Abstract
ObjectiveWe aimed to prospectively evaluate the association of oral microbiome with malignant esophageal lesions and its predictive potential as a biomarker of risk.MethodsWe conducted a case-control study nested within a population-based cohort with up to 8 visits of oral swab collection for each subject over an 11-year period in a high-risk area for esophageal cancer in China. The oral microbiome was evaluated with 16S ribosomal RNA (rRNA) gene sequencing in 428 pre-diagnostic oral specimens from 84 cases with esophageal lesions of severe squamous dysplasia and above (SDA) and 168 matched healthy controls. DESeq analysis was performed to identify taxa of differential abundance. Differential oral species together with subject characteristics were evaluated for their potential in predicting SDA risk by constructing conditional logistic regression models.ResultsA total of 125 taxa including 37 named species showed significantly different abundance between SDA cases and controls (all P<0.05 & false discovery rate-adjusted Q<0.10). A multivariate logistic model including 11 SDA lesion-related species and family history of esophageal cancer provided an area under the receiver operating characteristic curve (AUC) of 0.89 (95% CI, 0.84−0.93). Cross-validation and sensitivity analysis, excluding cases diagnosed within 1 year of collection of the baseline specimen and their matched controls, or restriction to screen-endoscopic-detected or clinically diagnosed case-control triads, or using only bacterial data measured at the baseline, yielded AUCs>0.84.ConclusionsThe oral microbiome may play an etiological and predictive role in esophageal cancer, and it holds promise as a non-invasive early warning biomarker for risk stratification for esophageal cancer screening programs.
Highlights
Esophageal cancer is the seventh most common cancer worldwide [1]
Overall microbiome diversity in relation to malignant esophageal lesions No significant trend over years of specimen collection prior to diagnosis of malignant esophageal lesions in the Shannon diversity index was found for severe dysplasia and above (SDA) cases (P=0.124) or controls (P=0.425) (Supplementary Figure S4)
One of the key problems in current microbiome-oncology research is the lack of prospective longitudinal studies, and the execution of such studies within the microbiome field is challenging but is urgently needed to provide direct evidence of causation [18]. In this first dynamic longitudinal investigation of the causative and predictive role of oral microbiome in malignant esophageal lesions, we show that specific oral species are differentially abundant with respect to disease status, and a panel of 11 bacteria can accurately distinguish SDA cases from healthy controls
Summary
Esophageal cancer is the seventh most common cancer worldwide [1]. Fifty-five percent of new cases occur annually in China, and 90% of these are esophageal squamous cell carcinoma (ESCC) [2]. Detection has been shown to improve survival and reduce mortality from the disease [2], with upper gastrointestinal endoscopic screening being widely accepted as an optimal secondary prevention strategy for esophageal lesions of severe dysplasia and above (SDA), including severe squamous dysplasia, carcinoma in situ (CIS), and ESCC, in high-risk populations. This approach has disadvantages such as its potential for complications [3]. Identification of high-risk individuals in the general population through the use of minimallyinvasive biomarkers could help to maximize the benefits of endoscopic screening by targeting those most likely to benefit
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