Grant Number:	1R01CA313241-01 Interpret this number
Primary Investigator:	De Smith, Adam
Organization:	Beckman Research Institute/City Of Hope
Project Title:	Mutational Epidemiology of Childhood Acute Lymphoblastic Leukemia in California
Fiscal Year:	2026

ABSTRACT Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and, despite high cure rates in developed countries, it remains a leading cause of childhood mortality. Moreover, survivors of childhood ALL face long-term treatment-related morbidities. Thus, prevention of ALL remains an important goal; however, there are few known modifiable risk factors. The rising incidence of childhood ALL, particularly among Hispanic/Latino children, suggests a role for common environmental exposures. Case-control studies have identified several environmental risk factors for childhood ALL, but these have largely relied on questionnaire data and, thus, may be prone to recall bias. Recent population-based geospatial studies reported significant associations between environmental exposures to air pollution, pesticides, and ultraviolet (UV) radiation and risk of ALL, although they provide no insights into biological mechanisms. We propose to address these shortcomings through “mutational epidemiology”, a promising approach that combines studying patterns of tumor mutations with epidemiological analyses to elucidate the causes of cancer. While mutational epidemiology studies of adult cancers have led to novel discoveries, this approach has yet to be applied to childhood leukemia. Two major patterns of somatic mutations are detectable in childhood ALL: i) single-base substitution (SBS) mutational signatures related to APOBEC mutagenesis, reactive oxygen species (ROS), and UV radiation; and ii) deletions mediated by “off- target” recombination-activating gene (RAG) recombination; yet the etiologies of these patterns are largely unknown. We will leverage the California Childhood Leukemia Study (CCLS), in which we have access to available diagnostic leukemia (tumor) and germline samples as well as rich epidemiological data, including residential history, questionnaire data, and omics data, from 630 childhood ALL patients of which ~50% are Hispanic/Latino. Through our innovative and collaborative approach, we hypothesize that we will identify risk factors for the somatic mutational patterns in childhood ALL. In our first aim, we will investigate risk factors for off-target RAG recombination through tumor-normal whole-genome sequencing (WGS) of 630 childhood ALL patients. We will expand upon our prior discovery of an association between early-life tobacco smoke exposure and RAG-mediated deletions in ALL to a larger set of patients and examine the potential role of air pollution (from geospatial models) and early-life infections. In our second aim, we will analyze tumor mutational signatures in the 630 patients, focusing on the APOBEC, ROS, and UV SBS signatures, and investigate associations with specific exposures of interest, including early-life infections, air pollution, pesticides of interest, and UV radiation. Finally, in our third aim, we will investigate whether genetic variation is associated with RAG-mediated deletions and mutational signatures and if genetic variants moderate the effects of environmental exposures on somatic mutational patterns. Our innovative mutational epidemiology study of childhood ALL will further our understanding of its causes, highlight novel avenues of prevention, and inform future epidemiological studies.





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