Biomarkers for the Early Detection of Pancreatic Cancer

描述(申请人提供)：急需用于胰腺癌早期检测的生物标记物。然而，具有群体筛查所需的敏感性和特异性的单个分子尚未被发现。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、基因组和转录组方法，并确定了生物标记物候选，但还没有一个平台或分子在大群体筛选中成功地得到验证。作为国家癌症研究所早期检测研究网络的一部分，我们正在采取有针对性的方法来组建一个候选生物标记物小组，因为还没有一个生物标记物显示出早期检测的希望。我们假设，通过识别胰腺癌中最早的异常遗传途径，可以发现一组胰腺癌早期检测的生物标志物。我们进一步假设，涉及功能缺失的肿瘤抑制基因突变/缺失和主要激活/扩增/过度表达的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发现生物标记物，并将3p12染色体途径作为胰腺癌肿瘤发生的靶点。三个不同的表达平台已经被用来开发一组在胰腺癌/正常样本中差异表达的基因，它们代表了3P通路中的潜在基因，以及一种新的肿瘤抑制/极性调节因子DEAR1，它被认为是胰腺癌的生物标志物。项目2正在利用集成的功能基因组学和路径网络分析方法，研究拷贝数改变的基因和miRNAs作为早期检测生物标记物。项目3正在研究1000名胰腺癌患者中的1,536个SNPs和相关协变量，以开发一个风险模型，以确定哪些人最有可能在早期患上胰腺癌，并可以使用项目1和2中开发的生物标记物小组进行分层筛查。

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.