Biomarkers for the Early Detection of Pancreatic Cancer

描述(最初由申请人提供)：识别与上皮内导管肿瘤的发展相关的基因变化以及与进展为浸润性癌症相关的基因变化有望为导致恶性转化和进展过程的遗传机制提供重要线索。这样的研究应该有助于开发新的标记物，用于早期发现上皮内病变和那些容易进展为浸润性癌症的病变。我们建议采用基于基因组学和分子遗传学的方法来确定特定染色体上可能的靶基因，这些染色体通常与胰腺癌有关，这些染色体含有缺失的基因(“功能肿瘤抑制基因”)和在胰腺癌中过度表达的基因(“功能癌基因的获得”)。此外，我们还建议在配对的正常和肿瘤样本之间进行基因组范围的微卫星不稳定性、甲基化分析和表达谱研究，以确定与胰腺癌的发生和发展相关的遗传异常。本项目的总体目标是通过对胰腺癌患者的肿瘤组织、血清和胰液进行分子遗传学、基因组阵列和表达阵列分析的综合方法，寻找胰腺癌的早期检测遗传生物标志物。要研究的染色体位点包括靶肿瘤抑制基因(S)，该基因含有Lp和3p染色体，以及20q和12p染色体上含有可能癌基因的最小扩增区域。我们假设，肿瘤抑制基因功能丧失、突变/缺失和主要激活/扩增/过度表达的癌基因通路是胰腺肿瘤早期发展的关键决定因素。根据这些基因座，我们将开发基于基因座特异性DNA的荧光原位杂交(FISH)和聚合酶链式反应(PCR)检测方法，以及蛋白质特异性免疫化学检测方法，用于早期检测胰腺上皮内瘤变。

DESCRIPTION (originally provided by applicant): Identification of genetic changes associated with the development of intraepithelial ductal neoplasia and those correlating with progression to invasive cancer are expected to provide important clues on the genetic mechanisms causing malignant transformation and progression processes. Such investigations should help develop novel markers for early detection of intraepithelial lesions and those predisposed to progress to invasive cancer. We are proposing to pursue genomics and molecular genetics based approaches to characterize putative target loci on selected specific individual chromosomes, frequently implicated in pancreatic cancer, which harbor genes deleted ("loss of function tumor suppressor genes") and over expressed in pancreatic cancer ("gain of function oncogenes"). Additionally, we are also proposing to do genome wide microsatellite instability, methylation assays and expression profiling studies between paired normal and tumor samples to identify genetic anomalies associated with initiation and progression of pancreatic cancer. The overall goal of this project is to identify early detection genetic biomarkers for pancreatic cancer with an integrated approach of molecular genetic, genomic array and expression array analyses of tumor tissues, serum and pancreatic juice from pancreatic cancer patients. The chromosomal loci to be studied will include the target tumor suppressor gene(s) harboring chromosomes lp and 3p and minimally amplified regions harboring putative oncogenes on chromosomes 20q and 12p. We hypothesize that 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 early phases of pancreatic neoplasia. From these loci, we will be developing locus specific DNA based fluorescent in situ hybridization (FISH) and polymerase chain reaction (PCR) assays and also protein specific immunochemical detection assays for early detection of intraepithelial pancreatic neoplasia.