Genomic Instability and The Roles of P53 and P19arf in Pancreatic Cancer

描述(由申请人提供)：胰腺导管腺癌(PDAC)在美国每年造成30,000人死亡。年龄是疾病发展的重要危险因素，其次是胰腺炎症、吸烟和罕见的家族性遗传综合征。分子图谱已经揭示了标志性的遗传损伤，包括K-RAS突变，p16lnk4a，p19Arf和p53抑癌基因的丢失，端粒磨损，以及猖獗的基因组不稳定性。在人类肿瘤中的观察表明，组织老化、细胞周转和伴随的端粒功能障碍在PDAC发病机制中起着重要作用。目前，我们还不清楚激活致癌K-RAS损伤、端粒磨损和肿瘤抑制检查点丢失之间的关系。基因工程小鼠(GEM)模型系统支持p19Arf和p53肿瘤抑制因子的多余作用。在小鼠身上的这些数据与人类的数据形成对比，人类的数据表明p19arf和p53的作用不重叠，因为50%的PDAC会导致这两个基因的丢失。此前在端粒酶基因敲除小鼠中的研究揭示了p19arf和p53在端粒缩短反应中的不同功能-即在端粒磨损和DNA损伤反应存在的情况下，p53检查点独立于p19arf功能限制肿瘤进展。结合人类PDAC分子数据、基因工程小鼠PDAC和端粒酶基因敲除，我们推测端粒诱导的基因组不稳定可能调节胰腺癌中p19arf和p53之间的遗传相互作用，在抑制肿瘤进展中发挥不同的作用。为了阐明这两个重要的肿瘤抑制基因的功能，我们将建立以端粒功能障碍为背景的p19Arf或p53缺失的小鼠PDAC模型。我们假设这个更准确的模型将证明p19Arf和p53在PDAC的基因组和生物进化中的不同作用。对这些肿瘤的基因组和靶向分子分析将深入了解端粒功能障碍、DNA损伤反应和衰老对PDAC进展的影响。具有与人类疾病相似的基因组复杂性的小鼠肿瘤的产生将提供机会来研究这种疾病的一个显著特征(即基因组不稳定性)，并使比较基因组图谱成为可能，这将促进新的PDAC癌症基因的发现。

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinomas (PDAC) accounts for >30,000 deaths a year in the United States. Age is a significant risk factor for the development of the disease followed by inflammatory conditions of the pancreas, smoking, and rare familial genetic syndromes. Molecular profiling has revealed signature genetic lesions including K-Ras mutations, loss of p16lnk4a, p19Arf and p53 tumor suppressor genes, telomere attrition, and rampant genomic instability. Observations in human tumors suggest a role for tissue aging, cell turnover, and attendant telomere dysfunction in PDAC pathogenesis. Presently we do not possess a clear understanding of the relationship between activating oncogenic K-RAS lesions, telomere attrition, and loss of tumor suppressor checkpoints. Genetically engineered mouse (GEM) model systems have supported redundant roles of the p19Arf and p53 tumor suppressors. These data in mice contrast human data which have pointed towards non-overlapping roles for p19arf and p53 in that >50% PDACs incur the loss of both genes. Previously studies in the telomerase knock-out mouse have revealed the differential function of p19arf vs. p53 in response to telomere shortening- namely that in the presence of telomere attrition and the DNA damage response the p53 checkpoint constrainins tumor progression independent of p19arf function. Together human PDAC molecular data, genetically engineered mouse PDACs, and the telomerase knockout have prompted us to hypothesize that telomere-induced genomic instability may modulate the genetic interaction between p19arf and p53 in pancreatic cancer, conferring differential roles in constraint of tumor progression. In order to clarify the functions of these two crucial tumor suppressor genes we will generate mouse PDAC models harboring loss of either p19Arf or P53 on a background of telomere dysfunction. We hypothesize that this more accurate model will demonstrate the separate roles of p19Arf vs. p53 in the genomic and biological evolution of PDAC. Genomic and targeted molecular analysis of these tumors will provide insight into the influence of telomere dysfunction, DNA-damage response, and senescence on PDAC progression. The generation of murine tumors with a genomic complexity analogous to the human disease will offer the opportunity to study a hallmark feature of the disease (i.e., genomic instability) and enable comparative genomic profiling which will enhance the discovery of novel PDAC cancer genes.