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

Georg E Luebeck,William D Hazelton,Thomas L Vaughan,Kit Curtius,Dominik Wodarz

doi:10.1371/journal.pcbi.1008961

Georg E Luebeck, William D Hazelton + Show 3 more

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https://doi.org/10.1371/journal.pcbi.1008961

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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.

Highlights

Esophageal squamous cell carcinoma (ESCC) is the main histologic type of esophageal cancer worldwide and remains a significant cause of cancer morbidity and mortality [1]
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
In the United States and other parts of the Western world, the incidence of ESCC has significantly decreased in the past 3 to 4 decades among virtually every race/ethnicity [1, 2], and is dominated by the incidence of esophageal adenocarcinoma (EAC) which continues to rise in Western countries for reasons that are still not fully understood [3, 4]

Summary

Introduction

Esophageal squamous cell carcinoma (ESCC) is the main histologic type of esophageal cancer worldwide and remains a significant cause of cancer morbidity and mortality [1]. In spite of the opposing incidence trends for ESCC and EAC, nutritional deficiencies and cigarette smoking are significant risk factors for both histologic subtypes [5,6,7]. Excess alcohol consumption is significantly associated with increased risk for ESCC (but weakly or inconsistently associated with EAC), while abdominal obesity and gastro-esophageal reflux are prominent risk factors for Barrett’s esophagus (BE) and EAC [4,5,6,7,8,9]. The high frequency of metachronous presentation suggests an underlying predisposition or tissue field-defect that significantly increases the risk of dysplastic lesions prior to the occurrence of ESCC [12,13,14]

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