562 results on '"de Smith, Adam J."'
Search Results
2. A noncoding regulatory variant in IKZF1 increases acute lymphoblastic leukemia risk in Hispanic/Latino children
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de Smith, Adam J, Wahlster, Lara, Jeon, Soyoung, Kachuri, Linda, Black, Susan, Langie, Jalen, Cato, Liam D, Nakatsuka, Nathan, Chan, Tsz-Fung, Xia, Guangze, Mazumder, Soumyaa, Yang, Wenjian, Gazal, Steven, Eng, Celeste, Hu, Donglei, Burchard, Esteban González, Ziv, Elad, Metayer, Catherine, Mancuso, Nicholas, Yang, Jun J, Ma, Xiaomei, Wiemels, Joseph L, Yu, Fulong, Chiang, Charleston WK, and Sankaran, Vijay G
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Biological Sciences ,Genetics ,Clinical Research ,Hematology ,Pediatric Cancer ,Cancer ,Childhood Leukemia ,Pediatric ,Rare Diseases ,Pediatric Research Initiative ,Aetiology ,2.1 Biological and endogenous factors ,Humans ,Child ,Genetic Predisposition to Disease ,Polymorphism ,Single Nucleotide ,Transcription Factors ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Hispanic or Latino ,Ikaros Transcription Factor ,B-ALL ,GWAS ,IKZF1 ,Indigenous American ,acute lymphoblastic leukemia ,cancer disparity ,cancer predisposition ,childhood leukemia ,fine-mapping ,hematopoiesis - Abstract
Hispanic/Latino children have the highest risk of acute lymphoblastic leukemia (ALL) in the US compared to other racial/ethnic groups, yet the basis of this remains incompletely understood. Through genetic fine-mapping analyses, we identified a new independent childhood ALL risk signal near IKZF1 in self-reported Hispanic/Latino individuals, but not in non-Hispanic White individuals, with an effect size of ∼1.44 (95% confidence interval = 1.33-1.55) and a risk allele frequency of ∼18% in Hispanic/Latino populations and
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- 2024
3. Gene-Environment Analyses Reveal Novel Genetic Candidates with Prenatal Tobacco Exposure in Relation to Risk for Childhood Acute Lymphoblastic Leukemia.
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Zhong, Charlie, Li, Shaobo, Arroyo, Katti, Morimoto, Libby M, de Smith, Adam J, Metayer, Catherine, Ma, Xiaomei, Kogan, Scott C, Gauderman, W James, and Wiemels, Joseph L
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Epidemiology ,Biomedical and Clinical Sciences ,Public Health ,Health Sciences ,Pediatric Research Initiative ,Genetic Testing ,Tobacco Smoke and Health ,Genetics ,Pediatric Cancer ,Perinatal Period - Conditions Originating in Perinatal Period ,Hematology ,Childhood Leukemia ,Rare Diseases ,Tobacco ,Cancer ,Pediatric ,Clinical Research ,Prevention ,2.2 Factors relating to the physical environment ,2.1 Biological and endogenous factors ,Aetiology ,Reproductive health and childbirth ,Good Health and Well Being ,Infant ,Newborn ,Pregnancy ,Female ,Humans ,Nicotiana ,Maternal Exposure ,Smoking ,DNA Methylation ,Transcription Factors ,Tobacco Smoke Pollution ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Prenatal Exposure Delayed Effects ,Medical and Health Sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
BackgroundAssociations between maternal tobacco exposure during pregnancy and childhood acute lymphoblastic leukemia (ALL) have yielded mixed results. This may be due to biases in self-reported smoking or other differences in individual-level risk factors. We utilized a biological marker of maternal tobacco exposure to evaluate the association between maternal tobacco exposure during pregnancy, genetics, and subsequent childhood ALL risk in two large population-based studies of childhood ALL in California.MethodsMaternal exposure to tobacco smoke was assessed with a validated methylation marker (cg05575921) of the aryl hydrocarbon receptor repressor (AHRR) gene in newborn dried blood spots. We adjusted for sex, birthweight, gestational age, mode of delivery, year of birth, AHRR quantitative trait locus (mQTL) rs77111113, and a polygenetic risk score for childhood ALL. We additionally adjusted for principal components in a gene-environment interaction testing method that incorporates gene-only and environment-only effects along with interactions.ResultsAHRR hypomethylation overall was not associated with childhood ALL. In gene-environment interaction testing, several genetic variants displayed significant interaction with AHRR hypomethylation and childhood ALL.ConclusionsOur results suggest that novel candidates in PTPRK and DPP6 may play a role in tobacco-related leukemogenesis. Further research is necessary to better understand the effects of tobacco and these variants on childhood ALL risk.ImpactDespite the lack of an overall "main effect," tobacco exposure during pregnancy affects childhood ALL risk depending on specific genetic variants.
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- 2023
4. Evaluating genomic polygenic risk scores for childhood acute lymphoblastic leukemia in Latinos
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Jeon, Soyoung, Lo, Ying Chu, Morimoto, Libby M, Metayer, Catherine, Ma, Xiaomei, Wiemels, Joseph L, de Smith, Adam J, and Chiang, Charleston WK
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Biological Sciences ,Genetics ,Hematology ,Pediatric Cancer ,Pediatric ,Cancer ,Rare Diseases ,Childhood Leukemia ,Human Genome ,Humans ,Genetic Predisposition to Disease ,Genomics ,Child ,United States ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Genome-Wide Association Study ,Hispanic or Latino ,Genetic Risk Score ,acute lymphoblastic leukemia ,latinos ,polygenic risk scores ,risk prediction - Abstract
The utility of polygenic risk score (PRS) models has not been comprehensively evaluated for childhood acute lymphoblastic leukemia (ALL), the most common type of cancer in children. Previous PRS models for ALL were based on significant loci observed in genome-wide association studies (GWASs), even though genomic PRS models have been shown to improve prediction performance for a number of complex diseases. In the United States, Latino (LAT) children have the highest risk of ALL, but the transferability of PRS models to LAT children has not been studied. In this study, we constructed and evaluated genomic PRS models based on either non-Latino White (NLW) GWAS or a multi-ancestry GWAS. We found that the best PRS models performed similarly between held-out NLW and LAT samples (PseudoR2 = 0.086 ± 0.023 in NLW vs. 0.060 ± 0.020 in LAT), and can be improved for LAT if we performed GWAS in LAT-only (PseudoR2 = 0.116 ± 0.026) or multi-ancestry samples (PseudoR2 = 0.131 ± 0.025). However, the best genomic models currently do not have better prediction accuracy than a conventional model using all known ALL-associated loci in the literature (PseudoR2 = 0.166 ± 0.025), which includes loci from GWAS populations that we could not access to train genomic PRS models. Our results suggest that larger and more inclusive GWASs may be needed for genomic PRS to be useful for ALL. Moreover, the comparable performance between populations may suggest a more oligogenic architecture for ALL, where some large effect loci may be shared between populations. Future PRS models that move away from the infinite causal loci assumption may further improve PRS for ALL.
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- 2023
5. Multi-ancestry genome-wide association study of 4069 children with glioma identifies 9p21.3 risk locus
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Foss-Skiftesvik, Jon, Li, Shaobo, Rosenbaum, Adam, Hagen, Christian Munch, Stoltze, Ulrik Kristoffer, Ljungqvist, Sally, Hjalmars, Ulf, Schmiegelow, Kjeld, Morimoto, Libby, de Smith, Adam J, Mathiasen, René, Metayer, Catherine, Hougaard, David, Melin, Beatrice, Walsh, Kyle M, Bybjerg-Grauholm, Jonas, Dahlin, Anna M, and Wiemels, Joseph L
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Human Genome ,Cancer Genomics ,Cancer ,Pediatric ,Prevention ,Neurosciences ,Genetics ,Brain Cancer ,Rare Diseases ,Pediatric Cancer ,Brain Disorders ,Aetiology ,2.1 Biological and endogenous factors ,Humans ,Child ,Genome-Wide Association Study ,Glioma ,Genotype ,Genetic Predisposition to Disease ,RNA ,Long Noncoding ,Astrocytoma ,Polymorphism ,Single Nucleotide ,Childhood brain tumors ,genetic susceptibility ,glioma ,GWAS ,pediatric neuro-oncology ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
BackgroundAlthough recent sequencing studies have revealed that 10% of childhood gliomas are caused by rare germline mutations, the role of common variants is undetermined and no genome-wide significant risk loci for pediatric central nervous system tumors have been identified to date.MethodsMeta-analysis of 3 population-based genome-wide association studies comprising 4069 children with glioma and 8778 controls of multiple genetic ancestries. Replication was performed in a separate case-control cohort. Quantitative trait loci analyses and a transcriptome-wide association study were conducted to assess possible links with brain tissue expression across 18 628 genes.ResultsCommon variants in CDKN2B-AS1 at 9p21.3 were significantly associated with astrocytoma, the most common subtype of glioma in children (rs573687, P-value of 6.974e-10, OR 1.273, 95% CI 1.179-1.374). The association was driven by low-grade astrocytoma (P-value of 3.815e-9) and exhibited unidirectional effects across all 6 genetic ancestries. For glioma overall, the association approached genome-wide significance (rs3731239, P-value of 5.411e-8), while no significant association was observed for high-grade tumors. Predicted decreased brain tissue expression of CDKN2B was significantly associated with astrocytoma (P-value of 8.090e-8).ConclusionsIn this population-based genome-wide association study meta-analysis, we identify and replicate 9p21.3 (CDKN2B-AS1) as a risk locus for childhood astrocytoma, thereby establishing the first genome-wide significant evidence of common variant predisposition in pediatric neuro-oncology. We furthermore provide a functional basis for the association by showing a possible link to decreased brain tissue CDKN2B expression and substantiate that genetic susceptibility differs between low- and high-grade astrocytoma.
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- 2023
6. Backtracking to the future: unraveling the origins of childhood leukemia
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de Smith, Adam J., Wiemels, Joseph L., Mead, Adam J., Roberts, Irene, Roy, Anindita, and Spector, Logan G.
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- 2024
- Full Text
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7. Associations between early‐life and in utero infections and cytomegalovirus‐positive acute lymphoblastic leukemia in children
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Gallant, Rachel E, Arroyo, Katti, Metayer, Catherine, Kang, Alice Y, de Smith, Adam J, and Wiemels, Joseph L
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Medical Microbiology ,Biomedical and Clinical Sciences ,Childhood Leukemia ,Cancer ,Perinatal Period - Conditions Originating in Perinatal Period ,Pediatric ,Infectious Diseases ,Pediatric Cancer ,Hematology ,Prevention ,Rare Diseases ,Conditions Affecting the Embryonic and Fetal Periods ,Clinical Research ,Detection ,screening and diagnosis ,4.1 Discovery and preclinical testing of markers and technologies ,Aetiology ,2.1 Biological and endogenous factors ,Infection ,Inflammatory and immune system ,Female ,Pregnancy ,Child ,Humans ,Cytomegalovirus ,Cytomegalovirus Infections ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Polymerase Chain Reaction ,Logistic Models ,childhood infection ,cytomegalovirus ,leukemia etiology ,maternal infection ,pediatric acute lymphoblastic leukemia ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
Childhood infections and cytomegalovirus (CMV) are associated with pediatric acute lymphoblastic leukemia (ALL). CMV dysregulates the host immune system and alters the immune response to subsequent antigenic exposures. We suspect that this immune dysregulation contributes to increased numbers of symptomatic infections in childhood allowing for expansion of pre-leukemic clones. We explored the association between childhood infections, maternal infections during pregnancy and CMV-positive ALL. Using a droplet digital PCR assay, we screened diagnostic ALL bone marrow samples from the California Childhood Leukemia Study (1995-2015) for the presence of CMV DNA identifying CMV-positive and CMV-negative cases. We performed a case-only analysis (n = 524) comparing the number and types of childhood infections and maternal infections during pregnancy between CMV-positive and CMV-negative ALL cases using logistic regression. With increasing numbers of infections in the first 12 months of life, children were more likely to classify to the highest tertile of CMV DNA in the bone marrow at diagnosis (OR: 1.04, 95% CI: 1.01-1.08). Specifically, those reporting cough or flu in the first 12 months were more likely to be CMV-positive at ALL diagnosis (OR: 2.15, 95% CI: 1.06-4.37 and OR: 2.06, 95% CI: 1.17-3.63 respectively). Furthermore, those with a history of maternal infection during pregnancy were more likely to be CMV-positive (OR: 2.12, 95% CI: 1.24-3.62). We hypothesize that children with underlying immune dysregulation develop more symptomatic infections in childhood and ultimately CMV-positive ALL; this underlying immune dysregulation may be due to early immune system alterations via CMV exposure (in utero or early infancy) proposing a potential link between CMV and ALL etiology.
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- 2023
8. Epigenomic signature of major congenital heart defects in newborns with Down syndrome
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Mouat, Julia S, Li, Shaobo, Myint, Swe Swe, Laufer, Benjamin I, Lupo, Philip J, Schraw, Jeremy M, Woodhouse, John P, de Smith, Adam J, and LaSalle, Janine M
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Biological Sciences ,Genetics ,Human Genome ,Congenital Heart Disease ,Brain Disorders ,Prevention ,Down Syndrome ,Rare Diseases ,Pediatric ,Cardiovascular ,Women's Health ,Heart Disease ,Intellectual and Developmental Disabilities (IDD) ,Congenital Structural Anomalies ,Aetiology ,2.1 Biological and endogenous factors ,Humans ,Male ,Infant ,Newborn ,Female ,Epigenomics ,DNA Methylation ,Epigenesis ,Genetic ,Heart Defects ,Congenital ,CpG Islands ,Chromatin ,Down syndrome ,Congenital heart defect ,Newborn dried blood spot ,DNA methylation ,Whole-genome bisulfite sequencing ,Epigenetics ,Epigenome-wide association study ,Differentially methylated regions ,nRBC ,Hypomethylation ,Genetics & Heredity ,Biochemistry and cell biology - Abstract
BackgroundCongenital heart defects (CHDs) affect approximately half of individuals with Down syndrome (DS), but the molecular reasons for incomplete penetrance are unknown. Previous studies have largely focused on identifying genetic risk factors associated with CHDs in individuals with DS, but comprehensive studies of the contribution of epigenetic marks are lacking. We aimed to identify and characterize DNA methylation differences from newborn dried blood spots (NDBS) of DS individuals with major CHDs compared to DS individuals without CHDs.MethodsWe used the Illumina EPIC array and whole-genome bisulfite sequencing (WGBS) to quantitate DNA methylation for 86 NDBS samples from the California Biobank Program: (1) 45 DS-CHD (27 female, 18 male) and (2) 41 DS non-CHD (27 female, 14 male). We analyzed global CpG methylation and identified differentially methylated regions (DMRs) in DS-CHD versus DS non-CHD comparisons (both sex-combined and sex-stratified) corrected for sex, age of blood collection, and cell-type proportions. CHD DMRs were analyzed for enrichment in CpG and genic contexts, chromatin states, and histone modifications by genomic coordinates and for gene ontology enrichment by gene mapping. DMRs were also tested in a replication dataset and compared to methylation levels in DS versus typical development (TD) WGBS NDBS samples.ResultsWe found global CpG hypomethylation in DS-CHD males compared to DS non-CHD males, which was attributable to elevated levels of nucleated red blood cells and not seen in females. At a regional level, we identified 58, 341, and 3938 CHD-associated DMRs in the Sex Combined, Females Only, and Males Only groups, respectively, and used machine learning algorithms to select 19 Males Only loci that could distinguish CHD from non-CHD. DMRs in all comparisons were enriched for gene exons, CpG islands, and bivalent chromatin and mapped to genes enriched for terms related to cardiac and immune functions. Lastly, a greater percentage of CHD-associated DMRs than background regions were differentially methylated in DS versus TD samples.ConclusionsA sex-specific signature of DNA methylation was detected in NDBS of DS-CHD compared to DS non-CHD individuals. This supports the hypothesis that epigenetics can reflect the variability of phenotypes in DS, particularly CHDs.
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- 2023
9. Periconceptional folate intake influences DNA methylation at birth based on dietary source in an analysis of pediatric acute lymphoblastic leukemia cases and controls
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Nickels, Eric M, Li, Shaobo, Morimoto, Libby, Kang, Alice Y, de Smith, Adam J, Metayer, Catherine, and Wiemels, Joseph L
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Biomedical and Clinical Sciences ,Nutrition and Dietetics ,Cancer ,Pediatric Research Initiative ,Human Genome ,Nutrition ,Hematology ,Pediatric Cancer ,Prevention ,Pediatric ,Genetics ,Rare Diseases ,Complementary and Integrative Health ,Clinical Research ,Childhood Leukemia ,Infant ,Newborn ,Child ,Humans ,Folic Acid ,DNA Methylation ,Dietary Supplements ,Diet ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,DNA ,DNA methylation ,folate ,acute lymphoblastic leukemia ,periconceptional nutrition ,epigenetics ,pediatric oncology ,Engineering ,Medical and Health Sciences ,Nutrition & Dietetics ,Clinical sciences ,Nutrition and dietetics - Abstract
BackgroundPericonceptional folate intake is associated with the establishment of DNA methylation in offspring; however, variations in this relation by food sources compared with folic acid supplements are not described. Also, maternal folate intake is associated with decreased risk of pediatric acute lymphoblastic leukemia (ALL), but the mechanism is not known.ObjectivesWe evaluated the relation between periconceptional folate intake by source and DNA methylation at birth in a cohort of pediatric ALL cases and controls in an epigenome-wide association study.MethodsGenome-wide DNA methylation status obtained from archived neonatal blood spots from pediatric ALL cases (n = 189) and controls (n = 205) in the California Childhood Leukemia Study (CCLS) from 1995-2008 was compared with periconceptional folate from total, food, and supplemental sources using multivariable linear regression. Further stratification was performed by income, education, ethnicity, and total folate intake. We evaluated variable DNA methylation response to periconceptional folate by ALL case status through an interaction term.ResultsTwo significant differentially methylated probes (DMPs) were associated with food and supplemental periconceptional folate intake in all subjects (n = 394). The top differentially methylated region at the promoter region of DUSP22(dual specificity phosphatase 22) demonstrated DNA hypermethylation in ALL cases but not in controls in response to total and food folate intake. We further identified 8 interaction term DMPs with variable DNA methylation response to folate intake by ALL case status. Further stratification of the cohort by education and ethnicity revealed a substantially higher number of DMPs associated with supplemental folic acid intake in Hispanic subjects with lower income and educational level.ConclusionsWe identified modest associations between periconceptional folate intake and DNA methylation differing by source, including variation by ALL case status. Hispanic subjects of lower income and education appear uniquely responsive to periconceptional folate supplementation.
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- 2022
10. Ras-mutant cancers are sensitive to small molecule inhibition of V-type ATPases in mice
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Tolani, Bhairavi, Celli, Anna, Yao, Yanmin, Tan, Yong Zi, Fetter, Richard, Liem, Christina R, de Smith, Adam J, Vasanthakumar, Thamiya, Bisignano, Paola, Cotton, Adam D, Seiple, Ian B, Rubinstein, John L, Jost, Marco, and Weissman, Jonathan S
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Biotechnology ,Genetics ,Rare Diseases ,Orphan Drug ,Digestive Diseases ,Lung Cancer ,Lung ,Cancer ,Colo-Rectal Cancer ,Humans ,Mice ,Animals ,Cell Line ,Tumor ,Vacuolar Proton-Translocating ATPases ,Proto-Oncogene Proteins p21(ras) ,ras Proteins ,Antineoplastic Agents ,Mutation ,Neoplasms - Abstract
Mutations in Ras family proteins are implicated in 33% of human cancers, but direct pharmacological inhibition of Ras mutants remains challenging. As an alternative to direct inhibition, we screened for sensitivities in Ras-mutant cells and discovered 249C as a Ras-mutant selective cytotoxic agent with nanomolar potency against a spectrum of Ras-mutant cancers. 249C binds to vacuolar (V)-ATPase with nanomolar affinity and inhibits its activity, preventing lysosomal acidification and inhibiting autophagy and macropinocytosis pathways that several Ras-driven cancers rely on for survival. Unexpectedly, potency of 249C varies with the identity of the Ras driver mutation, with the highest potency for KRASG13D and G12V both in vitro and in vivo, highlighting a mutant-specific dependence on macropinocytosis and lysosomal pH. Indeed, 249C potently inhibits tumor growth without adverse side effects in mouse xenografts of KRAS-driven lung and colon cancers. A comparison of isogenic SW48 xenografts with different KRAS mutations confirmed that KRASG13D/+ (followed by G12V/+) mutations are especially sensitive to 249C treatment. These data establish proof-of-concept for targeting V-ATPase in cancers driven by specific KRAS mutations such as KRASG13D and G12V.
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- 2022
11. Variant to function mapping at single-cell resolution through network propagation
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Yu, Fulong, Cato, Liam D, Weng, Chen, Liggett, L Alexander, Jeon, Soyoung, Xu, Keren, Chiang, Charleston WK, Wiemels, Joseph L, Weissman, Jonathan S, de Smith, Adam J, and Sankaran, Vijay G
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Biological Sciences ,Genetics ,Human Genome ,Aetiology ,1.1 Normal biological development and functioning ,2.1 Biological and endogenous factors ,Underpinning research ,Generic health relevance ,Humans ,Genome-Wide Association Study ,Polymorphism ,Single Nucleotide ,COVID-19 ,Genomics ,Epigenomics - Abstract
Genome-wide association studies in combination with single-cell genomic atlases can provide insights into the mechanisms of disease-causal genetic variation. However, identification of disease-relevant or trait-relevant cell types, states and trajectories is often hampered by sparsity and noise, particularly in the analysis of single-cell epigenomic data. To overcome these challenges, we present SCAVENGE, a computational algorithm that uses network propagation to map causal variants to their relevant cellular context at single-cell resolution. We demonstrate how SCAVENGE can help identify key biological mechanisms underlying human genetic variation, applying the method to blood traits at distinct stages of human hematopoiesis, to monocyte subsets that increase the risk for severe Coronavirus Disease 2019 (COVID-19) and to intermediate lymphocyte developmental states that predispose to acute leukemia. Our approach not only provides a framework for enabling variant-to-function insights at single-cell resolution but also suggests a more general strategy for maximizing the inferences that can be made using single-cell genomic data.
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- 2022
12. Investigating DNA methylation as a mediator of genetic risk in childhood acute lymphoblastic leukemia
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Xu, Keren, Li, Shaobo, Pandey, Priyatama, Kang, Alice Y, Morimoto, Libby M, Mancuso, Nicholas, Ma, Xiaomei, Metayer, Catherine, Wiemels, Joseph L, and de Smith, Adam J
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Biological Sciences ,Genetics ,Pediatric Cancer ,Hematology ,Pediatric ,Childhood Leukemia ,Rare Diseases ,Cancer ,Human Genome ,2.1 Biological and endogenous factors ,Aetiology ,Humans ,DNA Methylation ,Genome-Wide Association Study ,Polymorphism ,Single Nucleotide ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Transcription Factors ,Medical and Health Sciences ,Genetics & Heredity - Abstract
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.
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- 2022
13. Genetic variation near GRB10 associated with bone growth and osteosarcoma risk in canine and human populations
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Lucas, Sydney E., Yang, Tianzhong, Wimberly, Courtney E., Parmar, Kajal V., Hansen, Helen M., de Smith, Adam J., Morimoto, Libby M., Metayer, Catherine, Ostrom, Quinn T., Eward, William C., Graves, Laurie A., Wagner, Lars M., Wiemels, Joseph L., Spector, Logan G., and Walsh, Kyle M.
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- 2024
- Full Text
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14. Accelerated epigenetic aging in newborns with Down syndrome
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Xu, Keren, Li, Shaobo, Muskens, Ivo S, Elliott, Natalina, Myint, Swe Swe, Pandey, Priyatama, Hansen, Helen M, Morimoto, Libby M, Kang, Alice Y, Ma, Xiaomei, Metayer, Catherine, Mueller, Beth A, Roberts, Irene, Walsh, Kyle M, Horvath, Steve, Wiemels, Joseph L, and de Smith, Adam J
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Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Human Genome ,Intellectual and Developmental Disabilities (IDD) ,Aging ,Brain Disorders ,Down Syndrome ,Congenital ,Good Health and Well Being ,Adult ,Aging ,Premature ,DNA Methylation ,Epigenesis ,Genetic ,Epigenomics ,Humans ,Infant ,Newborn ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
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
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- 2022
15. Interaction between maternal killer immunoglobulin-like receptors and offspring HLAs and susceptibility of childhood ALL
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Feng, Qianxi, Zhou, Mi, Li, Shaobo, Morimoto, Libby, Hansen, Helen, Myint, Swe Swe, Wang, Rong, Metayer, Catherine, Kang, Alice, Fear, Anna Lisa, Pappas, Derek, Erlich, Henry, Hollenbach, Jill A, Mancuso, Nicholas, Trachtenberg, Elizabeth, de Smith, Adam J, Ma, Xiaomei, and Wiemels, Joseph L
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Reproductive Medicine ,Biomedical and Clinical Sciences ,Hematology ,Pediatric Cancer ,Genetics ,Childhood Leukemia ,Pediatric ,Clinical Research ,Cancer ,Rare Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Inflammatory and immune system ,Reproductive health and childbirth ,Good Health and Well Being ,Case-Control Studies ,Child ,Cytokines ,HLA Antigens ,Humans ,Immunoglobulins ,Killer Cells ,Natural ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Receptors ,KIR ,Cardiovascular medicine and haematology - Abstract
Acute lymphoblastic leukemia (ALL) in children is associated with a distinct neonatal cytokine profile. The basis of this neonatal immune phenotype is unknown but potentially related to maternal-fetal immune receptor interactions. We conducted a case-control study of 226 case child-mother pairs and 404 control child-mother pairs to evaluate the role of interaction between HLA genotypes in the offspring and maternal killer immunoglobulin-like receptor (KIR) genotypes in the etiology of childhood ALL, while considering potential mediation by neonatal cytokines and the immune-modulating enzyme arginase-II (ARG-II). We observed different associations between offspring HLA-maternal KIR activating profiles and the risk of ALL in different predicted genetic ancestry groups. For instance, in Latino subjects who experience the highest risk of childhood leukemia, activating profiles were significantly associated with a lower risk of childhood ALL (odds ratio [OR] = 0.59; 95% confidence interval [CI], 0.49-0.71) and a higher level of ARG-II at birth (coefficient = 0.13; 95% CI, 0.04-0.22). HLA-KIR activating profiles were also associated with a lower risk of ALL in non-Latino Asians (OR = 0.63; 95% CI, 0.38-1.01), although they had a lower tumor necrosis factor-α level (coefficient = -0.27; 95% CI, -0.49 to -0.06). Among non-Latino White subjects, no significant association was observed between offspring HLA-maternal KIR interaction and ALL risk or cytokine levels. The current study reports the association between offspring HLA-maternal KIR interaction and the development of childhood ALL with variation by predicted genetic ancestry. We also observed some associations between activating profiles and immune factors related to cytokine control; however, cytokines did not demonstrate causal mediation of the activating profiles on ALL risk.
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- 2022
16. Clinical characteristics of cytomegalovirus‐positive pediatric acute lymphoblastic leukemia at diagnosis
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Gallant, Rachel E, Arroyo, Katti, Bracci, Paige M, Li, Shaobo, Metayer, Catherine, Kogan, Scott C, Wendt, George A, Francis, Stephen S, de Smith, Adam J, and Wiemels, Joseph L
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Biomedical and Clinical Sciences ,Clinical Sciences ,Hematology ,Pediatric ,Orphan Drug ,Pediatric Cancer ,Cancer ,Rare Diseases ,Childhood Leukemia ,Child ,Cytomegalovirus ,Cytomegalovirus Infections ,Humans ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Cardiorespiratory Medicine and Haematology ,Immunology ,Cardiovascular medicine and haematology - Published
- 2022
17. Development of a Droplet Digital™ PCR DNA methylation detection and quantification assay of prenatal tobacco exposure
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Arroyo, Katti, Nargizyan, Anahit, Andrade, Francianne G, Myint, Swe Swe, Lu, Sabrina, Pandey, Priyatama, Yee, Amy, de Smith, Adam J, and Wiemels, Joseph L
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Biological Sciences ,Genetics ,Human Genome ,Biotechnology ,Cancer ,Good Health and Well Being ,CpG Islands ,DNA Methylation ,Genomics ,High-Throughput Nucleotide Sequencing ,Polymerase Chain Reaction ,Nicotiana ,bisulfite treatment ,CpG dense regions ,differentially methylated regions ,DNA methylation ,Droplet Digital (TM) PCR (ddPCR (TM)) ,gBlocks (TM) Gene Fragments ,Illumina Infinium BeadChip array ,Illumina MiSeq (TM) NGS system ,neighboring CpGs ,smoking biomarkers ,Droplet Digital™ PCR ,Illumina MiSeq™ NGS system ,gBlocks™ Gene Fragments ,Technology ,Bioinformatics ,Biological sciences - Abstract
DNA methylation is a labile modification associated with gene expression control and environmental adaptations. High throughput, scalable and quantitative assessments of specific DNA methylation modifications in complex genomic regions for use in large population studies are needed. The performance of Droplet Digital™ PCR (ddPCR™) was investigated for DNA methylation detection against next-generation bisulfite sequencing (NGS) to demonstrate the ability of ddPCR to detect and validate DNA methylation levels and complex patterns among neighboring CpGs in regions associated with prenatal tobacco exposure. While both techniques are reproducible, ddPCR demonstrates a unique advantage for high-throughput DNA methylation analysis in large-scale population studies and provides the specificity to accurately measure DNA methylation of target CpGs in complex regions.
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- 2022
18. Mitochondrial 1555 G>A variant as a potential risk factor for childhood glioblastoma
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Li, Shaobo, Gai, Xiaowu, Myint, Swe Swe, Arroyo, Katti, Morimoto, Libby, Metayer, Catherine, de Smith, Adam J, Walsh, Kyle M, and Wiemels, Joseph L
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Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Health Sciences ,Oncology and Carcinogenesis ,Brain Disorders ,Pediatric ,Rare Diseases ,Brain Cancer ,Neurosciences ,Cancer ,2.1 Biological and endogenous factors ,Aetiology ,mitochondrial genome ,pediatric glioblastoma ,risk factor ,variant - Abstract
BackgroundChildhood glioblastoma multiforme (GBM) is a highly aggressive disease with low survival, and its etiology, especially concerning germline genetic risk, is poorly understood. Mitochondria play a key role in putative tumorigenic processes relating to cellular oxidative metabolism, and mitochondrial DNA variants were not previously assessed for association with pediatric brain tumor risk.MethodsWe conducted an analysis of 675 mitochondrial DNA variants in 90 childhood GBM cases and 2789 controls to identify enrichment of mitochondrial variant associated with GBM risk. We also performed this analysis for other glioma subtypes including pilocytic astrocytoma. Nuclear-encoded mitochondrial gene variants were also analyzed.ResultsWe identified m1555 A>G was significantly associated with GBM risk (adjusted OR 29.30, 95% CI 5.25-163.4, P-value 9.5 X 10-4). No association was detected for other subtypes. Haplotype analysis further supported the independent risk contributed by m1555 G>A, instead of a haplogroup joint effect. Nuclear-encoded mitochondrial gene variants identified significant associations in European (rs62036057 in WWOX, adjusted OR = 2.99, 95% CI 1.88-4.75, P-value = 3.42 X 10-6) and Hispanic (rs111709726 in EFHD1, adjusted OR = 3.57, 95% CI 1.99-6.40, P-value = 1.41 X 10-6) populations in ethnicity-stratified analyses.ConclusionWe report for the first time a potential role played by a functional mitochondrial ribosomal RNA variant in childhood GBM risk, and a potential role for both mitochondrial and nuclear-mitochondrial DNA polymorphisms in GBM tumorigenesis. These data implicate cellular oxidative metabolic capacity as a contributor to the etiology of pediatric glioblastoma.
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- 2022
19. Localized variation in ancestral admixture identifies pilocytic astrocytoma risk loci among Latino children
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Li, Shaobo, Chiang, Charleston WK, Myint, Swe Swe, Arroyo, Katti, Chan, Tsz Fung, Morimoto, Libby, Metayer, Catherine, de Smith, Adam J, Walsh, Kyle M, and Wiemels, Joseph L
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Biological Sciences ,Genetics ,Human Genome ,Brain Disorders ,Prevention ,Pediatric ,Clinical Research ,Astrocytoma ,Child ,Chromosome Mapping ,Genome-Wide Association Study ,Hispanic or Latino ,Humans ,Polymorphism ,Single Nucleotide ,Developmental Biology - Abstract
BackgroundPilocytic astrocytoma (PA) is the most common pediatric brain tumor. PA has at least a 50% higher incidence in populations of European ancestry compared to other ancestral groups, which may be due in part to genetic differences.MethodsWe first compared the global proportions of European, African, and Amerindian ancestries in 301 PA cases and 1185 controls of self-identified Latino ethnicity from the California Biobank. We then conducted admixture mapping analysis to assess PA risk with local ancestry.ResultsWe found PA cases had a significantly higher proportion of global European ancestry than controls (case median = 0.55, control median = 0.51, P value = 3.5x10-3). Admixture mapping identified 13 SNPs in the 6q14.3 region (SNX14) contributing to risk, as well as three other peaks approaching significance on chromosomes 7, 10 and 13. Downstream fine mapping in these regions revealed several SNPs potentially contributing to childhood PA risk.ConclusionsThere is a significant difference in genomic ancestry associated with Latino PA risk and several genomic loci potentially mediating this risk.
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- 2022
20. Cytomegalovirus proteins, maternal pregnancy cytokines, and their impact on neonatal immune cytokine profiles and acute lymphoblastic leukemogenesis in children.
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Wiemels, Joseph L, Wang, Rong, Zhou, Mi, Hansen, Helen, Gallant, Rachel, Jung, Junghyun, Mancuso, Nicholas, De Smith, Adam J, Metayer, Catherine, Kogan, Scott C, and Ma, Xiaomei
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Reproductive Medicine ,Biomedical and Clinical Sciences ,Good Health and Well Being ,Child ,Cytokines ,Cytomegalovirus ,Cytomegalovirus Infections ,Female ,Humans ,Infant ,Newborn ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Pregnancy ,Immunology - Published
- 2022
21. Genetic determinants of blood-cell traits influence susceptibility to childhood acute lymphoblastic leukemia
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Kachuri, Linda, Jeon, Soyoung, DeWan, Andrew T, Metayer, Catherine, Ma, Xiaomei, Witte, John S, Chiang, Charleston WK, Wiemels, Joseph L, and de Smith, Adam J
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Epidemiology ,Biological Sciences ,Health Sciences ,Genetics ,Childhood Leukemia ,Human Genome ,Pediatric ,Pediatric Cancer ,Cancer ,Clinical Research ,Prevention ,Rare Diseases ,Hematology ,2.1 Biological and endogenous factors ,Aetiology ,Adult ,Aged ,Biomarkers ,Tumor ,Blood Platelets ,Case-Control Studies ,Child ,Female ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Humans ,Lymphocytes ,Male ,Mendelian Randomization Analysis ,Middle Aged ,Monocytes ,Neutrophils ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Prognosis ,Prospective Studies ,Quantitative Trait Loci ,United Kingdom ,GWAS ,Mendelian randomization ,acute lymphoblastic leukemia ,blood-cell traits ,lymphocytes ,Medical and Health Sciences ,Genetics & Heredity ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Despite overlap between genetic risk loci for ALL and hematologic traits, the etiological relevance of dysregulated blood-cell homeostasis remains unclear. We investigated this question in a genome-wide association study (GWAS) of childhood ALL (2,666 affected individuals, 60,272 control individuals) and a multi-trait GWAS of nine blood-cell indices in the UK Biobank. We identified 3,000 blood-cell-trait-associated (p < 5.0 × 10-8) variants, explaining 4.0% to 23.9% of trait variation and including 115 loci associated with blood-cell ratios (LMR, lymphocyte-to-monocyte ratio; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio). ALL susceptibility was genetically correlated with lymphocyte counts (rg = 0.088, p = 4.0 × 10-4) and PLR (rg = -0.072, p = 0.0017). In Mendelian randomization analyses, genetically predicted increase in lymphocyte counts was associated with increased ALL risk (odds ratio [OR] = 1.16, p = 0.031) and strengthened after accounting for other cell types (OR = 1.43, p = 8.8 × 10-4). We observed positive associations with increasing LMR (OR = 1.22, p = 0.0017) and inverse effects for NLR (OR = 0.67, p = 3.1 × 10-4) and PLR (OR = 0.80, p = 0.002). Our study shows that a genetically induced shift toward higher lymphocyte counts, overall and in relation to monocytes, neutrophils, and platelets, confers an increased susceptibility to childhood ALL.
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- 2021
22. Epigenetic Biomarkers of Prenatal Tobacco Smoke Exposure Are Associated with Gene Deletions in Childhood Acute Lymphoblastic Leukemia
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Xu, Keren, Li, Shaobo, Whitehead, Todd P, Pandey, Priyatama, Kang, Alice Y, Morimoto, Libby M, Kogan, Scott C, Metayer, Catherine, Wiemels, Joseph L, and de Smith, Adam J
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Epidemiology ,Biomedical and Clinical Sciences ,Public Health ,Health Sciences ,Prevention ,Human Genome ,Tobacco Smoke and Health ,Childhood Leukemia ,Genetics ,Pediatric ,Pediatric Cancer ,Tobacco ,Rare Diseases ,Drug Abuse (NIDA only) ,Substance Misuse ,Cancer ,Hematology ,Respiratory ,Good Health and Well Being ,Adult ,Basic Helix-Loop-Helix Transcription Factors ,Child ,Preschool ,CpG Islands ,DNA Methylation ,Epigenesis ,Genetic ,Female ,Gene Deletion ,Humans ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Pregnancy ,Prenatal Exposure Delayed Effects ,Repressor Proteins ,Tobacco Smoke Pollution ,Medical and Health Sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
BackgroundParental 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.MethodsHere, 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.ResultsWe 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).ConclusionsWe provide further evidence that prenatal tobacco-smoke exposure may influence the generation of somatic copy-number deletions in childhood B-ALL.ImpactAnalyses of deletion breakpoint sequences are required to further understand the mutagenic effects of tobacco smoke in childhood ALL.
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- 2021
23. Increased burden of familial-associated early-onset cancer risk among minority Americans compared to non-Latino Whites.
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Feng, Qianxi, Nickels, Eric, Muskens, Ivo S, de Smith, Adam J, Gauderman, W James, Yee, Amy C, Ricker, Charite, Mack, Thomas, Leavitt, Andrew D, Godley, Lucy A, and Wiemels, Joseph L
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early-onset cancer ,epidemiology ,familial risk ,global health ,hispanic paradox ,human ,latino americans ,linked cancer registry ,race/ethnicity ,Biochemistry and Cell Biology - Abstract
BackgroundThe role of race/ethnicity in genetic predisposition of early-onset cancers can be estimated by comparing family-based cancer concordance rates among ethnic groups.MethodsWe used linked California health registries to evaluate the relative cancer risks for first-degree relatives of patients diagnosed between ages 0 and 26, and the relative risks of developing distinct second primary malignancies (SPMs). From 1989 to 2015, we identified 29,631 cancer patients and 62,863 healthy family members. We calculated the standardized incident ratios (SIRs) of early-onset primary cancers diagnosed in proband siblings and mothers, as well as SPMs detected among early-onset patients. Analyses were stratified by self-identified race/ethnicity.ResultsGiven probands with cancer, there were increased relative risks of any cancer for siblings and mothers (SIR = 3.32; 95% confidence interval [CI]: 2.85-3.85) and of SPMs (SIR = 7.27; 95% CI: 6.56-8.03). Given a proband with solid cancer, both Latinos (SIR = 4.98; 95% CI: 3.82-6.39) and non-Latino Blacks (SIR = 7.35; 95% CI: 3.36-13.95) exhibited significantly higher relative risk of any cancer in siblings and mothers when compared to non-Latino White subjects (SIR = 3.02; 95% CI: 2.12-4.16). For hematologic cancers, higher familial risk was evident for Asian/Pacific Islanders (SIR = 7.56; 95% CI: 3.26-14.90) compared to non-Latino whites (SIR = 2.69; 95% CI: 1.62-4.20).ConclusionsThe data support a need for increased attention to the genetics of early-onset cancer predisposition and environmental factors in race/ethnic minority families in the United States.FundingThis work was supported by the V Foundation for funding this work (Grant FP067172).
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- 2021
24. In utero and early-life exposure to thirdhand smoke causes profound changes to the immune system
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Snijders, Antoine M, Zhou, Mi, Whitehead, Todd P, Fitch, Briana, Pandey, Priyatama, Hechmer, Aaron, Huang, Abel, Schick, Suzaynn F, de Smith, Adam J, Olshen, Adam B, Metayer, Catherine, Mao, Jian-Hua, Wiemels, Joseph L, and Kogan, Scott C
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Tobacco Smoke and Health ,Perinatal Period - Conditions Originating in Perinatal Period ,Hematology ,Childhood Leukemia ,Prevention ,Lymphoma ,Cancer ,Rare Diseases ,Pediatric Research Initiative ,Pediatric ,Tobacco ,Pediatric Cancer ,Aetiology ,2.1 Biological and endogenous factors ,Animals ,Immune System ,Leukemia ,Mice ,Transgenic ,Smoke ,Tobacco Smoke Pollution ,Nicotiana ,immunology ,leukemia ,lymphoma ,thirdhand smoke ,Medical and Health Sciences ,Cardiovascular System & Hematology ,Biomedical and clinical sciences ,Health sciences - Abstract
Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Thirdhand smoke (THS) is the residual tobacco contamination that remains after the smoke clears. We investigated the effects of THS exposure in utero and during early life in a transgenic Cdkn2a knockout mouse model that is vulnerable to the development of leukemia/lymphoma. Female mice, and their offspring, were exposed from the first day of pregnancy to weaning. Plasma cytokines, body weight and hematologic parameters were measured in the offspring. To investigate THS exposure effects on the development of leukemia/lymphoma, bone marrow (BM) was collected from control and THS-exposed mice and transplanted into BM-ablated recipient mice, which were followed for tumor development for 1 year. We found that in utero and early-life THS exposure caused significant changes in plasma cytokine concentrations and in immune cell populations; changes appeared more pronounced in male mice. Spleen (SP) and BM B-cell populations were significantly lower in THS-exposed mice. We furthermore observed that THS exposure increased the leukemia/lymphoma-free survival in BM transplantation recipient mice, potentially caused by THS-induced B-cell toxicity. A trend towards increased solid tumors in irradiated mice reconstituted with THS-exposed BM stimulates the hypothesis that the immunosuppressive effects of in utero and early-life THS exposure might contribute to carcinogenesis by lowering the host defense to other toxic exposures. Our study adds to expanding evidence that THS exposure alters the immune system and that in utero and early-life developmental periods represent vulnerable windows of susceptibility for these effects.
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- 2021
25. Trends in Acute Lymphoblastic Leukemia Incidence in the United States by Race/Ethnicity From 2000 to 2016.
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Feng, Qianxi, de Smith, Adam J, Vergara-Lluri, Maria, Muskens, Ivo S, McKean-Cowdin, Roberta, Kogan, Scott, Brynes, Russell, and Wiemels, Joseph L
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Rare Diseases ,Pediatric ,Cancer ,Hematology ,Clinical Research ,Pediatric Cancer ,Childhood Leukemia ,Adolescent ,Adult ,Ethnicity ,Female ,Humans ,Incidence ,Male ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Racial Groups ,Registries ,SEER Program ,United States ,Young Adult ,acute lymphoblastic leukemia ,Poisson regression ,race ,ethnicity ,socioeconomic position ,race/ethnicity ,Mathematical Sciences ,Medical and Health Sciences ,Epidemiology - Abstract
Incidence trends in acute lymphoblastic leukemia (ALL) demonstrate disparities by race and ethnicity. We used data from the Surveillance, Epidemiology, and End Results Registry to evaluate patterns in ALL incidence from 2000 to 2016, including the association between percentage of people born in a foreign country at the county level and ALL incidence. Among 23,829 persons of all ages diagnosed with ALL, 8,297 (34.8%) were Latinos, 11,714 (49.2%) were non-Latino (NL) Whites, and 1,639 (6.9%) were NL Blacks. Latinos had the largest increase in the age-adjusted incidence rate (AAIR) of ALL during this period compared with other races/ethnicities for both children and adults: The AAIR was 1.6 times higher for Latinos (AAIR = 2.43, 95% confidence interval (CI): 2.37, 2.49) than for NL Whites (AAIR = 1.56, 95% CI: 1.53, 1.59) (P
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- 2021
26. The genome-wide impact of trisomy 21 on DNA methylation and its implications for hematopoiesis.
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Muskens, Ivo S, Li, Shaobo, Jackson, Thomas, Elliot, Natalina, Hansen, Helen M, Myint, Swe Swe, Pandey, Priyatama, Schraw, Jeremy M, Roy, Ritu, Anguiano, Joaquin, Goudevenou, Katerina, Siegmund, Kimberly D, Lupo, Philip J, de Bruijn, Marella FTR, Walsh, Kyle M, Vyas, Paresh, Ma, Xiaomei, Roy, Anindita, Roberts, Irene, Wiemels, Joseph L, and de Smith, Adam J
- Subjects
Liver ,Hematopoietic Stem Cells ,Fetus ,Humans ,Down Syndrome ,Case-Control Studies ,Hematopoiesis ,DNA Methylation ,Epigenesis ,Genetic ,CpG Islands ,Genome ,Human ,Infant ,Newborn ,Female ,Male ,Core Binding Factor Alpha 2 Subunit ,GATA1 Transcription Factor ,Proto-Oncogene Protein c-fli-1 ,Promoter Regions ,Genetic ,Genome-Wide Association Study ,Epigenesis ,Genetic ,Genome ,Human ,Infant ,Newborn ,Promoter Regions - Abstract
Down syndrome is associated with genome-wide perturbation of gene expression, which may be mediated by epigenetic changes. We perform an epigenome-wide association study on neonatal bloodspots comparing 196 newborns with Down syndrome and 439 newborns without Down syndrome, adjusting for cell-type heterogeneity, which identifies 652 epigenome-wide significant CpGs (P
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- 2021
27. Cancer health disparities in racial/ethnic minorities in the United States
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Zavala, Valentina A, Bracci, Paige M, Carethers, John M, Carvajal-Carmona, Luis, Coggins, Nicole B, Cruz-Correa, Marcia R, Davis, Melissa, de Smith, Adam J, Dutil, Julie, Figueiredo, Jane C, Fox, Rena, Graves, Kristi D, Gomez, Scarlett Lin, Llera, Andrea, Neuhausen, Susan L, Newman, Lisa, Nguyen, Tung, Palmer, Julie R, Palmer, Nynikka R, Pérez-Stable, Eliseo J, Piawah, Sorbarikor, Rodriquez, Erik J, Sanabria-Salas, María Carolina, Schmit, Stephanie L, Serrano-Gomez, Silvia J, Stern, Mariana C, Weitzel, Jeffrey, Yang, Jun J, Zabaleta, Jovanny, Ziv, Elad, and Fejerman, Laura
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Digestive Diseases ,American Indian or Alaska Native ,Cancer ,Prevention ,Good Health and Well Being ,Ethnicity ,Female ,Health Status Disparities ,Humans ,Male ,Minority Groups ,Neoplasms ,United States ,Public Health and Health Services ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
There are well-established disparities in cancer incidence and outcomes by race/ethnicity that result from the interplay between structural, socioeconomic, socio-environmental, behavioural and biological factors. However, large research studies designed to investigate factors contributing to cancer aetiology and progression have mainly focused on populations of European origin. The limitations in clinicopathological and genetic data, as well as the reduced availability of biospecimens from diverse populations, contribute to the knowledge gap and have the potential to widen cancer health disparities. In this review, we summarise reported disparities and associated factors in the United States of America (USA) for the most common cancers (breast, prostate, lung and colon), and for a subset of other cancers that highlight the complexity of disparities (gastric, liver, pancreas and leukaemia). We focus on populations commonly identified and referred to as racial/ethnic minorities in the USA-African Americans/Blacks, American Indians and Alaska Natives, Asians, Native Hawaiians/other Pacific Islanders and Hispanics/Latinos. We conclude that even though substantial progress has been made in understanding the factors underlying cancer health disparities, marked inequities persist. Additional efforts are needed to include participants from diverse populations in the research of cancer aetiology, biology and treatment. Furthermore, to eliminate cancer health disparities, it will be necessary to facilitate access to, and utilisation of, health services to all individuals, and to address structural inequities, including racism, that disproportionally affect racial/ethnic minorities in the USA.
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- 2021
28. Genetic predisposition to longer telomere length and risk of childhood, adolescent and adult-onset ependymoma
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Zhang, Chenan, Ostrom, Quinn T, Semmes, Eleanor C, Ramaswamy, Vijay, Hansen, Helen M, Morimoto, Libby, de Smith, Adam J, Pekmezci, Melike, Vaksman, Zalman, Hakonarson, Hakon, Diskin, Sharon J, Metayer, Catherine, Taylor, Michael D, Wiemels, Joseph L, Bondy, Melissa L, and Walsh, Kyle M
- Subjects
Biomedical and Clinical Sciences ,Neurosciences ,Brain Cancer ,Pediatric Cancer ,Pediatric ,Rare Diseases ,Brain Disorders ,Prevention ,Cancer ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Acid Anhydride Hydrolases ,Adolescent ,Adult ,Age of Onset ,Brain Neoplasms ,Case-Control Studies ,Child ,DNA Helicases ,Ependymoma ,Female ,Genetic Predisposition to Disease ,Humans ,Infratentorial Neoplasms ,Male ,Mendelian Randomization Analysis ,RNA ,Ribonucleoproteins ,Telomerase ,Telomere ,Telomere Homeostasis ,Telomere-Binding Proteins ,Young Adult ,Pediatric cancer ,Telomere length ,Mendelian randomization ,Glioma International Case-Control Study ,Biochemistry and Cell Biology ,Clinical Sciences ,Biochemistry and cell biology - Abstract
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.
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- 2020
29. European genetic ancestry associated with risk of childhood ependymoma
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Zhang, Chenan, Ostrom, Quinn T, Hansen, Helen M, Gonzalez-Maya, Julio, Hu, Donglei, Ziv, Elad, Morimoto, Libby, de Smith, Adam J, Muskens, Ivo S, Kline, Cassie N, Vaksman, Zalman, Hakonarson, Hakon, Diskin, Sharon J, Kruchko, Carol, Barnholtz-Sloan, Jill S, Ramaswamy, Vijay, Ali-Osman, Francis, Bondy, Melissa L, Taylor, Michael D, Metayer, Catherine, Wiemels, Joseph L, and Walsh, Kyle M
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Clinical Research ,Cancer ,Pediatric ,American Indian or Alaska Native ,Human Genome ,Genetics ,Brain Disorders ,Black or African American ,Child ,Ependymoma ,Female ,Hispanic or Latino ,Humans ,Male ,United States ,White People ,disparities ,ependymoma ,ethnicity ,genetic ancestry ,pediatric cancer ,race ,Neurosciences ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
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.
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- 2020
30. History of Early Childhood Infections and Acute Lymphoblastic Leukemia Risk Among Children in a US Integrated Health-Care System
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Morimoto, Libby M, Kwan, Marilyn L, Deosaransingh, Kamala, Munneke, Julie R, Kang, Alice Y, Quesenberry, Charles, Kogan, Scott, de Smith, Adam J, Metayer, Catherine, and Wiemels, Joseph L
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Health Services and Systems ,Health Sciences ,Pediatric ,Childhood Leukemia ,Infectious Diseases ,Rare Diseases ,Clinical Research ,Prevention ,Pediatric Cancer ,Pediatric Research Initiative ,Cancer ,Hematology ,2.2 Factors relating to the physical environment ,Aetiology ,Infection ,Good Health and Well Being ,Adolescent ,California ,Case-Control Studies ,Child ,Child ,Preschool ,Female ,Humans ,Infant ,Infections ,Male ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,childhood ALL ,childhood leukemia ,early-life infections ,medical record ,Mathematical Sciences ,Medical and Health Sciences ,Epidemiology - Abstract
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).
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- 2020
31. Germline cancer predisposition variants and pediatric glioma: a population-based study in California
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Muskens, Ivo S, de Smith, Adam J, Zhang, Chenan, Hansen, Helen M, Morimoto, Libby, Metayer, Catherine, Ma, Xiaomei, Walsh, Kyle M, and Wiemels, Joseph L
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Rare Diseases ,Brain Disorders ,Genetic Testing ,Pediatric Cancer ,Neurosciences ,Prevention ,Brain Cancer ,Cancer ,Biotechnology ,Human Genome ,Genetics ,Clinical Research ,Pediatric ,2.1 Biological and endogenous factors ,Aetiology ,California ,Child ,Genetic Predisposition to Disease ,Germ-Line Mutation ,Glioma ,Humans ,pediatric glioma ,Li-Fraumeni syndrome ,glioblastoma ,germline variant ,exome sequencing ,Li–Fraumeni syndrome ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
BackgroundPediatric 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.MethodsDNA 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.ResultsWe 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).ConclusionA 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.
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- 2020
32. Germline variants in predisposition genes in children with Down syndrome and acute lymphoblastic leukemia
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Winer, Peleg, Muskens, Ivo S, Walsh, Kyle M, Vora, Ajay, Moorman, Anthony V, Wiemels, Joseph L, Roberts, Irene, Roy, Anindita, and de Smith, Adam J
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Child ,Down Syndrome ,Germ Cells ,Germ-Line Mutation ,Humans ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Cardiovascular medicine and haematology - Abstract
Rare and pathogenic germline variants, including in IKZF1, contribute to acute lymphoblastic leukemia in children with Down syndrome.
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- 2020
33. Pediatric glioma and medulloblastoma risk and population demographics: a Poisson regression analysis
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Muskens, Ivo S, Feng, Qianxi, Francis, Stephen S, Walsh, Kyle M, Mckean-Cowdin, Roberta, Gauderman, William J, de Smith, Adam J, and Wiemels, Joseph L
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Epidemiology ,Public Health ,Health Sciences ,Brain Cancer ,Neurosciences ,Health Disparities ,Cancer ,Brain Disorders ,Pediatric ,Minority Health ,Behavioral and Social Science ,Rare Diseases ,ethnicity ,pediatric brain tumor ,risk factors ,SEER ,SES - Abstract
BackgroundThe incidence of pediatric brain tumors varies by race and ethnicity, but these relationships may be confounded by socioeconomic status (SES). In this study, the Surveillance, Epidemiology, and End Results Program (SEER) database was evaluated for associations between race/ethnicity and pediatric glioma and medulloblastoma risk with adjustment for SES.MethodsPediatric glioma and medulloblastoma cases from the SEER database (years: 2000-2016) were included. Differences in incidence rates by ethnicity, sex, age, and SES-related factors were evaluated by calculation of age-adjusted incidence rates (AAIRs) and annual percent change (APC). SES-related factors (percentage without less than high school graduation, median household income, and percentage foreign-born) were derived from the census at the county-level (year: 2000). Multivariable Poisson regression models with adjustment for selected covariates were constructed to evaluate risk factors.ResultsThe highest AAIRs of pediatric glioma were observed among non-Hispanic Whites (AAIR: 2.91 per 100 000, 95%-CI: 2.84-2.99). An increasing incidence of pediatric glioma by calendar time was observed among non-Hispanic Whites and non-Hispanic Blacks (APC: 0.97%, 95%-CI: 0.28-1.68 and APC: 1.59%, 95%-CI: 0.03-3.18, respectively). Hispanic and non-Hispanic Black race/ethnicity was associated with lower risk when compared with non-Hispanic White (incidence rate ratios [IRRs]: 0.66, 95%-CI: 0.63-0.70; and 0.69, 95%-CI: 0.65-0.74, respectively). For medulloblastoma, the highest AAIR was observed for non-Hispanic Whites with a positive APC (1.52%, 95%-CI: 0.15-2.91). Hispanics and non-Hispanic Blacks had statistically significant lower IRRs compared with non-Hispanic Whites (IRRs: 0.83, 95%-CI: 0.73-0.94; and 0.72, 95%-CI: 0.59-0.87, respectively).ConclusionNon-Hispanic White race/ethnicity was associated with higher pediatric glioma and medulloblastoma IRRs in models with adjustments for SES.
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- 2020
34. Common genetic variation and risk of osteosarcoma in a multi-ethnic pediatric and adolescent population
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Zhang, Chenan, Hansen, Helen M, Semmes, Eleanor C, Gonzalez-Maya, Julio, Morimoto, Libby, Wei, Qingyi, Eward, William C, DeWitt, Suzanne B, Hurst, Jillian H, Metayer, Catherine, de Smith, Adam J, Wiemels, Joseph L, and Walsh, Kyle M
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Biomedical and Clinical Sciences ,Clinical Sciences ,Genetics ,Pediatric ,Prevention ,Human Genome ,Pediatric Cancer ,Minority Health ,Clinical Research ,Cancer ,Rare Diseases ,2.1 Biological and endogenous factors ,Adolescent ,Child ,Ethnicity ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Hispanic or Latino ,Humans ,Osteosarcoma ,Polymorphism ,Single Nucleotide ,Genome-wide association study ,Polygenic risk score ,Mendelian randomization ,Biological Sciences ,Engineering ,Medical and Health Sciences ,Endocrinology & Metabolism ,Clinical sciences - Abstract
Osteosarcoma, a malignant primary bone tumor most commonly diagnosed in children and adolescents, has a poorly understood genetic etiology. Genome-wide association studies (GWAS) and candidate-gene analyses have identified putative risk variants in subjects of European ancestry. However, despite higher incidence among African-American and Hispanic children, little is known regarding common heritable variation that contributes to osteosarcoma incidence and clinical presentation across racial/ethnic groups. In a multi-ethnic sample of non-Hispanic white, Hispanic, African-American and Asian/Pacific Islander children (537 cases, 2165 controls), we performed association analyses assessing previously-reported loci for osteosarcoma risk and metastasis, including meta-analysis across racial/ethnic groups. We also assessed a previously described association between genetic predisposition to longer leukocyte telomere length (LTL) and osteosarcoma risk in this independent multi-ethnic dataset. In our sample, we were unable to replicate previously-reported loci for osteosarcoma risk or metastasis detected in GWAS of European-ancestry individuals in either ethnicity-stratified analyses or meta-analysis across ethnic groups. Our analyses did confirm that genetic predisposition to longer LTL is a risk factor for osteosarcoma (ORmeta: 1.22; 95% CI: 1.09-1.36; P = 3.8 × 10-4), and the strongest effect was seen in Hispanic subjects (OR: 1.32; 95% CI: 1.12-1.54, P = 6.2 × 10-4). Our findings shed light on the replicability of osteosarcoma risk loci across ethnicities and motivate further characterization of these genetic factors in diverse clinical cohorts.
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- 2020
35. Germline genetic landscape of pediatric central nervous system tumors
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Muskens, Ivo S, Zhang, Chenan, de Smith, Adam J, Biegel, Jaclyn A, Walsh, Kyle M, and Wiemels, Joseph L
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Human Genome ,Rare Diseases ,Brain Cancer ,Cancer ,Genetic Testing ,Neurosciences ,Pediatric ,Pediatric Research Initiative ,Brain Disorders ,Genetics ,Pediatric Cancer ,Good Health and Well Being ,Biomarkers ,Tumor ,Central Nervous System Neoplasms ,Child ,Genetic Predisposition to Disease ,Genomics ,Germ-Line Mutation ,High-Throughput Nucleotide Sequencing ,Humans ,genetics ,pediatric brain tumor ,predisposition ,syndromes ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Central nervous system (CNS) tumors are the second most common type of cancer among children. Depending on histopathology, anatomic location, and genomic factors, specific subgroups of brain tumors have some of the highest cancer-related mortality rates or result in considerable lifelong morbidity. Pediatric CNS tumors often occur in patients with genetic predisposition, at times revealing underlying cancer predisposition syndromes. Advances in next-generation sequencing (NGS) have resulted in the identification of an increasing number of cancer predisposition genes. In this review, the literature on genetic predisposition to pediatric CNS tumors is evaluated with a discussion of potential future targets for NGS and clinical implications. Furthermore, we explore potential strategies for enhancing the understanding of genetic predisposition of pediatric CNS tumors, including evaluation of non-European populations, pan-genomic approaches, and large collaborative studies.
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- 2019
36. Increased neonatal level of arginase 2 in cases of childhood acute lymphoblastic leukemia implicates immunosuppression in the etiology
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Nielsen, Amalie B, Zhou, Mi, de Smith, Adam J, Wang, Rong, McCoy, Lucie, Hansen, Helen, Morimoto, Libby, Grønbæk, Kirsten, Johansen, Christoffer, Kogan, Scott C, Metayer, Catherine, Bracci, Paige M, Ma, Xiaomei, and Wiemels, Joseph L
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Paediatrics ,Biomedical and Clinical Sciences ,Arginase ,Biomarkers ,California ,Case-Control Studies ,Disease Susceptibility ,Female ,Humans ,Immunocompromised Host ,Infant ,Infant ,Newborn ,Male ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Prognosis ,Immunology - Published
- 2019
37. Predisposing germline mutations in high hyperdiploid acute lymphoblastic leukemia in children
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de Smith, Adam J, Lavoie, Geneviève, Walsh, Kyle M, Aujla, Sumeet, Evans, Erica, Hansen, Helen M, Smirnov, Ivan, Kang, Alice Y, Zenker, Martin, Ceremsak, John J, Stieglitz, Elliot, Muskens, Ivo S, Roberts, William, McKean‐Cowdin, Roberta, Metayer, Catherine, Roux, Philippe P, and Wiemels, Joseph L
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Biological Sciences ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Genetics ,Orphan Drug ,Cancer ,Pediatric Cancer ,Clinical Research ,Hematology ,Childhood Leukemia ,Pediatric ,Rare Diseases ,2.1 Biological and endogenous factors ,Aetiology ,Adaptor Proteins ,Signal Transducing ,Child ,Frameshift Mutation ,Gene Frequency ,Genetic Predisposition to Disease ,Germ-Line Mutation ,HEK293 Cells ,Humans ,Penetrance ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,acute lymphoblastic leukemia ,ALL ,FLT3 ,GAB2 ,germline mutations ,high hyperdiploidy ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
High hyperdiploidy (HD) is the most common cytogenetic subtype of childhood acute lymphoblastic leukemia (ALL), and a higher incidence of HD has been reported in ALL patients with congenital cancer syndromes. We assessed the frequency of predisposing germline mutations in 57 HD-ALL patients from the California Childhood Leukemia Study via targeted sequencing of cancer-relevant genes. Three out of 57 patients (5.3%) harbored confirmed germline mutations that were likely causal, in NBN, ETV6, and FLT3, with an additional six patients (10.5%) harboring putative predisposing mutations that were rare in unselected individuals (
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- 2019
38. BMI1 enhancer polymorphism underlies chromosome 10p12.31 association with childhood acute lymphoblastic leukemia
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de Smith, Adam J, Walsh, Kyle M, Francis, Stephen S, Zhang, Chenan, Hansen, Helen M, Smirnov, Ivan, Morimoto, Libby, Whitehead, Todd P, Kang, Alice, Shao, Xiaorong, Barcellos, Lisa F, McKean‐Cowdin, Roberta, Zhang, Luoping, Fu, Cecilia, Wang, Rong, Yu, Herbert, Hoh, Josephine, Dewan, Andrew T, Metayer, Catherine, Ma, Xiaomei, and Wiemels, Joseph L
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Human Genome ,Hematology ,Pediatric ,Rare Diseases ,Pediatric Cancer ,Genetics ,Clinical Research ,Childhood Leukemia ,2.1 Biological and endogenous factors ,Adolescent ,Adult ,California ,Cell Cycle Proteins ,Child ,Chromosome Mapping ,Chromosomes ,Human ,Pair 10 ,Core Binding Factor Alpha 1 Subunit ,Enhancer Elements ,Genetic ,Female ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Humans ,K562 Cells ,Linkage Disequilibrium ,Logistic Models ,Male ,Phosphotransferases (Alcohol Group Acceptor) ,Polycomb Repressive Complex 1 ,Polymorphism ,Single Nucleotide ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Trans-Activators ,Young Adult ,childhood acute lymphoblastic leukemia ,genome-wide association study ,fine-mapping ,BMI1 ,enhancer element ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
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.
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- 2018
39. Genome-wide trans-ethnic meta-analysis identifies novel susceptibility loci for childhood acute lymphoblastic leukemia
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Jeon, Soyoung, de Smith, Adam J., Li, Shaobo, Chen, Minhui, Chan, Tsz Fung, Muskens, Ivo S., Morimoto, Libby M., DeWan, Andrew T., Mancuso, Nicholas, Metayer, Catherine, Ma, Xiaomei, Wiemels, Joseph L., and Chiang, Charleston W. K.
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- 2022
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40. DNA methylation at birth in monozygotic twins discordant for pediatric acute lymphoblastic leukemia
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Nickels, Eric M., Li, Shaobo, Myint, Swe Swe, Arroyo, Katti, Feng, Qianxi, Siegmund, Kimberly D., de Smith, Adam J., and Wiemels, Joseph L.
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- 2022
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41. Incorporation of DNA methylation quantitative trait loci (mQTLs) in epigenome-wide association analysis: application to birthweight effects in neonatal whole blood
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Li, Shaobo, Mancuso, Nicholas, Metayer, Catherine, Ma, Xiaomei, de Smith, Adam J., and Wiemels, Joseph L.
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- 2022
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42. Exploring the genetic and epigenetic origins of juvenile myelomonocytic leukemia using newborn screening samples
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Behnert, Astrid, Meyer, Julia, Parsa, Jahan-Yar, Hechmer, Aaron, Loh, Mignon L., Olshen, Adam, de Smith, Adam J., and Stieglitz, Elliot
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- 2022
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43. Two HLA class II gene variants are independently associated with pediatric osteosarcoma risk
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Zhang, Chenan, Wiemels, Joseph L, Hansen, Helen M, Gonzalez-Maya, Julio, Endicott, Alyson A, de Smith, Adam J, Smirnov, Ivan V, Witte, John S, Morimoto, Libby M, Metayer, Catherine, and Walsh, Kyle M
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Epidemiology ,Biomedical and Clinical Sciences ,Health Sciences ,Pediatric ,Prevention ,Cancer ,Pediatric Cancer ,Genetics ,Human Genome ,2.1 Biological and endogenous factors ,Aetiology ,Adult ,Bone Neoplasms ,Case-Control Studies ,Female ,Follow-Up Studies ,Genes ,MHC Class II ,Genetic Predisposition to Disease ,Genotype ,Humans ,Male ,Meta-Analysis as Topic ,Osteosarcoma ,Polymorphism ,Single Nucleotide ,Prognosis ,Young Adult ,Medical and Health Sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
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 (r 2 = 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 (P range = 0.011-0.037). Meta-analysis of the two datasets identified HLA-DRB1*0301 as the most significantly associated variant (ORmeta = 0.62; P meta = 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, P meta = 1.2 × 10-3), and a third suggestive association at HLA-DQB1*0302 (ORmeta = 0.73, P meta = 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.
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- 2018
44. Genetic determinants of childhood and adult height associated with osteosarcoma risk
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Zhang, Chenan, Morimoto, Libby M, de Smith, Adam J, Hansen, Helen M, Gonzalez‐Maya, Julio, Endicott, Alyson A, Smirnov, Ivan V, Metayer, Catherine, Wei, Qingyi, Eward, William C, Wiemels, Joseph L, and Walsh, Kyle M
- Subjects
Epidemiology ,Biomedical and Clinical Sciences ,Health Sciences ,Prevention ,Pediatric ,Genetics ,Adult ,Body Height ,Bone Neoplasms ,California ,Case-Control Studies ,Child ,Child Development ,Female ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Humans ,Infant ,Newborn ,Male ,Multifactorial Inheritance ,Neonatal Screening ,Osteosarcoma ,Polymorphism ,Single Nucleotide ,Registries ,Risk Factors ,White People ,Young Adult ,height ,Mendelian randomization ,osteosarcoma ,pediatric cancer ,polygenic score ,Oncology and Carcinogenesis ,Public Health and Health Services ,Oncology & Carcinogenesis ,Oncology and carcinogenesis ,Public health - Abstract
BackgroundAlthough 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.MethodsThe 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.ResultsEach 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]).ConclusionsA 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.
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- 2018
45. Genomic characterization of chronic lymphocytic leukemia (CLL) in radiation-exposed Chornobyl cleanup workers.
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Ojha, Juhi, Dyagil, Iryna, Finch, Stuart C, Reiss, Robert F, de Smith, Adam J, Gonseth, Semira, Zhou, Mi, Hansen, Helen M, Sherborne, Amy L, Nakamura, Jean, Bracci, Paige M, Gudzenko, Nataliya, Hatch, Maureen, Babkina, Nataliya, Little, Mark P, Chumak, Vadim V, Walsh, Kyle M, Bazyka, Dimitry, Wiemels, Joseph L, and Zablotska, Lydia B
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Humans ,Neoplasms ,Radiation-Induced ,Incidence ,Prevalence ,Case-Control Studies ,Follow-Up Studies ,Radiation Dosage ,Genomics ,Occupational Exposure ,Genome ,Human ,Chernobyl Nuclear Accident ,Adult ,Middle Aged ,Ukraine ,Female ,Male ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Young Adult ,Radiation Exposure ,Chernobyl ,Chornobyl ,Chronic lymphocytic leukemia ,Ionizing radiation ,Mutation ,Telomere ,Neoplasms ,Radiation-Induced ,Genome ,Human ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Toxicology ,Public Health and Health Services - Abstract
BACKGROUND:Chronic lymphocytic leukemia (CLL) was the predominant leukemia in a recent study of Chornobyl cleanup workers from Ukraine exposed to radiation (UR-CLL). Radiation risks of CLL significantly increased with increasing bone marrow radiation doses. Current analysis aimed to clarify whether the increased risks were due to radiation or to genetic mutations in the Ukrainian population. METHODS:A detailed characterization of the genomic landscape was performed in a unique sample of 16 UR-CLL patients and age- and sex-matched unexposed general population Ukrainian-CLL (UN-CLL) and Western-CLL (W-CLL) patients (n = 28 and 100, respectively). RESULTS:Mutations in telomere-maintenance pathway genes POT1 and ATM were more frequent in UR-CLL compared to UN-CLL and W-CLL (both p
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- 2018
46. GWAS in childhood acute lymphoblastic leukemia reveals novel genetic associations at chromosomes 17q12 and 8q24.21.
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Wiemels, Joseph L, Walsh, Kyle M, de Smith, Adam J, Metayer, Catherine, Gonseth, Semira, Hansen, Helen M, Francis, Stephen S, Ojha, Juhi, Smirnov, Ivan, Barcellos, Lisa, Xiao, Xiaorong, Morimoto, Libby, McKean-Cowdin, Roberta, Wang, Rong, Yu, Herbert, Hoh, Josephine, DeWan, Andrew T, and Ma, Xiaomei
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Chromosomes ,Human ,Pair 8 ,Chromosomes ,Human ,Pair 17 ,Humans ,Genetic Predisposition to Disease ,Risk Factors ,Gene Frequency ,Polymorphism ,Single Nucleotide ,Adolescent ,Child ,Preschool ,Infant ,Infant ,Newborn ,Hispanic Americans ,California ,Female ,Male ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Genome-Wide Association Study ,Chromosomes ,Human ,Pair 8 ,Pair 17 ,Polymorphism ,Single Nucleotide ,Child ,Preschool ,Newborn - Abstract
Childhood acute lymphoblastic leukemia (ALL) (age 0-14 years) is 20% more common in Latino Americans than non-Latino whites. We conduct a genome-wide association study in a large sample of 3263 Californian children with ALL (including 1949 of Latino heritage) and 3506 controls matched on month and year of birth, sex, and ethnicity, and an additional 12,471 controls from the Kaiser Resource for Genetic Epidemiology Research on Aging Cohort. Replication of the strongest genetic associations is performed in two independent datasets from the Children's Oncology Group and the California Childhood Leukemia Study. Here we identify new risk loci on 17q12 near IKZF3/ZPBP2/GSDMB/ORMDL3, a locus encompassing a transcription factor important for lymphocyte development (IKZF3), and at an 8q24 region known for structural contacts with the MYC oncogene. These new risk loci may impact gene expression via local (four 17q12 genes) or long-range (8q24) interactions, affecting function of well-characterized hematopoietic and growth-regulation pathways.
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- 2018
47. To ERV Is Human: A Phenotype-Wide Scan Linking Polymorphic Human Endogenous Retrovirus-K Insertions to Complex Phenotypes.
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Wallace, Amelia D, Wendt, George A, Barcellos, Lisa F, de Smith, Adam J, Walsh, Kyle M, Metayer, Catherine, Costello, Joseph F, Wiemels, Joseph L, and Francis, Stephen S
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GWAS ,HERV-K ,eQTL ,polymorphism ,recombination ,Genetics ,Clinical Sciences ,Law - Abstract
Approximately 8% of the human genome is comprised of endogenous retroviral insertions (ERVs) originating from historic retroviral integration into germ cells. The function of ERVs as regulators of gene expression is well established. Less well studied are insertional polymorphisms of ERVs and their contribution to the heritability of complex phenotypes. The most recent integration of ERV, HERV-K, is expressed in a range of complex human conditions from cancer to neurologic diseases. Using an in-house computational pipeline and whole-genome sequencing data from the diverse 1,000 Genomes Phase 3 population (n = 2,504), we identified 46 polymorphic HERV-K insertions that are tagged by adjacent single nucleotide polymorphisms (SNPs). To test the potential role of polymorphic HERV-K in the heritability of complex diseases, existing databases were queried for enrichment of established relationships between the HERV-K insertion-associated SNPs (hiSNPs), and tissue specific gene expression and disease phenotypes. Overall, hiSNPs for the 46 polymorphic HERV-K sites were statistically enriched (p < 1.0E-16) for eQTLs across 44 human tissues. Fifteen of the 46 HERV-K insertions had hiSNPs annotated in the EMBL-EBI GWAS Catalog and cumulatively associated with >100 phenotypes. Experimental factor ontology enrichment analysis suggests that polymorphic HERV-K specifically contribute to neurologic and immunologic disease phenotypes, including traits related to intra cranial volume (FDR 2.00E-09), Parkinson's disease (FDR 1.80E-09), and autoimmune diseases (FDR 1.80E-09). These results provide strong candidates for context-specific study of polymorphic HERV-K insertions in disease-related traits, serving as a roadmap for future studies of the heritability of complex disease.
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- 2018
48. Non-additive and epistatic effects of HLA polymorphisms contributing to risk of adult glioma
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Zhang, Chenan, de Smith, Adam J, Smirnov, Ivan V, Wiencke, John K, Wiemels, Joseph L, Witte, John S, and Walsh, Kyle M
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Biomedical and Clinical Sciences ,Neurosciences ,Oncology and Carcinogenesis ,Biotechnology ,Human Genome ,Brain Disorders ,Clinical Research ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Brain Neoplasms ,Case-Control Studies ,Female ,Genetic Association Studies ,Genetic Predisposition to Disease ,Glioma ,HLA Antigens ,Haplotypes ,Heterozygote ,Homozygote ,Humans ,Male ,Middle Aged ,Models ,Genetic ,Polymorphism ,Single Nucleotide ,White People ,Brain tumor ,HLA ,MHC ,Non-additive effects ,Epistasis ,Interactions ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
Although genome-wide association studies have identified several susceptibility loci for adult glioma, little is known regarding the potential contribution of genetic variation in the human leukocyte antigen (HLA) region to glioma risk. HLA associations have been reported for various malignancies, with many studies investigating selected candidate HLA polymorphisms. However, no systematic analysis has been conducted in glioma patients, and no investigation into potential non-additive effects has been described. We conducted comprehensive genetic analyses of HLA variants among 1746 adult glioma patients and 2312 controls of European-ancestry from the GliomaScan Consortium. Genotype data were generated with the Illumina 660-Quad array, and we imputed HLA alleles using a reference panel of 5225 individuals in the Type 1 Diabetes Genetics Consortium who underwent high-resolution HLA typing via next-generation sequencing. Case-control comparisons were adjusted for population stratification using ancestry-informative principal components. Because alleles in different loci across the HLA region are linked, we created multigene haplotypes consisting of the genes DRB1, DQA1, and DQB1. Although none of the haplotypes were associated with glioma in additive models, inclusion of a dominance term significantly improved the model for multigene haplotype HLA-DRB1*1501-DQA1*0102-DQB1*0602 (P = 0.002). Heterozygous carriers of the haplotype had an increased risk of glioma [odds ratio (OR) 1.23; 95% confidence interval (CI) 1.01-1.49], while homozygous carriers were at decreased risk compared with non-carriers (OR 0.64; 95% CI 0.40-1.01). Our results suggest that the DRB1*1501-DQA1*0102-DQB1*0602 haplotype may contribute to the risk of glioma in a non-additive manner, with the positive dominance effect partly explained by an epistatic interaction with HLA-DRB1*0401-DQA1*0301-DQB1*0301.
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- 2017
49. Correlates of Prenatal and Early-Life Tobacco Smoke Exposure and Frequency of Common Gene Deletions in Childhood Acute Lymphoblastic Leukemia
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de Smith, Adam J, Kaur, Maneet, Gonseth, Semira, Endicott, Alyson, Selvin, Steve, Zhang, Luoping, Roy, Ritu, Shao, Xiaorong, Hansen, Helen M, Kang, Alice Y, Walsh, Kyle M, Dahl, Gary V, McKean-Cowdin, Roberta, Metayer, Catherine, and Wiemels, Joseph L
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Prevention ,Rare Diseases ,Health Effects of Indoor Air Pollution ,Genetics ,Cancer ,Tobacco Smoke and Health ,Pediatric Cancer ,Human Genome ,Childhood Leukemia ,Clinical Research ,Tobacco ,Social Determinants of Health ,Conditions Affecting the Embryonic and Fetal Periods ,Hematology ,Pediatric ,Perinatal Period - Conditions Originating in Perinatal Period ,Aetiology ,2.2 Factors relating to the physical environment ,Respiratory ,Good Health and Well Being ,Adolescent ,Basic Helix-Loop-Helix Transcription Factors ,Child ,Child ,Preschool ,Core Binding Factor Alpha 2 Subunit ,DNA Methylation ,Female ,Fetus ,Gene Deletion ,Humans ,Infant ,Male ,Poisson Distribution ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Pregnancy ,Proto-Oncogene Proteins c-ets ,Repressor Proteins ,Tobacco Smoke Pollution ,ETS Translocation Variant 6 Protein ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
Tobacco smoke exposure has been associated with risk of childhood acute lymphoblastic leukemia (ALL). Understanding the relationship between tobacco exposures and specific mutations may yield etiologic insights. We carried out a case-only analysis to explore whether prenatal and early-life tobacco smoke exposure influences the formation of leukemogenic genomic deletions. Somatic copy number of 8 genes frequently deleted in ALL (CDKN2A, ETV6, IKZF1, PAX5, RB1, BTG1, PAR1 region, and EBF1) was assessed in 559 pretreatment tumor samples from the California Childhood Leukemia Study. Parent and child's passive tobacco exposure was assessed using interview-assisted questionnaires as well as DNA methylation in aryl-hydrocarbon receptor repressor (AHRR), a sentinel epigenetic biomarker of exposure to maternal smoking during pregnancy. Multivariable Poisson regressions were used to test the association between the smoking exposures and total number of deletions. Deletion burden varied by subtype, with a lower frequency in high-hyperdiploid and higher frequency in ETV6-RUNX1 fusion ALL. The total number of deletions per case was positively associated with tobacco smoke exposure, in particular for maternal ever-smoking (ratio of means, RM, 1.31; 95% CI, 1.08-1.59), maternal smoking during pregnancy (RM, 1.48; 95% CI, 1.12-1.94), and during breastfeeding (RM, 2.11; 95% CI, 1.48-3.02). The magnitude of association with maternal ever-smoking was stronger in male children compared with females (Pinteraction = 0.04). The total number of deletions was also associated with DNA methylation at the AHRR epigenetic biomarker (RM, 1.32; 95% CI, 1.02-1.69). Our results suggest that prenatal and early-life tobacco smoke exposure increase the frequency of somatic deletions in children who develop ALL. Cancer Res; 77(7); 1674-83. ©2017 AACR.
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- 2017
50. In utero cytomegalovirus infection and development of childhood acute lymphoblastic leukemia
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Francis, Stephen Starko, Wallace, Amelia D, Wendt, George A, Li, Linlin, Liu, Fenyong, Riley, Lee W, Kogan, Scott, Walsh, Kyle M, de Smith, Adam J, Dahl, Gary V, Ma, Xiaomei, Delwart, Eric, Metayer, Catherine, and Wiemels, Joseph L
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Rare Diseases ,Pediatric Cancer ,Infectious Diseases ,Cancer ,Perinatal Period - Conditions Originating in Perinatal Period ,Childhood Leukemia ,Minority Health ,Hematology ,Conditions Affecting the Embryonic and Fetal Periods ,Prevention ,Women's Health ,Clinical Research ,Health Disparities ,Pediatric ,2.1 Biological and endogenous factors ,Infection ,Bone Marrow Examination ,Case-Control Studies ,Cytomegalovirus Infections ,Hispanic or Latino ,Humans ,Infant ,Newborn ,Neonatal Screening ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Prevalence ,White People ,Cardiorespiratory Medicine and Haematology ,Paediatrics and Reproductive Medicine ,Immunology ,Biochemistry and cell biology ,Cardiovascular medicine and haematology ,Paediatrics - Abstract
It is widely suspected, yet controversial, that infection plays an etiologic role in the development of acute lymphoblastic leukemia (ALL), the most common childhood cancer and a disease with a confirmed prenatal origin in most cases. We investigated infections at diagnosis and then assessed the timing of infection at birth in children with ALL and age, gender, and ethnicity matched controls to identify potential causal initiating infections. Comprehensive untargeted virome and bacterial analyses of pretreatment bone marrow specimens (n = 127 ALL in comparison with 38 acute myeloid leukemia cases in a comparison group) revealed prevalent cytomegalovirus (CMV) infection at diagnosis in childhood ALL, demonstrating active viral transcription in leukemia blasts as well as intact virions in serum. Screening of newborn blood samples revealed a significantly higher prevalence of in utero CMV infection in ALL cases (n = 268) than healthy controls (n = 270) (odds ratio [OR], 3.71, confidence interval [CI], 1.56-7.92, P = .0016). Risk was more pronounced in Hispanics (OR=5.90, CI=1.89-25.96) than in non-Hispanic whites (OR=2.10 CI= 0.69-7.13). This is the first study to suggest that congenital CMV infection is a risk factor for childhood ALL and is more prominent in Hispanic children. Further investigation of CMV as an etiologic agent for ALL is warranted.
- Published
- 2017
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