Childhood Cancer & the Environment: Activating Clinicians for Prevention

Abstract: The health impacts of extreme weather and air pollution are expected to worsen into the future. There is growing evidence that vulnerable populations, including pediatric patients with cancer, may be at increased risk. There is limited progress, however, on translating these growing risks into clinical prevention strategies. We describe the utilization of a simple risk communication framework and list resources to help pediatric oncology providers engage in discussion of extreme weather and air pollution with patients to reduce their risk.

Abstract: 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.

Abstract: The etiology of pediatric cancer is likely multifactorial including a combination of genetic alterations and environmental exposures. Infection and antigenic exposures have been identified as contributors to the development of pediatric cancers particularly acute lymphoblastic leukemia (ALL), the most common pediatric malignancy. Viral infections such as Epstein-Barr virus (EBV) and human papilloma virus (HPV) have a well-established association with Hodgkin lymphoma (EBV), Burkitt lymphoma (EBV), and head and neck cancers (HPV). More recent evidence suggests CMV is associated with glioblastoma multiforme and ALL. The incidence of pediatric cancer is much lower than the incidence of these viral infections, indicating that there are likely other factors at play. Aside from these specific viral infections, antigenic exposures in general have been associated with pediatric cancers as well. Early life antigenic exposures are known to impact the gut microbiome which is a crucial component to developing a competent immune system. Higher microbial exposure in early life, such as vaginal delivery (versus cesarean delivery), daycare attendance, and breastfeeding have been associated with lower incidence of pediatric ALL, and this effect is hypothesized to be mediated by the gut microbiome. In this review, we highlight the association between infection, antigenic exposures, and pediatric cancer and potential underlying mechanisms that facilitate this association.

Abstract: Folate (vitamin B9) is an essential micronutrient and plays a critical role in one-carbon metabolism, DNA synthesis, and epigenetic regulation, particularly during early embryonic development. While the preventive role of maternal periconceptional folate intake against neural tube defects as well as other birth defects is well established, growing evidence suggests that folate status may also influence childhood cancer risk. In this review, we examine the biological mechanisms linking folate to childhood cancer, with a focus on acute lymphoblastic leukemia (ALL). We synthesize findings from population-wide natural experiments, observational studies, and meta-analyses, with particular attention to timing, dosage, and source of folate intake. Meta-analyses consistently report protective associations between maternal folic acid supplementation and childhood ALL, while evidence for natural dietary folate is more limited and less consistent. Genetic variants in folate metabolism pathways, particularly in the MTHFR gene, may modify these associations, and gene–environment interactions are increasingly recognized as important. Maternal folate status during the periconceptional period has also been linked to changes in offspring DNA methylation and potentially to long-term health outcomes, including at specific epigenetic loci such as IGF2 and ZFP57, as well as across the epigenome. The overall evidence supports the continued promotion of adequate maternal folate intake. Future research should prioritize causal inference methods, epigenome-wide analyses, and greater inclusion of underrepresented populations to clarify the role of folate in childhood cancer etiology.

Abstract: Childhood cancer incidence has steadily risen both in the United States and worldwide, yet its environmental contributors remain underrecognized in clinical care. Children and cancer survivors are particularly susceptible to environmental exposures due to their unique physiology and the long-term health vulnerabilities that follow cancer treatment. Although exposures to substances such as pesticides, air pollution, and household chemicals are linked to increased cancer risk, limited clinical frameworks and clinician training leave oncologists underprepared to address growing environmental health concerns from families.

A holistic pediatric oncology environmental health program in Murcia, Spain offers a scalable vision for embedding the environment into longitudinal cancer care. In the United States, survey data from two large academic pediatric cancer centers revealed strong clinician interest in addressing environmental health in pediatric oncology, leading to the development of a consultative model. Workshops and a standardized environmental health history tool, adapted for clinical use and integration into the medical record, have laid the groundwork for implementation of an environmental consult service across 3 care settings: cancer predisposition clinics, survivorship programs, and as requested. These efforts aim to reduce family anxiety, offer actionable risk-reduction strategies, and empower primary teams with the knowledge to engage in meaningful conversations.

The patient-centered tools, interdisciplinary training, and structured integration into clinical workflows are designed to strengthen environmental health knowledge and practice of pediatric oncologists in the United States.

Abstract: Upstream oil and gas development (OGD) can release carcinogenic and radioactive agents into air and water. This review summarizes evidence on the relationship between residential proximity to upstream OGD and cancer risk among children, adolescents, and young adults (CAYA).