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.

Public Health Relevance

We do not yet understand the causes of childhood leukemia. The goal of this project is to discover genetic risk factors for childhood acute lymphoblastic leukemia, and examine the relationship between these genetic risk and fetal growth variables in leukemia incidence. We will explore the impact of these variables on Hispanics and Whites in California to investigate why Hispanics have a higher rate of leukemia, significantly improving our understanding of the causes of this disease in the most vulnerable populations.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA155461-03
Application #
8471006
Study Section
Special Emphasis Panel (ZRG1-PSE-B (02))
Program Officer
Caga-Anan, Emilie Charlisse F
Project Start
2011-07-01
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
3
Fiscal Year
2013
Total Cost
$1,561,623
Indirect Cost
$265,196
Name
University of California San Francisco
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
de Smith, Adam J; Walsh, Kyle M; Francis, Stephen S et al. (2018) BMI1 enhancer polymorphism underlies chromosome 10p12.31 association with childhood acute lymphoblastic leukemia. Int J Cancer 143:2647-2658
Zhang, Chenan; Wiemels, Joseph L; Hansen, Helen M et al. (2018) Two HLA Class II Gene Variants Are Independently Associated with Pediatric Osteosarcoma Risk. Cancer Epidemiol Biomarkers Prev 27:1151-1158
Wiemels, Joseph L; Walsh, Kyle M; de Smith, Adam J et al. (2018) GWAS in childhood acute lymphoblastic leukemia reveals novel genetic associations at chromosomes 17q12 and 8q24.21. Nat Commun 9:286
Zhang, Chenan; Morimoto, Libby M; de Smith, Adam J et al. (2018) Genetic determinants of childhood and adult height associated with osteosarcoma risk. Cancer 124:3742-3752
Petridou, Eleni Th; Georgakis, Marios K; Erdmann, Friederike et al. (2018) Advanced parental age as risk factor for childhood acute lymphoblastic leukemia: results from studies of the Childhood Leukemia International Consortium. Eur J Epidemiol :
Francis, Stephen Starko; Wallace, Amelia D; Wendt, George A et al. (2017) In utero cytomegalovirus infection and development of childhood acute lymphoblastic leukemia. Blood 129:1680-1684
Wang, Rong; Wiemels, Joseph L; Metayer, Catherine et al. (2017) Cesarean Section and Risk of Childhood Acute Lymphoblastic Leukemia in a Population-Based, Record-Linkage Study in California. Am J Epidemiol 185:96-105
Wang, Rong; Metayer, Catherine; Morimoto, Libby et al. (2017) Parental Age and Risk of Pediatric Cancer in the Offspring: A Population-Based Record-Linkage Study in California. Am J Epidemiol 186:843-856
de Smith, Adam J; Kaur, Maneet; Gonseth, Semira et al. (2017) Correlates of Prenatal and Early-Life Tobacco Smoke Exposure and Frequency of Common Gene Deletions in Childhood Acute Lymphoblastic Leukemia. Cancer Res 77:1674-1683
Triebwasser, Corey; Wang, Rong; DeWan, Andrew T et al. (2016) Birth weight and risk of paediatric Hodgkin lymphoma: Findings from a population-based record linkage study in California. Eur J Cancer 69:19-27

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