Grant Number:	1R01CA175737-01A1 Interpret this number
Primary Investigator:	Wiemels, Joseph
Organization:	University Of California, San Francisco
Project Title:	Perinatal Immune Development and Risk of Childhood Acute Lymphoblastic Leukemia
Fiscal Year:	2014

DESCRIPTION (provided by applicant): Childhood leukemia is the most common childhood cancer but the causes of the disease are uncertain in the vast majority of cases. Epidemiology studies have pointed to patterns of infection being influential risk factors for leukemia - with exposure to a wide variety and number of childhood contacts (e.g., daycare and older siblings) being protective for leukemia. These associations are strongest for the pre-B cell immunophenotype of leukemia, which we will study here. New epidemiologic evidence suggests that vigorous response to infections, meaning infections that require care from medical professionals, is a risk factor for leukemia. Additionally, children who contract leukemia have a deficit of the immunosuppressive cytokine IL10 at birth when compared to control children who did not get leukemia, meaning that they enter the world with a congenital immune aberration. We hypothesize, based on these observations, that features of neonatal immune function, namely a lack of immunosuppression, are important in risk of pre-B cell acute lymphoblastic leukemia (pre-B ALL). In the current study we will further define this immunosuppressive phenotype in more detail and examine the developmental fetal genetic interaction and maternal environmental factors that influence this fetal phenotype. We will assemble a series of 500 ALL case children and their mothers, and 500 controls with their mothers to assess whether two genetic factors (HLA-C and KIR) critical in developing a supportive immune environment for a fetus within its mother can influence fetal immune status and leukemia case/control status. We will additionally assess, with 200 case mothers and 500 control mothers, whether neonatal immune function phenotype is influenced by maternal immune status during pregnancy. We will define fetal immune phenotype by additional markers besides only IL10 levels, including TGF-¿, IFN-¿, and T- regulatory cell marker - a differentially-methylated region of the critical transcription factor FOXP3. The impact of maternal cytokines and IGE levels, and KIR genotypes (along with HLA-C genotypes in the neonate) will first be assessed on neonatal immune function among controls. Both maternal and fetal immune phenotypes will then be assessed for their impact in prediction of case status. The results of this study will further defie critical characteristics in immune development that influence a cancer of the immune system. These results will benefit efforts to understand the etiology of leukemia as well aid predictive and preventative modalities for childhood leukemia, and set the stage for follow-up studies that examine postnatal factors that combine together with congenital immune immunosuppression to produce leukemia.




A Pregnancy and Childhood Epigenetics Consortium (PACE) meta-analysis highlights potential relationships between birth order and neonatal blood DNA methylation.
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EPub date: 2024-01-09 00:00:00.0.
PMID: 38195839
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Evaluating Genomic Polygenic Risk Scores for Childhood Acute Lymphoblastic Leukemia in Latinos.
Authors: Jeon S. , Lo Y.C. , Morimoto L.M. , Metayer C. , Ma X. , Wiemels J.L. , de Smith A.J. , Chiang C.W.K. .
Source: Hgg Advances, 2023-09-13 00:00:00.0; 4(4), p. 100239.
EPub date: 2023-09-13 00:00:00.0.
PMID: 37710962
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Evaluating Genomic Polygenic Risk Scores for Childhood Acute Lymphoblastic Leukemia in Latinos.
Authors: Jeon S. , Lo Y.C. , Morimoto L.M. , Metayer C. , Ma X. , Wiemels J.L. , de Smith A.J. , Chiang C.W.K. .
Source: Medrxiv : The Preprint Server For Health Sciences, 2023-06-12 00:00:00.0; , .
EPub date: 2023-06-12 00:00:00.0.
PMID: 37398036
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One-Carbon (Folate) Metabolism Pathway at Birth and Risk of Childhood Acute Lymphoblastic Leukemia: A Biomarker Study in Newborns.
Authors: Metayer C. , Imani P. , Dudoit S. , Morimoto L. , Ma X. , Wiemels J.L. , Petrick L.M. .
Source: Cancers, 2023-02-05 00:00:00.0; 15(4), .
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Incorporation of DNA methylation quantitative trait loci (mQTLs) in epigenome-wide association analysis: application to birthweight effects in neonatal whole blood.
Authors: Li S. , Mancuso N. , Metayer C. , Ma X. , de Smith A.J. , Wiemels J.L. .
Source: Clinical Epigenetics, 2022-12-01 00:00:00.0; 14(1), p. 158.
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Investigating DNA methylation as a mediator of genetic risk in childhood acute lymphoblastic leukemia.
Authors: Xu K. , Li S. , Pandey P. , Kang A.Y. , Morimoto L.M. , Mancuso N. , Ma X. , Metayer C. , Wiemels J.L. , de Smith A.J. .
Source: Human Molecular Genetics, 2022-10-28 00:00:00.0; 31(21), p. 3741-3756.
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Cytomegalovirus proteins, maternal pregnancy cytokines, and their impact on neonatal immune cytokine profiles and acute lymphoblastic leukemogenesis in children.
Authors: Wiemels J.L. , Wang R. , Zhou M. , Hansen H. , Gallant R. , Jung J. , Mancuso N. , De Smith A.J. , Metayer C. , Kogan S.C. , et al. .
Source: Haematologica, 2022-09-01 00:00:00.0; 107(9), p. 2266-2270.
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Authors: Li S. , Sok P. , Xu K. , Muskens I.S. , Elliott N. , Myint S.S. , Pandey P. , Hansen H.M. , Morimoto L.M. , Kang A.Y. , et al. .
Source: Blood Advances, 2022-07-26 00:00:00.0; 6(14), p. 4132-4136.
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Interaction between maternal killer immunoglobulin-like receptors and offspring HLAs and susceptibility of childhood ALL.
Authors: Feng Q. , Zhou M. , Li S. , Morimoto L. , Hansen H. , Myint S.S. , Wang R. , Metayer C. , Kang A. , Fear A.L. , et al. .
Source: Blood Advances, 2022-06-28 00:00:00.0; 6(12), p. 3756-3766.
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Accelerated epigenetic aging in newborns with Down syndrome.
Authors: Xu K. , Li S. , Muskens I.S. , Elliott N. , Myint S.S. , Pandey P. , Hansen H.M. , Morimoto L.M. , Kang A.Y. , Ma X. , et al. .
Source: Aging Cell, 2022-06-06 00:00:00.0; , p. e13652.
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Genome-wide trans-ethnic meta-analysis identifies novel susceptibility loci for childhood acute lymphoblastic leukemia.
Authors: Jeon S. , de Smith A.J. , Li S. , Chen M. , Chan T.F. , Muskens I.S. , Morimoto L.M. , DeWan A.T. , Mancuso N. , Metayer C. , et al. .
Source: Leukemia, 2021-11-08 00:00:00.0; , .
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Genetic determinants of blood-cell traits influence susceptibility to childhood acute lymphoblastic leukemia.
Authors: Kachuri L. , Jeon S. , DeWan A.T. , Metayer C. , Ma X. , Witte J.S. , Chiang C.W.K. , Wiemels J.L. , de Smith A.J. .
Source: American Journal Of Human Genetics, 2021-10-07 00:00:00.0; 108(10), p. 1823-1835.
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Source: Nature Communications, 2021-02-05 00:00:00.0; 12(1), p. 821.
EPub date: 2021-02-05 00:00:00.0.
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Birth Characteristics and Risk of Early-Onset Synovial Sarcoma.
Authors: Wiemels J.L. , Wang R. , Feng Q. , Clark C.J. , Amatruda J.F. , Rubin E. , Yee A.C. , Morimoto L.M. , Metayer C. , Ma X. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2020 Jun; 29(6), p. 1162-1167.
EPub date: 2020-04-03 00:00:00.0.
PMID: 32245786
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Early Infection with Cytomegalovirus and Risk of Childhood Hematologic Malignancies.
Authors: Wiemels J.L. , Talbäck M. , Francis S. , Feychting M. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2019 06; 28(6), p. 1024-1027.
EPub date: 2019-04-17 00:00:00.0.
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Predisposing germline mutations in high hyperdiploid acute lymphoblastic leukemia in children.
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Source: Genes, Chromosomes & Cancer, 2019-05-18 00:00:00.0; , .
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Increased neonatal level of arginase 2 in cases of childhood acute lymphoblastic leukemia implicates immunosuppression in etiology.
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GWAS in childhood acute lymphoblastic leukemia reveals novel genetic associations at chromosomes 17q12 and 8q24.21.
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