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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-PSE-B (02))
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Caga-Anan, Emilie Charlisse F
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University of California San Francisco
Public Health & Prev Medicine
Schools of Medicine
San Francisco
United States
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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
Gonseth, Semira; Roy, Ritu; Houseman, E Andres et al. (2015) Periconceptional folate consumption is associated with neonatal DNA methylation modifications in neural crest regulatory and cancer development genes. Epigenetics 10:1166-76
de Smith, Adam J; Walsh, Kyle M; Hansen, Helen M et al. (2015) Somatic Mutation Allelic Ratio Test Using ddPCR (SMART-ddPCR): An Accurate Method for Assessment of Preferential Allelic Imbalance in Tumor DNA. PLoS One 10:e0143343
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Walsh, Kyle M; de Smith, Adam J; Hansen, Helen M et al. (2015) A Heritable Missense Polymorphism in CDKN2A Confers Strong Risk of Childhood Acute Lymphoblastic Leukemia and Is Preferentially Selected during Clonal Evolution. Cancer Res 75:4884-94
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