Thymic epithelial tumors (TETs) belong to a group of tumors that rarely occur, but have unresolved mechanisms and heterogeneous clinical behaviors. Current care of TET patients demands biomarkers of high sensitivity and specificity for accurate histological classification and prognosis management. In this study, 134 fresh-frozen tissue samples (84 tumor, 40 tumor adjacent, and 10 normal thymus) were recruited to generate a quantitative and systematic view of proteomic landscape of TETs. Among them, 90 samples were analyzed by data-independent acquisition mass spectrometry (DIA-MS) leading to discovery of novel classifying molecules among different TET subtypes. The correlation between clinical outcome and the identified molecules was probed, and the prioritized proteins of interest were further validated on the remaining samples (n = 44) via parallel reaction monitoring (PRM) as well as immunohistochemical and confocal imaging analysis. In particular, two proteins, the cellular mRNA deadenylase CCR4 (carbon catabolite repressor 4)-NOT (negative on TATA) complex subunit 2/9 (CNOT2/9) and the serine hydroxymethyltransferase that catalyzes the reversible interconversions of serine and glycine (SHMT1), were found at dramatic low levels in the thymic epithelia of more malignant subtype, thymic squamous cell carcinoma (TSCC). Interestingly, the mRNA levels of these two genes were shown to be closely correlated with prognosis of the TET patients. These results extended the existing human tissue proteome atlas and allowed us to identify several new protein classifiers for TET subtyping. Newly identified subtyping and prognosis markers, CNOT2/9 and SHMT1, will expand current diagnostic arsenal in terms of higher specificity and prognostic insights for TET diagnosis and management.

中文翻译：

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破译基于组织的蛋白质组特征揭示了胸腺上皮肿瘤的新型亚型和预后标志物。

胸腺上皮肿瘤（TET）属于很少发生但机制尚未解决且临床行为异质的一组肿瘤。TET患者的当前护理要求具有高敏感性和特异性的生物标志物，以进行准确的组织学分类和预后管理。在这项研究中，招募了134个新鲜冷冻的组织样本（84个肿瘤，40个邻近肿瘤和10个正常胸腺）以生成TETs蛋白质组学景观的定量和系统视图。其中，通过数据独立采集质谱（DIA-MS）分析了90个样品，从而发现了不同TET亚型之间的新型分类分子。探讨了临床结果与已鉴定分子之间的相关性，并通过平行反应监测（PRM）以及免疫组化和共聚焦成像分析，在其余样品（n = 44）上进一步验证了感兴趣的优先蛋白质。特别是两种蛋白质，细胞mRNA腺苷酸酶CCR4（碳分解代谢物阻遏物4）-NOT（对TATA阴性）复合亚基2/9（CNOT2 / 9）和丝氨酸羟甲基转移酶，催化丝氨酸和甘氨酸的可逆相互转化（SHMT1）在更恶性的亚型胸腺鳞状细胞癌（TSCC）的胸腺上皮细胞中发现低水平。有趣的是，这两个基因的mRNA水平显示与TET患者的预后密切相关。这些结果扩展了现有的人类组织蛋白质组图谱，并使我们能够识别几种新的TET亚型蛋白质分类器。