利用新一代靶向定量SWATH和PRM质谱技术筛查早期肝细胞癌蛋白生物标志物

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. Early diagnosis of HCC is vital for patient survival, and the identification of biomarkers for early HCC detection is a crucial clinical need. The search for HCC biomarkers from clinical specimens using shotgun proteomics approaches has been employed by researchers and great progress has been made during the past decade. However, shotgun proteomics is based on data dependent acquisition (DDA) mode and suffers from moderate to poor sample to sample reproducibility as a result of stochastic precursor sampling. The second generation targeted quantitative proteomics is based on data independent acquisition (DIA) mode, and it can capture almost all MS signals in one LC-MS measurement, therefore increases the sample throughput and minimizes technical variations. In this study, we’ll employ SWATH, a high throughput quantitative proteomics strategy, and PRM, a targeted parallel reaction monitoring MS measurement, to integrate them into a seamless robust pipeline, to detect potential protein biomarker candidates for early stage HCC of Chinese population, especially those with positive HBV virus infections.

肝细胞癌（HCC）是全球范围内死亡率最高的三大肿瘤之一。在中国，HCC每年导致的死亡人数超过30万。早期的生物标志物检测对HCC病人的临床诊断、治疗以及预后来说至关重要。近十年来,“鸟枪”蛋白质组学研究被越来越多地应用到临床肿瘤标志物检测的研究中。“鸟枪”蛋白质组方法依赖于传统的数据依赖采集模式（DDA），能够在多维分馏后鉴定高达近万个蛋白质。但是由于实验过程固有的随机特性和色谱分离时的多肽共流出效应，对复杂样品的鉴定与定量结果的可重复性和准确性较弱。新一代蛋白组学方发法基于非数据依赖采集模式（DIA），可以极大程度增加数据采集的通量并降低系统误差。因此，本项目拟采用新一代高通量SWATH/MS靶向定量蛋白组学方法，对HCC患者的肿瘤组织样本进行蛋白组学分析。本研究将建立一套SWATH/MS与PRM/MS平行反应靶向质谱检测方法相联用的工作流程，重点挖掘针对中国人群的HCC肿瘤生物标志物。

肝癌是全世界范围内癌症死亡的首要原因之一。肝细胞癌（HCC）和胆管细胞癌（CCA）已经在肿瘤生物学方面得到了广泛的研究。然而，对HCC和CCA的分子特征仍然缺乏全面和系统的了解。在此，我们利用非数据依赖采集模式质谱方法（DIA/SWATH）对HCC和CCA的蛋白质组图谱进行了描述。通过比较HCC和CCA的定量蛋白质组，我们发现HCC的脂质代谢异常，而CCA的细胞外基质相关途径被激活。接下来，我们开发了一个三蛋白分类器来区分CCA和HCC，在51名患者的独立验证队列中取得了0.92的曲线下面积（AUC）和90%的准确性。本研究中提出的HCC和CCA的不同分子特征为这两种主要的重要原发性肝癌的肿瘤生物学提供了新的见解。我们的发现可能有助于开发更有效的诊断方案和新的靶向药物治疗。

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