Biomarkers for the Early Detection of Pancreatic Cancer

描述（由申请人提供）：迫切需要用于胰腺癌早期检测的生物标志物。然而，具有敏感性和特异性的个体分子尚未被发现用于基于人群的筛查。CA-19-9已被广泛研究，但未能证明早期发现和诊断所需的预测价值。尽管已经使用了许多平台，包括蛋白质组学、基因组学和转录组学方法，并确定了候选生物标志物，但没有一个平台或分子在大规模人群筛选中成功验证。作为国家癌症研究所早期检测研究网络的一部分，我们正在采取一种有针对性的方法来组建一个生物标志物候选小组，因为没有一种生物标志物显示出早期检测的希望。我们假设一组早期检测胰腺癌的生物标志物可以通过识别胰腺癌中最早的遗传通路异常而被发现。我们进一步假设，涉及肿瘤抑制基因的功能丧失、突变/缺失和显性激活/扩增/过度表达癌基因的遗传途径是胰腺肿瘤早期发展的关键决定因素。项目1利用功能基因组学方法发现生物标志物，并以染色体3p12途径为目标，研究胰腺癌的肿瘤发生。研究人员利用三个独立的表达平台开发了一组在胰腺肿瘤/正常样本中差异表达的基因，这些基因代表了3p途径中的潜在基因，以及一种新的肿瘤抑制/极性调节因子DEAR1，它被表征为胰腺癌的生物标志物。项目2是利用集成的功能基因组学和通路网络分析方法，研究拷贝数改变基因和mirna作为早期检测的生物标志物。项目3正在检查1000名胰腺癌患者的1536个snp和相关共变量，以开发一个风险模型，以确定那些最有可能在早期发展为胰腺癌的个体，并可以使用项目1和项目2中开发的生物标志物小组进行分层筛选。

DESCRIPTION (provided by applicant): Biomarkers for the early detection of pancreatic cancer are urgently needed. However, individual molecules with the sensitivity and specificity needed for population-based screening have not been discovered. CA-19-9 has been studied extensively and yet has failed to demonstrate the predictive value necessary for early detection and diagnosis. Although many platforms, including proteomic, genomic and transcriptomic approaches have been utilized and biomarker candidates identified, no one platform or molecule has been successfully validated in large population screens. As a part of the National Cancer Institute Early Detection Research Network, we are taking a targeted approach to assemble a panel of biomarker candidates, given that no one biomarker has shown promise for early detection. We hypothesize that a panel of early detection biomarkers for pancreatic cancer could be discovered by the identification of the earliest genetic pathways aberrant in pancreatic cancer. We furthermore hypothesize that genetic pathways involving tumor suppressor genes with loss of function mutations/deletions and dominantly activated/amplified/over expressed oncogenes are critical determinants in the development of the early phases of pancreatic neoplasia. Project 1 is utilizing a functional genomics approach toward biomarker discovery and is targeting the chromosome 3p12 pathway to tumorigenesis in pancreatic cancer. Three separate expression platforms have been utilized to develop a panel of genes differentially expressed in pancreatic tumor/normal samples and which represent potential genes in the 3p pathway as well as a novel tumor suppressor/polarity regulator DEAR1 is being characterized as a pancreatic cancer biomarker. Project 2 is examining copy number altered genes and miRNAs as early detection biomarkers utilizing an integrated functional genomics and pathway network analysis approach. Project 3 is examining a panel of 1,536 SNPs and relevant covariates in 1000 pancreatic cancer patients to develop a risk model to identify those individuals most likely to develop pancreatic cancer at an early age and could be stratified for screening using biomarker panels developed in projects one and two.