Clark et al. Environmental Health( 2026) 25:12 Page 2 of 13
Introduction Ewing sarcoma is a rare, aggressive cancer of the bones and soft tissues occurring primarily in children and adolescents( median age of onset: 14 – 15 years) [ 1 ] and most commonly among children of European ancestry [ 2, 3 ]. While the prognosis for children in whom the disease is localized is fair( 5-year survival: 65 – 80 %), once metastasis occurs the survival rate drops dramatically( 5-year survival: < 30 %)[ 3 – 6 ] The incidence of Ewing sarcoma has been increasing in North America, particularly in younger children( 1.79 % average annual change for the 0 – 9 year age group from 1988 – 2012) [ 7 ].
Current understanding of the etiology of Ewing sarcoma is limited [ 8 – 10 ]. The development of Ewing sarcoma generally results from chromosomal translocations between the EWSR1 gene and a member of the ETSfamily of genes [ 3, 8, 11 ], most commonly FLI-1. The resulting EWS-FLI1 fusion protein binds to GGAA microsatellites in target genes [ 12 ], and can enhance oncogenesis by interfering with normal cellular activities, such as cell cycle regulation and differentiation [ 8 – 14 ]. Evidence from cell models suggests that the presence of EWS-FLI1 alone( present in 85 % of cases) may not be sufficient to cause Ewing sarcoma, and that co-occurring mutations or modifications are necessary [ 15 – 17 ]. Environmental exposures could provide a mechanism for such co-occurring mutations – and even the formation of the translocation itself.
No specific environmental risk factors for Ewing sarcoma have been identified to date, and Ewing sarcoma is underrepresented in the environmental literature to date. There have been a few investigations into the role of geospatially varying environmental risk factors in the occurrence of potential clusters of Ewing sarcoma [ 18, 19 ]. Pesticides [ 20 – 25 ], proximity to industrial activity( particularly to those industries releasing polyaromatic hydrocarbons)[ 26 ], and air pollution [ 27 ] have all been implicated. Occupational parental exposures and exposures during pregnancy have also been linked to Ewing sarcoma risk, which suggests a potential prenatal or early life origin [ 19, 21 ]. The results of these studies tend to be mixed, perhaps in part due to the rarity of Ewing sarcoma limiting the statistical power.
Oil and gas development( OGD), which uses and releases carcinogenic compounds [ 28 – 32 ], is another potential risk factor. OGD has been linked to increased childhood leukemia risk [ 33 – 37 ], but its potential influence on risk of other pediatric cancers remains understudied. Additionally, more than 4.6 million people live within 1 km of one of the 2.3 million to more than 3 million documented plugged or abandoned wells in the United States [ 38 ]; little is known about the potential emissions or health effects associated with these wells [ 39 – 44 ]. The emergence of suspected clusters of other cancers such as Ewing sarcoma in children living near active and abandoned OGD warrants investigation [ 5, 6 ].
Despite public concern about potential clusters of rare childhood cancers like Ewing sarcoma arising near OGD, the literature on this topic is sparse and focused primarily on leukemia [ 28, 33, 34, 45 – 48 ]. The single peer-reviewed study evaluating Ewing sarcoma risk in the context of OGD exposure examined a small number of cases( n = 20). Additionally, most OGD research to date has focused on only active wells rather than abandoned / plugged wells, which may emit similar contaminants [ 40 ]. To better understand patterns of exposure to both active and abandoned OGD wells and their impacts on an understudied, rare cancer we conducted a population-based case-control study of prenatal exposure to OGD and risk of childhood Ewing sarcoma in California, the most populous state in the United States.
Methods Study population and data sources Our study population is drawn from the California Linkage Study of Early-onset Cancers( CALSEC), a linkage of cancer diagnoses( age 0 – 39 years) reported to the California Cancer Registry from 1988 to 2015 and statewide birth records from 1978 to 2015. CALSEC also includes millions of controls who were born in California and had not been diagnosed with any cancer at the age of 0 – 39 years by 2015 based on information from the California Cancer Registry. Our initial study sample included a total of 619 children who were born in California during 1978 – 2015 and diagnosed with first primary and malignant Ewing sarcoma at the age of 0 – 19 years during 1988 – 2015( i. e., cases), as well as 30,950 control subjects frequency-matched to cases on year of birth at a 50:1 ratio. After exclusions for missing residential address information or inadequate geocode quality( n = 61 cases and 3,150 matched controls, most born during 1978 – 1981, when only ZIP code level information was available) the final study sample consists of 558 cases and 27,800 birth year-matched controls.
Individual level covariates( e. g., sex, race, ethnicity, birth weight) were abstracted directly from birth records. For socio-economic status( SES) at the census tract level, we used the Centers for Disease Control / Agency for Toxic Substances and Disease Registry Social Vulnerability Index( SVI)[ 49 ], a composite index representing sixteen different factors related to socio-economic status, household characteristics, housing type and transportation, and racial and ethnic minority status. The SVI is represented as a percentile( 0 to 1.0), with increasing values corresponding with increasing vulnerability. The covariates assessed as potential confounders were selected a priori based upon the literature and included sex, maternal race and ethnicity, birth weight,