Biomarkers for the Early Detection of Pancreatic Cancer

描述（最初由申请人提供）：鉴定与上皮内导管瘤形成相关的遗传变化以及与浸润性癌症进展相关的遗传变化，预计将为导致恶性转化和进展过程的遗传机制提供重要线索。 这样的研究将有助于开发新的标记物，用于早期检测上皮内病变和易发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表征选定的特定个体染色体上的推定靶基因座，这些基因座通常与胰腺癌有关，其含有在胰腺癌中缺失的基因（“肿瘤抑制基因功能丧失”）和过度表达的基因（“癌基因功能获得”）。此外，我们还建议在配对的正常和肿瘤样本之间进行全基因组微卫星不稳定性，甲基化测定和表达谱研究，以确定与胰腺癌发生和进展相关的遗传异常。 该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，识别胰腺癌的早期检测遗传生物标志物。待研究的染色体基因座将包括携带染色体lp和3 p的靶肿瘤抑制基因以及在染色体20 q和12 p上携带推定致癌基因的最小扩增区域。 我们假设，途径涉及肿瘤抑制基因的功能丧失突变/缺失和显性激活/扩增/过度表达的癌基因是关键的决定因素，在胰腺肿瘤的早期阶段的发展。 从这些位点，我们将开发位点特异性DNA荧光原位杂交（FISH）和聚合酶链反应（PCR）检测，也蛋白质特异性免疫化学检测分析，早期检测上皮内胰腺肿瘤。

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.