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，尚未发现具有基于人群的筛查所需的灵敏度和特异性的单个分子。CA-19-9已被广泛研究，但未能证明早期检测和诊断所需的预测价值。尽管已经利用了许多平台，包括蛋白质组学、基因组学和转录组学方法，并且鉴定了生物标志物候选物，但是还没有一个平台或分子在大群体筛选中被成功验证。作为美国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装一组生物标志物候选者，因为没有一种生物标志物显示出早期检测的前景。我们假设，胰腺癌的早期检测生物标志物的面板可以发现的最早的遗传途径异常的胰腺癌的鉴定。我们进一步假设，涉及肿瘤抑制基因功能缺失突变/缺失和显性激活/扩增/过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正在利用功能基因组学方法进行生物标志物的发现，并将染色体3 p12通路作为胰腺癌肿瘤发生的靶点。三个独立的表达平台已被用于开发一组在胰腺肿瘤/正常样品中差异表达的基因，这些基因代表3 p途径中的潜在基因，以及一种新的肿瘤抑制因子/极性调节因子DEAR 1被表征为胰腺癌生物标志物。项目2是利用整合的功能基因组学和途径网络分析方法来检查拷贝数改变的基因和miRNA作为早期检测生物标志物。项目3正在检查1000名胰腺癌患者的1，536个SNP和相关协变量的面板，以开发风险模型，以确定最有可能在早期发展胰腺癌的个体，并可以使用项目1和2中开发的生物标志物面板进行分层筛选。

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.