全球范围内，甲状腺癌（TC）的发病率在过去的50年间不断增加。过度诊断导致对乏活性甲状腺病变的不必要治疗率较高。对于早期发现TC的准确方法需求极大。本研究旨在发展一种增强的同位素标记的高通量血浆定量蛋白质组学方法，以在发现队列中鉴定生物标志物。选定的候选者在训练队列和验证队列中通过酶联免疫吸附法（ELISA）进行测试。总共定量了1063种蛋白质，其中129种蛋白质在患者和健康受试者之间表达差异显著。ISG15和PLXNB2的血清水平在乳头状甲状腺癌（PTC）或甲状腺腺瘤患者中显著升高，与健康受试者（p < 0.001）和结节性肿大患者（p < 0.001）相比。将ISG15和PLXNB2的组合标记进行受试者工作特征（ROC）分析，能够显著区分PTC与健康对照（HC）受试者。类似的区别也存在于甲状腺腺瘤和HC受试者之间。值得注意的是，这种组合标记能够区分I期PTC和HC受试者（曲线下面积（AUC）= 0.872）。结果表明，ISG15和PLXNB2是PTC和甲状腺腺瘤的独立诊断性生物标志物，对PTC的早期检测具有良好的潜力。

The incidence of thyroid cancer (TC) has been increasing over the last 50 years worldwide. A higher rate of overdiagnosis in indolent thyroid lesions has resulted in unnecessary treatment. An accurate detection of TC at an early stage is highly demanded. We aim to develop an enhanced isobaric labeling-based high-throughput plasma quantitative proteomics to identify biomarkers in a discovery cohort. Selected candidates were tested by enzyme-linked immunosorbent assay (ELISA) in the training cohort and validation cohort. In total, 1063 proteins were quantified, and 129 proteins were differentially expressed between patients and healthy subjects. Serum levels of ISG15 and PLXNB2 were significantly elevated in patients with papillary thyroid cancer (PTC) or thyroid adenoma, compared to healthy subjects (p < 0.001) and patients with nodular goiter (p < 0.001). Receiver operating characteristic (ROC) analysis of combined markers (ISG15 and PLXNB2) significantly distinguished PTC from healthy control (HC) subjects. Similar differentiations were also found between thyroid adenoma and HC subjects. Notably, this combined marker could distinguish stage-I PTC from HC subjects (area under the curve (AUC) = 0.872). Our results revealed that ISG15 and PLXNB2 are independent diagnostic biomarkers for PTC and thyroid adenoma, showing a promising value for the early detection of PTC.