Investigating the causes of childhood acute lymphoblastic leukemia through mutational epidemiology

Acute lymphoblastic leukemia (ALL) is the most common cancer in children, and prevention of this disease would significantly reduce childhood mortality and morbidity. While the role of germline genetic variation in the etiology of ALL is well established, the contribution of modifiable risk factors is less well known. Epidemiologic studies have identified several environmental and infectious or immune-related factors associated with childhood ALL, although studies often relied on questionnaire data, which can be prone to recall bias, and/or provided limited information on the potential leukemogenic role of these exogenous exposures. Environmental exposures that have carcinogenic properties (e.g., tobacco smoke, ultraviolet radiation) can leave behind molecular footprints in tumor samples that have specific patterns of mutations, and these mutational signatures can be leveraged to study cancer etiology. Mutational epidemiology has thus emerged as a novel approach to investigate the potential carcinogenic role of exogenous exposures in cancer development, by leveraging the availability of sequencing data in large numbers of patients and combining epidemiological methods with analysis of mutational signatures, which may reveal a personalized history of causative exposures. Such studies have already yielded discoveries in adult solid tumors, identifying novel risk factors and providing insights into environmental factors that may underlie global variation in cancer incidence. However, this approach has yet to be applied to childhood cancer epidemiology. Sequencing studies of childhood ALL have revealed specific patterns of somatic alterations, including mutational signatures related to APOBEC enzymes, reactive oxygen species, and ultraviolet radiation, as well as deletions mediated by illegitimate V(D)J recombination. In this review, we discuss current knowledge on the modifiable and non-modifiable risk factors for childhood ALL, the patterns of somatic genomic alterations that have been identified in ALL patient samples, and how mutational epidemiology could help to pinpoint the leukemogenic role of environmental exposures which will be critical for future prevention strategies.