||1R01CA262263-01A1 Interpret this number
||De Smith, Adam
||University Of Southern California
||Understanding the Increased Risk of Childhood Acute Lymphoblastic Leukemia in Latinos
Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer and, despite advances in treatment, it
is still one of the leading causes of childhood death in the United States (US), and survivors face significant
lifelong treatment-related morbidities. Children of Latino ethnicity have the highest and fastest-increasing risk of
ALL in the US, and have lower survival than non-Latino whites; however, this ethnic disparity in incidence and
outcome is not fully understood. Elucidating the increased risk of ALL in Latino children may reveal novel insights
in the etiology of ALL in both Latino and non-Latino populations, and may highlight potential avenues for disease
prevention. We hypothesize that germline genetic variation plays an essential role in the increased ALL risk in
Latinos, that this risk is imparted via Native American ancestry, and that ALL risk alleles were selected in Native
Americans during European colonization of the Americas due to their beneficial effects on immune response to
new infections. We have assembled the largest ever case-control set of childhood ALL in Latinos, including over
5,400 cases and 27,000 controls from three independent studies in California, plus studies in Texas, Children’s
Oncology Group/St. Jude Children’s Research Hospital, and Guatemala. In our first aim, we will perform three
complementary approaches to discover novel common risk loci associated with childhood ALL: i) a genome-
wide association study (GWAS) meta-analysis, ii) admixture mapping to capitalize on the recently admixed
nature of Latino genomes, and iii) a transcriptome-wide association study to identify novel loci and to pinpoint
causal genes at known and novel risk regions. In our second aim, we will characterize the genetic variants in
terms of their association with local Native American ancestry and whether they exhibit evidence of directional
natural selection on the Native American branch of the human population tree. We will also characterize the
aggregate effects of common variants on childhood ALL risk and how this varies by ethnicity, via comprehensive
modeling of polygenic risk scores (PRS) for ALL in Latinos and in non-Latino whites. Finally, we will incorporate
our genetic findings into epidemiologic analyses, by accounting for common (PRS) genetic variants in ALL risk
models for immune-related risk factors in Latinos and non-Latino whites, including cesarean delivery and in utero
cytomegalovirus infection, both of which have shown stronger effects on ALL risk in Latinos and are potentially
modifiable risk factors. The results of this study will shed light on the etiology of childhood ALL in general and of
the increased risk of ALL in Latino children, which will help to alleviate this ethnic disparity and may inform future
approaches for childhood leukemia prevention.
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