Profiling the Chemical Exposomic Landscape of Esophageal Squamous Cell Carcinoma

While the cancer genome is well-studied, the nongenetic exposome of cancer remains elusive, particularly for regionally prevalent cancers with poor prognosis. Here, by employing a combined knowledge- and data-driven strategy, we profile the chemical exposome of plasma from 53 healthy controls, 14 esophagitis and 101 esophageal squamous cell carcinoma (ESCC) patients, and 46 esophageal tissues across 12 Chinese provinces, integrating inorganic, endogenous, and exogenous chemicals. We first show that components of the ESCC chemical exposome mediate the relationship between ESCC-related dietary/lifestyle factors and clinic health status indicators. Then, the geographic location of patients is revealed to mostly drive the ESCC chemical exposome, exhibiting more pronounced chemical variations in geographically narrower areas of high incidence, with region-specific chemicals, including a probable environmental carcinogen, influencing cancer endemicity. Finally, analysis of cancer evolutionary trajectory indicates major alterations in chemical exposome during disease initiation, suggesting that certain pollutants may hold promise as noninvasive indicators for early disease risk management. Overall, this scalable strategy of profiling chemical exposome provides a blueprint for future exposome-disease studies and highlights the importance of comprehensively considering chemical mixtures to better understand geographic disparities in cancer risk and the etiology of carcinogenesis.