparing SDAI-remission group (clinical remission: CR) and non-remission group, there were no significant differences in any of the baseline clinical parameters. There was no significant difference in the serum levels of IL-6, sIL-6R and sgp130 between the CR and non-CR groups, but the serum levels of sTNFR I and sTNFR II in the CR group were significantly lower than non-CR group. Univariate logistic regression analysis suggested Biologics and JAKinibs naive (odds ratio (OR) 3.58, p = 0.015), baseline Log sTNFR II levels (OR 0.013, P=0.034) as predictors of SDAI remission treated with JAKinibs at 6 months. Although not significant, Stage IV (OR 0.211, P=0.082) and baseline Log sTNFR I serum levels (OR 0.013, P=0.065) were associated with clinical remission.ConclusionRA patients could be easily stratified prior to JAKinibs intervention with serum sTNFR II and sTNFR I levels, not but IL-6 axis cytokines (IL-6, sIL-6R and sgp130).Univariate logistic regression analysis for clinical remission in patients treated with JAKinibs. Odds Ratio[95% C.I.]P ValueAge, year0.973[0.942 - 1.010]0.104Female (%)0.820[0.231 - 2.910]0.759BMI0.968[0.847 - 1.110]0.627Duration, year0.952[0.897 - 1.010]0.110StageIreferrenceII0.857[0.218 - 3.370]0.825III0.444[0.072 - 2.740]0.382IV0.211[0.036 - 1.220]0.082Biologic/JAKi naïve3.580[1.280 - 9.950]0.015JAKi Drug-Baricitinibreferrence-Tofacitinib1.780[0.659 - 4.800]0.256MTX use1.640[0.532 - 5.30]0.390PSL use0.476[0.176 - 1.290]0.143SASP use0.783[0.268 - 2.290]0.654IGU use0.328[0.039 - 2.750]0.304BUC use0.436[0.051 - 3.760]0.450TAC use0.233[0.029 - 1.910]0.1750W IL-6, pg/mL0.991[0.977 - 1.000]0.1980W sIL-6R, ng/mL0.983[0.947 - 1.02]0.3690W sgp130, ng/mL0.998[0.994 - 1.000]0.4440W sTNFR II/I ratio0.808[0.222 - 2.940]0.7460W Log sTNFR II, pg/mL0.002[0.0000653 - 0.634]0.0340W Log sTNFR I, pg/mL0.013[0.000126 - 1.300]0.065Disclosure of InterestsNone declared

Background: The etiology of non-Hodgkin lymphoma (NHL) in children and in adolescents and young adults (AYA) is not well understood. Methods: We evaluated potential associations between mode of delivery, birth characteristics, and NHL risk in a population-based case–control study, which included 3,064 cases of NHL [490 with Burkitt lymphoma, 981 with diffuse large B-cell lymphoma (DLBCL), and 978 with T-cell NHL) diagnosed at the age of 0 to 37 years in California during 1988 to 2015 and 153,200 controls frequency matched on year of birth. Odds ratios (OR) and 95% confidence intervals (CI) were estimated from an unconditional multivariable logistic regression model that included year of birth and birth characteristics. Results: Individuals born via cesarean section had a decreased risk of pediatric Burkitt lymphoma (age 0–14 years; OR = 0.71, 95% CI: 0.51–0.99) and pediatric T-cell NHL (OR = 0.73, 95% CI: 0.55–0.97) compared with those born vaginally. Having a birth order of second (OR = 0.73, 95% CI: 0.57–0.93) or third or higher (OR = 0.76, 95% CI: 0.58–0.99) was associated with a lower risk of pediatric T-cell NHL compared with first-borns. AYA (age 15–37 years) with a heavier birthweight had an elevated risk of DLBCL (OR for each kg = 1.16, 95% CI: 1.00–1.35). Associations between other birth characteristics, including plurality, maternal age, maternal education, and NHL risk, also exhibited variations across subgroups based on age of diagnosis and histologic subtype. Conclusions: These findings support a role of mode of delivery and birth characteristics in the etiology of early-onset NHL. Impact: This study underscores the etiologic heterogeneity of early-onset NHL.

Real-time rendering of closed-loop visual environments is important for next-generation understanding of brain function and behaviour, but is often prohibitively difficult for non-experts to implement and is limited to few laboratories worldwide. We developed BonVision as an easy-to-use open-source software for the display of virtual or augmented reality, as well as standard visual stimuli. BonVision has been tested on humans and mice, and is capable of supporting new experimental designs in other animal models of vision. As the architecture is based on the open-source Bonsai graphical programming language, BonVision benefits from native integration with experimental hardware. BonVision therefore enables easy implementation of closed-loop experiments, including real-time interaction with deep neural networks, and communication with behavioural and physiological measurement and manipulation devices.

Background: Incidence rates of thyroid cancer in children and young adults (age 0-19 years) have nearly doubled over a recent 15-year period in the United States. Children with thyroid cancer may require long-term therapy and surveillance and are at greater risk for second primary malignancies. High-dose exposure to ionizing radiation is the only known nongenetic risk factor; the vast majority of cases have an unknown etiology. Methods: We conducted a population-based nested case-control study to evaluate the relationship between a range of birth characteristics and the risk of pediatric thyroid cancer. Using linked birth records and cancer registry data from California, we included 1012 cases who were diagnosed with first primary thyroid cancer at the age of 0-19 years from 1988 to 2015 and 50,600 birth-year matched controls (1:50 case to control ratio). We estimated adjusted odds ratios (OR) and 95% confidence intervals (CI) by using multivariable logistic regression models applied to the full population and stratified by thyroid cancer subtypes (papillary and follicular), race/ethnicity (white and Hispanic), and age at diagnosis (0-14 and 15-19 years). Results: Hispanic ethnicity (OR: 1.20 [CI 1.01-1.42]), higher birth weight (OR: 1.11 [CI 1.04-1.18] per 500g), and higher maternal education (13-15 years OR: 1.35 [CI 1.09-1.68], 16+ years OR: 1.35 [CI 1.07-1.71]) were associated with an increased risk of pediatric thyroid cancer, while male sex (OR: 0.21 [CI 0.18-0.25]) and higher birth order (third or higher OR: 0.81 [CI 0.68-0.98]) were associated with a decreased risk. Some heterogeneity was observed across subtype, most notably an elevated OR with higher birth order for follicular thyroid cancer, in contrast to the reduced risk for this category among papillary thyroid cancer cases (p-value for interaction = 0.01). Hispanic ethnicity was a risk factor for papillary, but not follicular thyroid cancer (p-value for interaction = 0.07). Conclusions: In this population-based study of birth characteristics and pediatric thyroid cancer, we identified several important risk factors for pediatric thyroid cancer, including female sex, Hispanic ethnicity, higher birth weight, higher maternal educational attainment, and lower birth order. Our data provide new areas for replication and investigation of biological mechanisms for this poorly understood malignancy.

Conventional hydrides obtained thus far contain at least one type of metal with high hydrogen affinity, which can form metal hydrides near ambient pressure. In contrast, we synthesized metal hydrides comprising only metals with low hydrogenation affinity which are metals that do not form metal hydrides MHx (M stands for metal element, x > 0.5) below 1 GPa. This is because such hydrides are rare and would demonstrate novel properties and functionalities. To provide a guideline for synthesizing such hydrides, we clarified the hydrogenation reaction processes of FexMo1−x alloys at 6 GPa and 750 °C over a wide composition range of 0.41 ≤ x ≤ 0.88, where both Fe and Mo demonstrate low hydrogen affinities. Depending on the alloy composition, the hydrogenation reaction process can be classified into three types. Two kinds of novel hydrides were synthesized herein. First, FexMo1−xH (0.50 ≤ x ≤ 0.74) with metal elements at the vertices of hexagonal close-packed (hcp) lattices, and second, Fe0.88Mo0.12H with a complex crystal structure, which is likely to be a long-period close-packed structure.

Context dependent top-down modulation in visual processing has been a topic of wide interest. Recent findings on context dependent modulation, combined with the tools available to investigate network mechanisms in the mouse, make the mouse primary visual cortex an ideal system to investigate context-dependent modulation. However, the distribution of inputs to V1 from across the brain is still relatively unknown. In this study, we investigate inputs to V1 by injecting cholera toxin B subunit (CTB), a retrograde tracer, across the extent of V1. To identify CTB labelled cell bodies and quantify their distribution across various brain regions, we developed a software pipeline that maps each labelled cell body to its corresponding brain region. We found over fourteen brain regions that provided inputs to V1. Higher visual areas (HVAs) provided the most inputs to V1, followed by the retrosplenial, cingulate, and other sensory cortices. As our injections spanned a range of coordinates along the mediolateral axis of V1, we asked if there was any topographic organisation of inputs to V1: do particular areas project preferentially to specific regions of V1. Based on the distribution of inputs from different HVAs, injection sites broadly clustered into two groups, consistent with a retinotopic separation into sites within the central visual field and the peripheral visual field. Furthermore, the number of cells detected in HVAs was correlated to the azimuthal retinotopic location of each injection site. This topographic organization of feedback projections along the medio-lateral axis of V1 suggests that V1 cells representing peripheral vs central visual fields are differentially modulated by HVAs, which may have an ethological relevance for a navigating animal.

Background: Synovial sarcoma is a rare cancer with peak incidence in the young adult period. Despite poor outcomes of this aggressive cancer, there is little epidemiologic research addressing its etiology. Methods: We collected birth characteristic data on synovial sarcoma cases born during 1978–2015 and diagnosed during 1988–2015 in California (n = 244), and 12,200 controls frequency-matched on year of birth. We also constructed a dataset of cancer cases in siblings of sarcoma subjects to assess familial risk. Results: In multivariable logistic regression analyses, synovial sarcoma was more frequent in Hispanics compared with non-Hispanic whites [OR, 1.48; 95% confidence interval (CI), 1.06–2.08]. Higher birth weight was a risk factor in Hispanics; each 500 g increase in birth weight was associated with a 22% increase in disease risk (OR, 1.22; 95% CI, 1.00–1.48). Also, a strong role for birth order was suggested, with highest risk for the first born (second child compared with first: OR, 0.61; 95% CI, 0.44–0.84; third or later compared with first: OR, 0.53; 95% CI, 0.36–0.77). Siblings of patients with synovial sarcoma did not display elevated cancer incidence, suggesting the low likelihood that strong familial predisposition alleles play a significant role in this disease. Conclusions: The associations with birth weight and birth order suggest that nutritional, developmental, and environmental factors may play a role in the etiology of synovial sarcoma. Impact: Further epidemiologic research on synovial sarcoma should evaluate epigenetic and developmental mechanisms and the formation of the archetypical t(X;18) translocation that defines this disease.

Honeycomb-like porous chitosan (CS) films are attractive tools for developing functional materials for filters, catalyses, adsorbents, biomaterials

Surrogate measures of infectious exposures have been consistently associated with lower childhood acute lymphoblastic leukemia (ALL) risk. However, recent reports have suggested that physician-diagnosed early-life infections increase ALL risk, thereby raising the possibility that stronger responses to infections might promote risk. We examined whether medically diagnosed infections were related to childhood ALL risk in an integrated health-care system in the United States. Cases of ALL (n = 435) diagnosed between 1994–2014 among children aged 0–14 years, along with matched controls (n = 2,170), were identified at Kaiser Permanente Northern California. Conditional logistic regression was used to estimate risk of ALL associated with history of infections during first year of life and across the lifetime (up to diagnosis). History of infection during first year of life was not associated with ALL risk (odds ratio (OR) = 0.85, 95% confidence interval (CI): 0.60, 1.21). However, infections with at least 1 medication prescribed (i.e., more “severe” infections) were inversely associated with risk (OR = 0.42, 95% CI: 0.20, 0.88). Similar associations were observed when the exposure window was expanded to include medication-prescribed infections throughout the subjects’ lifetime (OR = 0.52, 95% CI: 0.32, 0.85).

Visual systems can exploit spatial correlations in the visual scene by using retinotopy, the organizing principle by which neighboring cells encode neighboring spatial locations. However, retinotopy is often lost, such as when visual pathways are integrated with other sensory modalities. How is spatial information processed in the absence of retinotopy? Here, we focused on visual looming responsive LC6 cells in Drosophila, a population whose dendrites collectively tile the visual field, but whose axons form a single glomerulus—a structure lacking retinotopic organization—in the central brain. We identified multiple glomerulus neurons and found that they respond to looming in different portions of the visual field, unexpectedly preserving spatial information. Through EM reconstruction of all LC6 synaptic inputs to the glomerulus, we found that LC6 and downstream cell types form circuits within the glomerulus that establish spatial readout of visual features and contralateral suppression—mechanisms that transform visual information for behavioral control.

Objective To evaluate fenebrutinib, an oral and highly selective noncovalent inhibitor of Bruton's tyrosine kinase (BTK), in patients with active rheumatoid arthritis (RA). Methods Patients with RA and an inadequate response to methotrexate (MTX) (cohort 1; n = 480) were randomized to receive fenebrutinib (50 mg once daily, 150 mg once daily, or 200 mg twice daily), adalimumab (40 mg every other week), or placebo. Patients with RA and an inadequate response to tumor necrosis factor inhibitors (cohort 2; n = 98) received fenebrutinib (200 mg twice daily) or placebo. Both cohorts continued MTX therapy. Results In cohort 1, the percentages of patients in whom American College of Rheumatology 50% improvement criteria (ACR50) was achieved at week 12 were similar in the fenebrutinib 50 mg once daily and placebo groups, and were higher in the fenebrutinib 150 mg once daily group (28%) and 200 mg twice daily group (35%) than in the placebo group (15%) (P = 0.016 and P = 0.0003, respectively). Fenebrutinib 200 mg twice daily and adalimumab (36%) were comparable (P = 0.81). In cohort 2, ACR50 was achieved in more patients receiving fenebrutinib 200 mg twice daily (25%) than placebo (12%) (P = 0.072). The most common adverse events in the fenebrutinib groups included nausea, headache, anemia, and upper respiratory tract infections. Fenebrutinib had significant effects on myeloid and B cell biomarkers (CCL4 and rheumatoid factor). Fenebrutinib and adalimumab caused overlapping as well as distinct changes in B cell and myeloid biomarkers. Conclusion Fenebrutinib demonstrates efficacy comparable to adalimumab in patients with an inadequate response to MTX, and safety consistent with existing immunomodulatory therapies for RA. These data support targeting both B and myeloid cells via this novel mechanism for potential efficacy in the treatment of RA.

Real-time rendering of closed-loop visual environments is necessary for next-generation understanding of brain function and behaviour, but is prohibitively difficult for non-experts to implement and is limited to few laboratories worldwide. We developed BonVision as an easy- to-use software for display of virtual or augmented reality as well as standard visual stimuli. As the architecture is based on the open-source Bonsai graphical programming language, BonVision benefits from Bonsai’s native integration with experimental hardware. BonVision therefore enables easy implementation of closed-loop experiments and communication with behavioural and physiological measurement and manipulation devices, while being open-source, easy to install, and able to run on standard personal computers.

Background The incidence of testicular germ cell tumors (TGCT) is increasing steadily in the United States, particularly among Latinos. TGCT is thought to be initiated in utero and exposure to endocrine-disrupting chemicals, suspected contributors to TGCT pathogenesis, during this critical developmental period may contribute to the rise. Objectives To assess the relationship between fetal exposure to agricultural endocrine-disrupting pesticides (EDPs) and TGCT risk among adolescents in a diverse population in California. Methods We conducted a registry-based case-control study of TGCT. Cases, diagnosed between 1997 and 2011, were 15–19 years of age (n = 381). Controls were matched on birth year and race/ethnicity (n = 762). Quantities (kilograms) of 33 pesticides applied within 3 km and 1 km radii of each individual's address before birth were estimated using the Pesticide Use Reporting database. Odds ratios (OR), 95% confidence intervals (CI), and population attributable risk (PAR) were calculated for each EDP (using log-2 transformed values). Risk models considered race/ethnicity, birth year, and neighborhood socioeconomic status. Results A doubling of nearby acephate applications (3 km and 1 km radii) and malathion applications (1 km radius) was associated with increased risks of TGCT among Latinos only (OR = 1.09; 95% CI:1.01–1.17; 1.30; 95% CI:1.08–1.57, and 1.19; 95% CI:1.01–1.39, respectively), whereas application of carbaryl within a 3 km radius increased TGCT risk in non-Latinos only (OR = 1.14, 95% CI:1.01–1.28). We estimate that acephate was associated with approximately 10% of the TGCT PAR, malathion with 3% and carbaryl with 1%. Conclusions TGCT among adolescents in California was associated with prenatal residential proximity to acephate and malathion among Latinos, and with carbaryl among non-Latinos. These results suggest that the rise in TGCT risk among Latinos may be associated with exposure to these pesticides.

Genome-wide association studies of childhood acute lymphoblastic leukemia (ALL) have identified regions of association at PIP4K2A and upstream of BMI1 at chromosome 10p12.31-12.2. The contribution of both loci to ALL risk and underlying functional variants remain to be elucidated. We carried out single nucleotide polymorphism (SNP) imputation across chromosome 10p12.31-12.2 in Latino and non-Latino white ALL cases and controls from two independent California childhood leukemia studies, and additional Genetic Epidemiology Research on Aging study controls. Ethnicity-stratified association analyses were performed using logistic regression, with meta-analysis including 3,133 cases (1,949 Latino, 1,184 non-Latino white) and 12,135 controls (8,584 Latino, 3,551 non-Latino white). SNP associations were identified at both BMI1 and PIP4K2A. After adjusting for the lead PIP4K2A SNP, genome-wide significant associations remained at BMI1, and vice-versa (pmeta < 10-10 ), supporting independent effects. Lead SNPs differed by ethnicity at both peaks. We sought functional variants in tight linkage disequilibrium with both the lead Latino SNP among Admixed Americans and lead non-Latino white SNP among Europeans. This pinpointed rs11591377 (pmeta = 2.1 x 10-10 ) upstream of BMI1, residing within a hematopoietic stem cell enhancer of BMI1, and which showed significant preferential binding of the risk allele to MYBL2 (p = 1.73 x 10-5 ) and p300 (p = 1.55 x 10-3 ) transcription factors using binomial tests on ChIP-Seq data from a SNP heterozygote. At PIP4K2A, we identified rs4748812 (pmeta = 1.3 x 10-15 ), which alters a RUNX1 binding motif and demonstrated chromosomal looping to the PIP4K2A promoter. Fine-mapping chromosome 10p12 in a multi-ethnic ALL GWAS confirmed independent associations and identified putative functional variants upstream of BMI1 and at PIP4K2A.

Background: Allergic disease is suspected to play a role in the development of childhood acute lymphoblastic leukemia (ALL). Studies conducted over the last several decades have yielded mixed results. Methods: We examined the association between allergy, a common immune-mediated disorder, and ALL in the California Childhood Leukemia Study (CCLS), a case–control study of 977 children diagnosed with ALL and 1,037 matched controls (1995–2015). History of allergies in the first year of life was obtained from interviews, mainly reported by mothers. Logistic regression analyses were conducted to estimate ORs and 95% confidence intervals (CIs), controlling for birth order, daycare attendance, and mode of delivery. In addition, we conducted meta-analyses with data from the CCLS and 12 published studies and employed a new method to estimate between-study heterogeneity (R_b). Results: Overall, no associations were observed between childhood ALL risk and specific allergy phenotypes or any allergy, as a group. However, having any allergy was associated with an increased risk of ALL among the youngest study participants. In the meta-analysis random-effects models, reduced odds of ALL were associated with hay fever (metaOR = 0.65; 95% CI, 0.47–0.90); however, restricting the analysis to studies that used medical records for assessment of allergy or recently published studies led to null or attenuated results. Conclusions: Overall, our findings do not support a clear association between allergy and childhood ALL. Impact: The degree to which epidemiologic studies can inform the relationship between allergies and risk of childhood ALL is limited by R_b. Cancer Epidemiol Biomarkers Prev; 27(10); 1142–50. ©2018 AACR.

Background: The genetic etiology of osteosarcoma remains poorly understood despite the publication of a genome-wide association study. Association between HLA genetic variants and risk of several cancers has been observed, but HLA variation is not well captured by standard SNP arrays. Methods: We genotyped 207 Californian pediatric osteosarcoma cases and 696 controls of European ancestry using a custom genome-wide array supplemented with approximately 6,000 additional probes across the MHC region. We subsequently imputed 4-digit classical HLA alleles using a reference panel of 5,225 individuals who underwent high-resolution HLA typing via next-generation sequencing. Case–control comparisons were adjusted for ancestry-informative principal components, and top associations from the discovery analysis underwent replication in an independent dataset of 657 cases and 1,183 controls. Results: Three highly correlated HLA class II variants (r2 = 0.33–0.98) were associated with osteosarcoma risk in discovery analyses, including HLA-DRB1*0301 (OR = 0.52; P = 3.2 × 10−3), HLA-DQA1*0501 (OR = 0.74; P = 0.031), and HLA-DQB1*0201 (OR = 0.51; P = 2.7 × 10−3). Similar associations were observed in the replication data (Prange = 0.011–0.037). Meta-analysis of the two datasets identified HLA-DRB1*0301 as the most significantly associated variant (ORmeta = 0.62; Pmeta = 1.5 × 10−4), reaching Bonferroni-corrected statistical significance. The meta-analysis also revealed a second significant independent signal at HLA-DQA1*01:01 (ORmeta = 1.33, Pmeta = 1.2 × 10−3), and a third suggestive association at HLA-DQB1*0302 (ORmeta = 0.73, Pmeta = 6.4 × 10−3). Conclusions: Multiple independent HLA class II alleles may influence osteosarcoma risk. Impact: Additional work is needed to extend our observations to other patient populations and to clarify the potential causal mechanisms underlying these associations. Understanding immunologic contributions to the etiology of osteosarcoma may inform rational therapeutic targets. Cancer Epidemiol Biomarkers Prev; 27(10); 1151–8. ©2018 AACR.

Background Although increased height has been associated with osteosarcoma risk in previous epidemiologic studies, to the authors' knowledge the relative contribution of stature during different developmental timepoints remains unclear. Furthermore, the question of how genetic determinants of height impact osteosarcoma etiology remains unexplored. Genetic variants associated with stature in previous genome-wide association studies may be biomarkers of osteosarcoma risk. Methods The authors tested the associations between osteosarcoma risk and polygenic scores for adult height (416 variants), childhood height (6 variants), and birth length (5 variants) in 864 osteosarcoma cases and 1879 controls of European ancestry. Results Each standard deviation increase in the polygenic score for adult height, corresponding to a 1.7-cm increase in stature, was found to be associated with a 1.10-fold increase in the risk of osteosarcoma (95% confidence interval [95% CI], 1.01-1.19; P =.027). Each standard deviation increase in the polygenic score for childhood height, corresponding to a 0.5-cm increase in stature, was associated with a 1.10-fold increase in the risk of osteosarcoma (95% CI, 1.01-1.20; P =.023). The polygenic score for birth length was not found to be associated with osteosarcoma risk (P =.11). When adult and childhood height scores were modeled together, they were found to be independently associated with osteosarcoma risk (P =.037 and P = .043, respectively). An expression quantitative trait locus for cartilage intermediate layer protein 2 (CILP2), rs8103992, was significantly associated with osteosarcoma risk after adjustment for multiple comparisons (odds ratio, 1.35; 95% CI, 1.16-1.56 [P = 7.93×10-5 and Padjusted =.034]). Conclusions A genetic propensity for taller adult and childhood height attainments contributed independently to osteosarcoma risk in the current study data. These results suggest that the biological pathways affecting normal bone growth may be involved in osteosarcoma etiology.