Modeling historic incidence trends implies early field cancerization in esophageal squamous cell carcinoma

Abstract

Patterns of cancer incidence, viewed over extended time periods, reveal important aspects of multistage carcinogenesis. Here we show how a multistage clonal expansion (MSCE) model for cancer can be harnessed to identify biological processes that shape the surprisingly dynamic and disparate incidence patterns of esophageal squamous cell carcinoma (ESCC) in the US population. While the dramatic rise in esophageal adenocarcinoma (EAC) in the US has been largely attributed to reflux related increases in the prevalence of Barrett’s esophagus (BE), the premalignant field in which most EAC are thought to arise, only scant evidence exists for field cancerization contributing to ESCC. Our analyses of incidence patterns suggest that ESCC is associated with a premalignant field that may develop very early in life. Although the risk of ESCC, which is substantially higher in Blacks than Whites, is generally assumed to be associated with late-childhood and adult exposures to carcinogens, such as from tobacco smoking, alcohol consumption and various industrial exposures, the temporal trends we identify for ESCC suggest an onset distribution of field-defects before age 10, most strongly among Blacks. These trends differ significantly in shape and strength from field-defect trends that we estimate for US Whites. Moreover, the rates of ESCC-predisposing field-defects predicted by the model for cohorts of black children are decreasing for more recent birth cohorts (for Blacks born after 1940). These results point to a potential etiologic role of factors acting early in life, perhaps related to nutritional deficiencies, in the development of ESCC and its predisposing field-defect. Such factors may explain some of the striking racial differences seen in ESCC incidence patterns over time in the US. We used a cell-level carcinogenesis model to analyze incidence patterns of esophageal squamous cell carcinoma (ESCC) in the US. We found an important role of an esophageal field-defect that is predicted to occur predominantly in childhood and predisposes to ESCC in adult life. Age-specific ESCC incidence patterns are also known to differ considerably between Blacks and Whites, and between males and females in the US, but the model consistently predicts early-childhood field-defects in all four groups. The estimated historical field-defect trends appear consistent with possible early childhood nutritional deficiencies.