Biomarkers for the Early Detection of Pancreatic Cancer

描述（最初由申请人提供）：识别与上皮内导管瘤变发生相关的基因变化以及与浸润性癌症进展相关的基因变化，有望为恶性转化和进展过程的遗传机制提供重要线索。这些研究应该有助于开发新的标志物，用于早期检测上皮内病变和那些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假定目标位点，这些位点通常与胰腺癌有关，其中包含基因缺失（“功能肿瘤抑制基因丧失”）和胰腺癌中过度表达（“功能癌基因获得”）。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、甲基化分析和表达谱研究，以确定与胰腺癌发生和进展相关的遗传异常。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，确定胰腺癌早期检测的遗传生物标志物。待研究的染色体位点将包括包含lp和3p染色体的靶肿瘤抑制基因，以及包含20q和12p染色体上推定致癌基因的最小扩增区域。我们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/过度表达癌基因的途径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）和聚合酶链反应（PCR）检测，以及用于胰腺上皮内瘤变早期检测的蛋白质特异性免疫化学检测。

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.