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

基因组不稳定性以及 P53 和 P19arf 在胰腺癌中的作用

• 批准号: 7135604
• 负责人: Aram F. Hezel
• 金额: $ 14.06万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-04 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7135604
• 关键词: genetics; human; model; neoplasm /cancer; pancreas neoplasms; role; telomere

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.

描述（由申请人提供）：在美国，胰腺导管腺癌 (PDAC) 每年导致超过 30,000 人死亡。年龄是该疾病发生的一个重要危险因素，其次是胰腺炎症、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、p16lnk4a、p19Arf 和 p53 肿瘤抑制基因的丢失、端粒磨损和普遍的基因组不稳定性。对人类肿瘤的观察表明，组织衰老、细胞更新和随之而来的端粒功能障碍在 PDAC 发病机制中发挥着作用。目前，我们对激活致癌 K-RAS 病变、端粒磨损和肿瘤抑制检查点丢失之间的关系还没有清楚的了解。基因工程小鼠 (GEM) 模型系统支持 p19Arf 和 p53 肿瘤抑制因子的冗余作用。这些小鼠数据与人类数据形成对比，人类数据表明 p19arf 和 p53 的作用不重叠，因为 >50% 的 PDAC 会导致这两种基因的丢失。先前对端粒酶敲除小鼠的研究揭示了 p19arf 与 p53 在响应端粒缩短方面的差异功能，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。人类 PDAC 分子数据、基因工程小鼠 PDAC 和端粒酶敲除共同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 p19arf 和 p53 之间的遗传相互作用，从而在限制肿瘤进展中发挥不同的作用。为了阐明这两个关键肿瘤抑制基因的功能，我们将生成在端粒功能障碍背景下缺失 p19Arf 或 P53 的小鼠 PDAC 模型。我们假设这个更准确的模型将证明 p19Arf 与 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为研究该疾病的标志性特征（即基因组不稳定性）提供机会，并实现比较基因组分析，这将促进新型 PDAC 癌症基因的发现。