改变的免疫球蛋白G（IgG）N-糖基化与衰老、炎症和疾病状态有关，但其对食管鳞状细胞癌（ESCC）的影响尚不清楚。据我们所知，这是首个研究探索和验证IgG N-糖基化与ESCC癌变进展之间关联性的研究，并为ESCC的预测识别和有针对性的预防提供创新的生物标记物。共招募了来自发现人群（n = 348）和验证人群（n = 148）的496名ESCC（n = 114）、癌前病变（n = 187）和对照（n = 195）个体参加研究。分析了IgG N-糖基化谱，并使用分步有序Logistic模型在发现人群中组成了一个与ESCC相关的糖基分数。使用自举过程的接收器操作特征曲线（ROC）评估了糖基分数的性能。在发现人群中，GP20（双半乳糖联谊单唾液酸双天线支链与核心和天线岛）的调整OR、IGP33（所有富含岛状糖基化单唾液酸和双唾液酸结构的比率）、IGP44（在总中性IgG糖基化中高甘露糖糖基结构的比例）、IGP58（在总中性IgG糖基化中所有富含岛状糖基化结构的比例）、IGP75（在所有富含岛状双半乳糖联谊结构的总中性IgG糖基化中具有分支葡萄糖N-乙酰氨基组的发生率）和糖基分数分别为4.03（95％CI：3.03-5.36，P＜0.001）、0.69（95％CI：0.55-0.87，P＜0.001）、0.56（95％CI：0.45-0.69，P＜0.001）、0.52（95％CI：0.41-0.65，P＜0.001）、7.17（95％CI：4.77-10.79，P＜0.001）和2.86（95％CI：2.33-3.53，P＜0.001）。与最低部分的个体相比，糖基分数最高部分的个体具有增加的风险（OR：11.41）。平均多级AUC为0.822（95％CI：0.786-0.849）。在验证人群中验证了这些发现，平均AUC为0.807（95％CI：0.758-0.864）。我们的研究表明，IgG N-糖基化和提出的糖基分数似乎是预测ESCC的有希望的标志物，有助于食管癌的早期预防。从生物机制的角度，IgG岛状糖基化和甘露糖基化可能与ESCC的癌变进展有关，并为癌症进展的个体化干预提供潜在的治疗靶点。版权所有©2023 Pan，Wu，Zhang，Zhang，Liu，Li，Feng，Wang，Liu，Zhao，Zhang，Liu，张，刘，陶，罗，王，杨，张，李和Guo。

Altered Immunoglobulin G (IgG) N-glycosylation is associated with aging, inflammation, and diseases status, while its effect on esophageal squamous cell carcinoma (ESCC) remains unknown. As far as we know, this is the first study to explore and validate the association of IgG N-glycosylation and the carcinogenesis progression of ESCC, providing innovative biomarkers for the predictive identification and targeted prevention of ESCC.In total, 496 individuals of ESCC (n=114), precancerosis (n=187) and controls (n=195) from the discovery population (n=348) and validation population (n=148) were recruited in the study. IgG N-glycosylation profile was analyzed and an ESCC-related glycan score was composed by a stepwise ordinal logistic model in the discovery population. The receiver operating characteristic (ROC) curve with the bootstrapping procedure was used to assess the performance of the glycan score.In the discovery population, the adjusted OR of GP20 (digalactosylated monosialylated biantennary with core and antennary fucose), IGP33 (the ratio of all fucosylated monosyalilated and disialylated structures), IGP44 (the proportion of high mannose glycan structures in total neutral IgG glycans), IGP58 (the percentage of all fucosylated structures in total neutral IgG glycans), IGP75 (the incidence of bisecting GlcNAc in all fucosylated digalactosylated structures in total neutral IgG glycans), and the glycan score are 4.03 (95% CI: 3.03-5.36, P<0.001), 0.69 (95% CI: 0.55-0.87, P<0.001), 0.56 (95% CI: 0.45-0.69, P<0.001), 0.52 (95% CI: 0.41-0.65, P<0.001), 7.17 (95% CI: 4.77-10.79, P<0.001), and 2.86 (95% CI: 2.33-3.53, P<0.001), respectively. Individuals in the highest tertile of the glycan score own an increased risk (OR: 11.41), compared with those in the lowest. The average multi-class AUC are 0.822 (95% CI: 0.786-0.849). Findings are verified in the validation population, with an average AUC of 0.807 (95% CI: 0.758-0.864).Our study demonstrated that IgG N-glycans and the proposed glycan score appear to be promising predictive markers for ESCC, contributing to the early prevention of esophageal cancer. From the perspective of biological mechanism, IgG fucosylation and mannosylation might involve in the carcinogenesis progression of ESCC, and provide potential therapeutic targets for personalized interventions of cancer progression.Copyright © 2023 Pan, Wu, Zhang, Zhang, Liu, Li, Feng, Wang, Liu, Zhao, Zhang, Liu, Zhang, Liu, Tao, Luo, Wang, Yang, Zhang, Li and Guo.