Cancer Proteome Center at Washington Univ, Univ of North Carolina

描述（由申请人提供）：生物标志物是癌症的独特，可检测的特征，对早期诊断和治疗至关重要。许多癌症的起因是服务于器官生长和代谢的关键途径的体细胞突变。十多年来，蛋白质组学一直在努力寻找具有临床应用价值的生物标志物。有成千上万的已发表的研究和成千上万的候选生物标志物对癌症管理的未知价值。随着全基因组测序的出现，描绘癌症蛋白质组（基因组读数）的挑战和巨大的潜在价值正在展开。因此，一种新的模式正在出现——“基因组剔除”导向的蛋白质组学。在这个应用中，我们提出了一个全面的，基于血液的，蛋白质生物标志物的发现和验证管道，从癌症生物学开始的地方开始：从驱动体细胞突变开始，解决生物标志物的发现。在发现阶段，我们将利用正在进行的全基因组测序工作确定的癌症中复发性基因组突变（即在任何特定癌症中发生率大于5%的突变）的信息，集中收集和分析NCI CPTC提供的样品的高通量、定量蛋白质组学数据，并结合独特的资源，如全面测序的“人鼠”乳腺癌异种移植。蛋白质组学分析将包括多种高分辨率，当前和先进的蛋白质组学方法，可以表征完整的蛋白质，大规模复杂的肽混合物和蛋白质修饰，以阐明细胞途径和网络的蛋白质组学外观。具有严格统计模型的生物信息学工具将被应用于用蛋白质组学数据直接查询基因组（蛋白质基因组学）的挑战。这将提供癌症基因组学所需的正交性，以生物学上验证拷贝数改变、点突变、剪接变异以及功能突变和表观遗传变化丧失的复杂生物学效应，并将这些发现转化为可操作的临床信息。随着蛋白质组学和基因组学知识的融合，临床和生物学将做出选择候选生物标志物的知情决定。每个候选物的特性将通过证明生物标记测定的能力来验证，以可靠地区分来自健康个体和来自癌症患者的血液样本。

DESCRIPTION (provided by applicant): Biomarkers are unique, detectable signatures of cancer that are vital to early diagnosis and treatment. The causes of many cancers are somatic mutations in critical pathways that serve organ growth and metabolism. For over a decade there have been intense proteomic efforts to find biomarkers with clinical utility. There are thousands of published studies and thousands of candidate biomarkers of unknown value for the management of cancer. With the advent of whole genome sequencing, the challenge and immense potential value of characterizing the cancer proteome the readout of the genome-is unfolding. A new paradigm is therefore emerging -"genome-out" directed proteomics. In this application, we propose a comprehensive, blood-based, protein biomarker discovery and verification pipeline that addresses biomarker discovery by starting where the cancer biology begins: with the driving somatic mutations. In the discovery phase, we will use information about recurrent genomic mutations in cancer (i.e. those that occur with a greater than 5% incidence in any given cancer) that are identified by ongoing whole-genome sequencing efforts to focus our collection and analyses of high-throughput, quantitative proteomic data on samples provided by the NCI CPTC in concert with unique resources such as comprehensively sequenced "human in mouse" breast cancer xenografts. Proteomic analyses will include a multiplicity of high-resolution, current and advanced proteomics methods that can characterize intact proteins, massively complex peptide mixtures and protein modifications to elucidate the proteomic facade of cellular pathways and networks. Bioinformatic tools with rigorous statistical models will be applied to meet the challenges of querying the genome directly with proteomic data (proteogenomics). This will provide the orthogonality that cancer genomics requires to biologically validate copy number alterations, point mutations, splice variants, and the complex biological effects from loss of function mutations and epigenetic changes and translate these findings into actionable clinical information. With this melding of proteomic and genomic knowledge, clinically and biologically informed decisions will be made to select candidate biomarkers. The properties of each candidate will be verified by demonstrating an ability of the biomarker assay to reliably distinguish between blood samples taken from healthy individuals from those accrued from patients with cancer.