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

描述（由申请人提供）：在美国，胰腺导管腺癌（PDAC）每年导致> 30，000例死亡。年龄是该疾病发展的重要危险因素，其次是胰腺炎性疾病、吸烟和罕见的家族遗传综合征。分子分析揭示了标志性的遗传病变，包括K-Ras突变，p16 lnk 4a，p19 Arf和p53肿瘤抑制基因的丢失，端粒磨损和猖獗的基因组不稳定性。在人类肿瘤中的观察表明组织衰老、细胞更新和伴随的端粒功能障碍在PDAC发病机制中的作用。目前，我们还没有一个明确的认识之间的关系，激活致癌K-RAS病变，端粒磨损，肿瘤抑制检查点的损失。基因工程小鼠（GEM）模型系统支持p19 Arf和p53肿瘤抑制因子的冗余作用。小鼠中的这些数据与人类数据形成对比，人类数据已经指向p19 arf和p53的非重叠作用，因为>50%的PDAC引起两种基因的丢失。先前在端粒酶敲除小鼠中的研究已经揭示了p19 arf与p53响应于端粒缩短的不同功能-即在存在端粒磨损和DNA损伤反应的情况下，p53检查点独立于p19 arf功能而限制肿瘤进展。人类PDAC分子数据，基因工程小鼠PDAC，和端粒酶敲除一起促使我们假设端粒诱导的基因组不稳定性可能调节胰腺癌中p19 arf和p53之间的遗传相互作用，赋予肿瘤进展的约束不同的角色。为了阐明这两个关键的肿瘤抑制基因的功能，我们将产生小鼠PDAC模型窝藏的端粒功能障碍的背景下的p19 Arf或P53的损失。我们假设这个更精确的模型将证明p19 Arf与p53在PDAC的基因组和生物进化中的单独作用。这些肿瘤的基因组和靶向分子分析将提供对端粒功能障碍、DNA损伤反应和衰老对PDAC进展的影响的深入了解。具有类似于人类疾病的基因组复杂性的鼠肿瘤的产生将提供研究疾病的标志性特征（即，基因组不稳定性），并能够进行比较基因组分析，这将增强新的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.