Proteomics Study of Non-viral Related Hepatocellular Carcinoma Risk

项目总结/摘要 在美国，肝细胞癌的发病率是世界上发病率增长最快的肿瘤之一。 无论男女这种发病率的急剧增加与中位生存率不到1 年，因为大多数肝癌病例在晚期被诊断出来，没有资格接受治愈性治疗， 无症状、早期局限性肝细胞癌的预后显著改善， 手术切除或肝移植可显著提高5年生存率。此外， 目前在临床实践中没有有效的早期肝细胞癌检测的监测策略。我们 因此，提出鉴定新的肝细胞癌特异性血浆蛋白生物标志物， 有助于早期肝细胞癌的检测，此时更有可能治愈。虽然 蛋白质组学是一个非常有用的高通量肝癌分析平台 生物标志物的发现，通过基于蛋白质组学的方法鉴定生物标志物是有限的，由于缺乏 系统的蛋白质组筛选及其准确检测低丰度蛋白质的有限能力。SOMAscan， 一种新型的高度多重、高灵敏度的基于适体的免疫样生物标志物发现技术， 已成功应用于其他疾病的生物标志物发现。最近，根据我们的 初步数据，我们提供了坚实的证据，SOMAscan的潜在能力，以确定新的，低 丰富，血液为基础的生物标志物在肝脏疾病具有很高的准确性。因此，我们将应用SOMAscan 通过系统地测量1，305个生物学相关基因的表达水平， 人血浆蛋白，包括在整个动态范围内低丰度的细胞因子。我们将进一步 使用ELISA在独立研究中验证候选蛋白质生物标志物。在完成此 一项拟议的研究，我们希望已经确定了新的血浆蛋白生物标志物，可能有助于早期 检测肝细胞癌，并产生新的见解肝细胞癌的发病机制。 蛋白质组学在队列中的整合和最先进的蛋白质组学平台具有潜力 最终改变肝细胞癌的检测和管理，从而降低死亡率 这种致命的疾病。

Project Summary/Abstract In the United States, hepatocellular carcinoma has one of the most rapidly increasing incidence rates among both men and women. This sharp increase in incidence is coupled with a median survival of less than one year, as most liver cancer cases are diagnosed at late stages and are not eligible for curative therapy, while outcomes dramatically improve for asymptomatic, early stage localized hepatocellular carcinoma, with significant improved 5-year survival rates with surgical resection or liver transplantation. Furthermore, there is currently no effective surveillance strategy for early hepatocellular carcinoma detection in clinical practice. We therefore propose to identify new hepatocellular carcinoma-specific plasma protein biomarkers that can contribute to the detection of early stage hepatocellular carcinoma when cure is more likely. Although proteomics is an extremely useful and high-throughput analytical platform for hepatocellular carcinoma biomarker discovery, identifying biomarkers through proteomics-based approaches is limited due to the lack of a systematic proteome screen and its limited ability to accurately detect low-abundance proteins. SOMAscan, a novel highly multiplexed, high sensitivity aptamer-based immuno-like biomarker discovery technology, has been applied successfully for biomarker discovery in some other diseases. More recently, based on our preliminary data, we provide solid evidence as to the potential ability of SOMAscan to identify novel, low abundance, blood-based biomarkers in liver diseases with great accuracy. We will therefore apply SOMAscan to hepatocellular carcinoma by systematically measuring the expression level of 1,305 biologically relevant human plasma proteins, including low abundant cytokines across the whole dynamic range. We will further validate the candidate protein biomarkers in an independent study using ELISA. Upon completion of this proposed study we expect to have identified novel plasma protein biomarkers that could contribute to early detection of hepatocellular carcinoma and generate new insights into hepatocellular carcinoma pathogenesis. The integration of proteomics within the cohorts and the state-of-the-art proteomics platform has the potential to ultimately transform hepatocellular carcinoma detection and management, therefore reducing the mortality of this deadly disease.