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Grant Details

Grant Number: 5R01CA155461-04 Interpret this number
Primary Investigator: Wiemels, Joseph
Organization: University Of California, San Francisco
Project Title: Genome-Wide Association Study of Childhood Leukemia By Hispanic Status
Fiscal Year: 2014
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Abstract

DESCRIPTION (provided by applicant): Although acute lymphoblastic leukemia (ALL) is the most common malignancy in children (0 - 14 years), there are few known risk factors. In the United States, Hispanic children have higher incidence of ALL than any other ethnic/racial groups; they have 1.3 times of the risk for ALL than non-Hispanic white children. Two small genome-wide association studies (GWAS) recently identified 2-3 genetic risk factors for childhood ALL, but only in European white populations with non-population based ascertainment. High birth weight and other markers of fetal growth have been consistently linked to an increased risk of childhood ALL in most studies, and Hispanics appear to have accelerated fetal growth early on during pregnancy. In the current application, we seek to significantly advance leukemia research by clarifying the roles of genetic susceptibility and fetal growth in the etiology of childhood ALL in a large population-based sample of Hispanics and non-Hispanic whites in California, using high dimension arrays specifically designed for the two ethnic groups. We will (1) link California birth records with California Cancer Registry data (1988 - 2008) to assemble a population-based case-control study with an unprecedented size (4,000 cases and 4,000 controls, about half of which will be Hispanics and half non-Hispanic whites); (2) obtain the archived neonatal dried blood spots of all cases and controls from the California Department of Public Health; (3) genotype the study population with custom Affymetrix whole genome arrays designed for the California population, with optimized designs for Hispanics and non-Hispanic whites separately; (4) use data from these cases and controls to identify distinct and shared genetic risk alleles for Hispanics and non-Hispanic whites; and (5) validate top GWAS hits in the California Childhood Leukemia Study (an ongoing NIH-funded case-control study with a separate and distinct subject ascertainment, >1000 cases, > 1000 controls, approximately half of which will be Hispanics and half non- Hispanic whites) and in a Brazilian childhood leukemia study with Latin American cases (n = 200) and controls (n = 400). In addition, we will utilize data on the characteristics of all births in California during 1988 - 2008 to develop an algorithm to predict birth weight based on factors such as gestational age, gender, birth order, parental race, parental Hispanic status, and parental ages, and calculate a proportion of expected birth weight (PEBW) for all cases and controls (n = 8000) by dividing their actual observed birth weight by the expected birth weight derived from the algorithm. Subsequently, we will determine whether the PEBW or birth weight is associated with (i) childhood ALL, (ii) the top GWAS hits, and (iii) the SNPs in genes potentially related to fetal growth, in Hispanics and non-Hispanic whites separately. Given the unprecedented sample size, especially the large number of Hispanics included, and ethnic-specific genotyping panels with great genome coverage, this study will clarify the role of genetic susceptibility in childhood ALL, the mechanism involving fetal growth, and in the process identify potential reasons for the puzzling ethnic difference in disease incidence.

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Publications

Predisposing germline mutations in high hyperdiploid acute lymphoblastic leukemia in children.
Authors: de Smith A.J. , Lavoie G. , Walsh K.M. , Aujla S. , Evans E. , Hansen H.M. , Smirnov I. , Kang A.Y. , Zenker M. , Ceremsak J.J. , et al. .
Source: Genes, chromosomes & cancer, 2019 Oct; 58(10), p. 723-730.
EPub date: 2019-05-27.
PMID: 31102422
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Heritable variation at the chromosome 21 gene ERG is associated with acute lymphoblastic leukemia risk in children with and without Down syndrome.
Authors: de Smith A.J. , Walsh K.M. , Morimoto L.M. , Francis S.S. , Hansen H.M. , Jeon S. , Gonseth S. , Chen M. , Sun H. , Luna-Fineman S. , et al. .
Source: Leukemia, 2019-07-11; , .
EPub date: 2019-07-11.
PMID: 31296947
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Parental age and the risk of childhood acute myeloid leukemia: results from the Childhood Leukemia International Consortium.
Authors: Panagopoulou P. , Skalkidou A. , Marcotte E. , Erdmann F. , Ma X. , Heck J.E. , Auvinen A. , Mueller B.A. , Spector L.G. , Roman E. , et al. .
Source: Cancer epidemiology, 2019 Apr; 59, p. 158-165.
EPub date: 2019-02-15.
PMID: 30776582
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Advanced parental age as risk factor for childhood acute lymphoblastic leukemia: results from studies of the Childhood Leukemia International Consortium.
Authors: Petridou E.T. , Georgakis M.K. , Erdmann F. , Ma X. , Heck J.E. , Auvinen A. , Mueller B.A. , Spector L.G. , Roman E. , Metayer C. , et al. .
Source: European journal of epidemiology, 2018 Oct; 33(10), p. 965-976.
EPub date: 2018-05-14.
PMID: 29761423
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Genetic determinants of childhood and adult height associated with osteosarcoma risk.
Authors: Zhang C. , Morimoto L.M. , de Smith A.J. , Hansen H.M. , Gonzalez-Maya J. , Endicott A.A. , Smirnov I.V. , Metayer C. , Wei Q. , Eward W.C. , et al. .
Source: Cancer, 2018-09-15; 124(18), p. 3742-3752.
EPub date: 2018-10-12.
PMID: 30311632
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Two HLA Class II Gene Variants Are Independently Associated with Pediatric Osteosarcoma Risk.
Authors: Zhang C. , Wiemels J.L. , Hansen H.M. , Gonzalez-Maya J. , Endicott A.A. , de Smith A.J. , Smirnov I.V. , Witte J.S. , Morimoto L.M. , Metayer C. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2018 10; 27(10), p. 1151-1158.
EPub date: 2018-07-23.
PMID: 30038050
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BMI1 enhancer polymorphism underlies chromosome 10p12.31 association with childhood acute lymphoblastic leukemia.
Authors: de Smith A.J. , Walsh K.M. , Francis S.S. , Zhang C. , Hansen H.M. , Smirnov I. , Morimoto L. , Whitehead T.P. , Kang A. , Shao X. , et al. .
Source: International journal of cancer, 2018-12-01; 143(11), p. 2647-2658.
EPub date: 2018-10-03.
PMID: 29923177
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GWAS in childhood acute lymphoblastic leukemia reveals novel genetic associations at chromosomes 17q12 and 8q24.21.
Authors: Wiemels J.L. , Walsh K.M. , de Smith A.J. , Metayer C. , Gonseth S. , Hansen H.M. , Francis S.S. , Ojha J. , Smirnov I. , Barcellos L. , et al. .
Source: Nature communications, 2018-01-18; 9(1), p. 286.
EPub date: 2018-01-18.
PMID: 29348612
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Parental Age and Risk of Pediatric Cancer in the Offspring: A Population-Based Record-Linkage Study in California.
Authors: Wang R. , Metayer C. , Morimoto L. , Wiemels J.L. , Yang J. , DeWan A.T. , Kang A. , Ma X. .
Source: American journal of epidemiology, 2017-10-01; 186(7), p. 843-856.
PMID: 28535175
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Correlates of Prenatal and Early-Life Tobacco Smoke Exposure and Frequency of Common Gene Deletions in Childhood Acute Lymphoblastic Leukemia.
Authors: de Smith A.J. , Kaur M. , Gonseth S. , Endicott A. , Selvin S. , Zhang L. , Roy R. , Shao X. , Hansen H.M. , Kang A.Y. , et al. .
Source: Cancer research, 2017-04-01; 77(7), p. 1674-1683.
EPub date: 2017-02-15.
PMID: 28202519
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In utero cytomegalovirus infection and development of childhood acute lymphoblastic leukemia.
Authors: Francis S.S. , Wallace A.D. , Wendt G.A. , Li L. , Liu F. , Riley L.W. , Kogan S. , Walsh K.M. , de Smith A.J. , Dahl G.V. , et al. .
Source: Blood, 2017-03-23; 129(12), p. 1680-1684.
EPub date: 2016-12-15.
PMID: 27979823
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Cesarean Section and Risk of Childhood Acute Lymphoblastic Leukemia in a Population-Based, Record-Linkage Study in California.
Authors: Wang R. , Wiemels J.L. , Metayer C. , Morimoto L. , Francis S.S. , Kadan-Lottick N. , DeWan A.T. , Zhang Y. , Ma X. .
Source: American journal of epidemiology, 2017-01-15; 185(2), p. 96-105.
EPub date: 2016-12-16.
PMID: 27986703
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Birth weight and risk of paediatric Hodgkin lymphoma: Findings from a population-based record linkage study in California.
Authors: Triebwasser C. , Wang R. , DeWan A.T. , Metayer C. , Morimoto L. , Wiemels J.L. , Kadan-Lottick N. , Ma X. .
Source: European journal of cancer (Oxford, England : 1990), 2016 12; 69, p. 19-27.
EPub date: 2016-11-01.
PMID: 27814470
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Clonal and microclonal mutational heterogeneity in high hyperdiploid acute lymphoblastic leukemia.
Authors: de Smith A.J. , Ojha J. , Francis S.S. , Sanders E. , Endicott A.A. , Hansen H.M. , Smirnov I. , Termuhlen A.M. , Walsh K.M. , Metayer C. , et al. .
Source: Oncotarget, 2016-11-08; 7(45), p. 72733-72745.
PMID: 27683039
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Genetic contribution to variation in DNA methylation at maternal smoking-sensitive loci in exposed neonates.
Authors: Gonseth S. , de Smith A.J. , Roy R. , Zhou M. , Lee S.T. , Shao X. , Ohja J. , Wrensch M.R. , Walsh K.M. , Metayer C. , et al. .
Source: Epigenetics, 2016 09; 11(9), p. 664-673.
EPub date: 2016-07-12.
PMID: 27403598
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Common genetic variants associated with telomere length confer risk for neuroblastoma and other childhood cancers.
Authors: Walsh K.M. , Whitehead T.P. , de Smith A.J. , Smirnov I.V. , Park M. , Endicott A.A. , Francis S.S. , Codd V. , ENGAGE Consortium Telomere Group , Samani N.J. , et al. .
Source: Carcinogenesis, 2016 06; 37(6), p. 576-582.
EPub date: 2016-04-01.
PMID: 27207662
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A Heritable Missense Polymorphism in CDKN2A Confers Strong Risk of Childhood Acute Lymphoblastic Leukemia and Is Preferentially Selected during Clonal Evolution.
Authors: Walsh K.M. , de Smith A.J. , Hansen H.M. , Smirnov I.V. , Gonseth S. , Endicott A.A. , Xiao J. , Rice T. , Fu C.H. , McCoy L.S. , et al. .
Source: Cancer research, 2015-11-15; 75(22), p. 4884-94.
EPub date: 2015-11-02.
PMID: 26527286
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Epigenetic remodeling in B-cell acute lymphoblastic leukemia occurs in two tracks and employs embryonic stem cell-like signatures.
Authors: Lee S.T. , Muench M.O. , Fomin M.E. , Xiao J. , Zhou M. , de Smith A. , Martín-Subero J.I. , Heath S. , Houseman E.A. , Roy R. , et al. .
Source: Nucleic acids research, 2015-03-11; 43(5), p. 2590-602.
EPub date: 2015-02-17.
PMID: 25690899
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Periconceptional folate consumption is associated with neonatal DNA methylation modifications in neural crest regulatory and cancer development genes.
Authors: Gonseth S. , Roy R. , Houseman E.A. , de Smith A.J. , Zhou M. , Lee S.T. , Nusslé S. , Singer A.W. , Wrensch M.R. , Metayer C. , et al. .
Source: Epigenetics, 2015; 10(12), p. 1166-76.
PMID: 26646725
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Somatic Mutation Allelic Ratio Test Using ddPCR (SMART-ddPCR): An Accurate Method for Assessment of Preferential Allelic Imbalance in Tumor DNA.
Authors: de Smith A.J. , Walsh K.M. , Hansen H.M. , Endicott A.A. , Wiencke J.K. , Metayer C. , Wiemels J.L. .
Source: PloS one, 2015; 10(11), p. e0143343.
EPub date: 2015-11-17.
PMID: 26575185
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A functional polymorphism in the CEBPE gene promoter influences acute lymphoblastic leukemia risk through interaction with the hematopoietic transcription factor Ikaros.
Authors: Wiemels J.L. , de Smith A.J. , Xiao J. , Lee S.T. , Muench M.O. , Fomin M.E. , Zhou M. , Hansen H.M. , Termuhlen A. , Metayer C. , et al. .
Source: Leukemia, 2016 05; 30(5), p. 1194-7.
EPub date: 2015-09-16.
PMID: 26437776
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PTPRG inhibition by DNA methylation and cooperation with RAS gene activation in childhood acute lymphoblastic leukemia.
Authors: Xiao J. , Lee S.T. , Xiao Y. , Ma X. , Houseman E.A. , Hsu L.I. , Roy R. , Wrensch M. , de Smith A.J. , Chokkalingam A. , et al. .
Source: International journal of cancer, 2014-09-01; 135(5), p. 1101-9.
EPub date: 2014-02-19.
PMID: 24496747
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Genomic ancestry and somatic alterations correlate with age at diagnosis in Hispanic children with B-cell acute lymphoblastic leukemia.
Authors: Walsh K.M. , de Smith A.J. , Welch T.C. , Smirnov I. , Cunningham M.J. , Ma X. , Chokkalingam A.P. , Dahl G.V. , Roberts W. , Barcellos L.F. , et al. .
Source: American journal of hematology, 2014 Jul; 89(7), p. 721-5.
EPub date: 2014-04-18.
PMID: 24753091
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The role of KIR genes and their cognate HLA class I ligands in childhood acute lymphoblastic leukemia.
Authors: de Smith A.J. , Walsh K.M. , Ladner M.B. , Zhang S. , Xiao C. , Cohen F. , Moore T.B. , Chokkalingam A.P. , Metayer C. , Buffler P.A. , et al. .
Source: Blood, 2014-04-17; 123(16), p. 2497-503.
EPub date: 2014-02-11.
PMID: 24518758
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Associations between genome-wide Native American ancestry, known risk alleles and B-cell ALL risk in Hispanic children.
Authors: Walsh K.M. , Chokkalingam A.P. , Hsu L.I. , Metayer C. , de Smith A.J. , Jacobs D.I. , Dahl G.V. , Loh M.L. , Smirnov I.V. , Bartley K. , et al. .
Source: Leukemia, 2013 Dec; 27(12), p. 2416-9.
EPub date: 2013-04-25.
PMID: 23615557
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A global DNA methylation and gene expression analysis of early human B-cell development reveals a demethylation signature and transcription factor network.
Authors: Lee S.T. , Xiao Y. , Muench M.O. , Xiao J. , Fomin M.E. , Wiencke J.K. , Zheng S. , Dou X. , de Smith A. , Chokkalingam A. , et al. .
Source: Nucleic acids research, 2012 Dec; 40(22), p. 11339-51.
EPub date: 2012-10-16.
PMID: 23074194
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Perspectives on the causes of childhood leukemia.
Authors: Wiemels J. .
Source: Chemico-biological interactions, 2012-04-05; 196(3), p. 59-67.
EPub date: 2012-02-02.
PMID: 22326931
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Unusual space-time patterning of the Fallon, Nevada leukemia cluster: Evidence of an infectious etiology.
Authors: Francis S.S. , Selvin S. , Yang W. , Buffler P.A. , Wiemels J.L. .
Source: Chemico-biological interactions, 2012-04-05; 196(3), p. 102-9.
EPub date: 2011-02-23.
PMID: 21352818
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Profound deficit of IL10 at birth in children who develop childhood acute lymphoblastic leukemia.
Authors: Chang J.S. , Zhou M. , Buffler P.A. , Chokkalingam A.P. , Metayer C. , Wiemels J.L. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2011 Aug; 20(8), p. 1736-40.
EPub date: 2011-06-08.
PMID: 21653647
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