ABSTRACT: Background: To assess potential roles for tumor-associated autoantibodies (TAAs) in esophageal squamous cell carcinoma (ESCC) screening: detecting early-stage malignancy, and predicting future cancer risk. Methods: Thirteen candidate autoantibodies identified in previous literatures were measured using multiplex serological assays in sera from cases and matched controls nested in two population-level screening cohorts in China. To evaluate the role of TAAs in detecting prevalent esophageal malignant lesions, an identification set (150 cases vs. 560 controls) and an external validation set (34 cases vs. 121 controls) were established with pre-screening sera collected ≤ 12 months prior to screening-related diagnosis. To explore the role of TAAs in predicting future ESCC risk, an exploration set (105 cases vs. 416 controls) with pre-diagnostic sera collected > 12 months before clinical diagnosis was established. Two models, the questionnaire-based model and full model additionally incorporating TAA markers, were constructed. Area under the receiver operating characteristic curve (AUC) and net reclassification improvement (NRI) were calculated to compare the performance of the two models. Findings: In the identification set, NY-ESO-1 (OR=2·12, 95% CI=1·02-4·40) and STIP1 (OR=1·83, 95% CI=1·10-3·05) were positively associated with higher risk of esophageal malignancy. Elevated MMP-7 was associated with higher risk of malignancy in females (ORfemale=5·07, 95% CI=1·30-19·71). The estimates in validation set were consistent with these results, but were close to null in exploration set. Integration of selected TAAs improved the performance of questionnaire-based models in detecting prevalent esophageal malignancy (female: AUCfull model=0·745, 95% CI=0·675-0·814, AUCquestionnaire-based model=0·658, 95% CI=0·585-0·732, NRI=0·604, P<0·0001; male: AUCfull model=0·662, 95% CI=0·596-0·728, AUCquestionnaire-based model=0·619, 95% CI=0·548-0·690, NRI=0·357, P=0·0028). This improvement was also seen in validation set, but was not similarly effective in distinguishing long-term incident cases from healthy controls. Interpretation: Serological autoantibodies against NY-ESO-1, STIP1, and MMP-7 perform well in detecting early-stage esophageal malignancy, but are less effective in predicting future ESCC risks. Funding: This work was supported by the National Science & Technology Fundamental Resources Investigation Program of China (2019FY101102), the National Natural Science Foundation of China (82073626), the National Key R&D Program of China (2016YFC0901404), the Beijing-Tianjin-Hebei Basic Research Cooperation Project (J200016), the Digestive Medical Coordinated Development Center of Beijing Hospitals Authority (XXZ0204), and the Natural Science Foundation of Beijing Municipality (7182033).
