Gene Amplification and Deletion in Pancreatic Cancer

胰腺癌中的基因扩增和缺失

• 批准号: 7099096
• 负责人: JONATHAN R POLLACK
• 金额: $ 29.37万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-19 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7099096
• 关键词: DNA methylation; RNA interference; athymic mouse; biological signal transduction; cell morphology; cell motility; clinical research; comparative genomic hybridization; fluorescent in situ hybridization; gene deletion mutation; gene expression profiling; human subject; immunocytochemistry; microarray technology; molecular oncology; natural gene amplification; neoplasm /cancer genetics; neoplasm /cancer invasiveness; neoplastic growth; pancreas neoplasms; tissue /cell culture; ubiquitin protein ligase; xenotransplantation

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth-most common cause of cancer-related death in the United States. Understanding the genetic abnormalities underlying pancreatic cancer pathogenesis is critical for developing robust clinical assays for early detection, as well as for mechanistic therapeutic strategies. The long term objectives of this study are to identify pathogenetic gene amplifications and deletions in pancreatic cancer, and to functionally characterize the underlying oncogenes and tumor suppressor genes. Array-based comparative genomic hybridization (array CGH) on pancreatic cancer cell lines defined previously unrecognized DNA amplifications and deletions, harboring novel candidate oncogenes and tumor suppressor genes. These studies identified two candidate cancer genes in particular whose altered copy number and expression may contribute to pancreatic cancer: SMURF1, which modulates TGFp signaling, and DKK3, likely involved in WNT signaling. A major goal of this proposal is to characterize the function of SMURF1 and DKK3 in pancreatic cancer development and progression through studying tumor growth in cell culture and in mice. A second major goal is to extend array CGH studies to primary pancreatic tumors, thereby discovering additional candidate pancreatic cancer genes. These studies will further knowledge of the role of gene amplification and deletion in pancreatic cancer, in particular in regards to the TGFp and WNT pathways, and may provide new strategies for therapeutic intervention. The specific scientific aims of this proposal are: (1) to characterize the role of gene amplification in the pathogenesis of pancreatic cancer, focusing on SMURF1, a modulator of TGFp signaling; (2) to characterize the role of gene deletion in the development of pancreatic cancer, focusing on DKK3, a potential modulator of WNT signaling; and (3) to identify additional novel DNA amplifications and deletions in pancreatic cancer, by array CGH analysis of primary pancreatic tumors.

描述（由申请人提供）：胰腺癌是美国癌症相关死亡的第四大常见原因。了解胰腺癌发病机制的遗传异常对于开发早期检测的可靠临床检测方法以及机械治疗策略至关重要。这项研究的长期目标是确定胰腺癌中的致病基因扩增和缺失，并从功能上表征潜在的癌基因和抑癌基因。对胰腺癌细胞系进行基于阵列的比较基因组杂交（阵列 CGH），定义了以前未识别的 DNA 扩增和缺失，包含新的候选癌基因和抑癌基因。这些研究特别确定了两个候选癌症基因，其拷贝数和表达的改变可能导致胰腺癌：调节 TGFp 信号传导的 SMURF1 和可能参与 WNT 信号传导的 DKK3。该提案的一个主要目标是通过研究细胞培养物和小鼠中的肿瘤生长来表征 SMURF1 和 DKK3 在胰腺癌发生和进展中的功能。第二个主要目标是将阵列 CGH 研究扩展到原发性胰腺肿瘤，从而发现其他候选胰腺癌基因。这些研究将进一步了解基因扩增和缺失在胰腺癌中的作用，特别是在 TGFp 和 WNT 通路方面，并可能为治疗干预提供新策略。该提案的具体科学目标是：（1）表征基因扩增在胰腺癌发病机制中的作用，重点关注TGFp信号调节剂SMURF1； (2) 表征基因缺失在胰腺癌发展中的作用，重点关注 WNT 信号传导的潜在调节剂 DKK3； (3) 通过原发性胰腺肿瘤的阵列 CGH 分析来鉴定胰腺癌中其他新的 DNA 扩增和缺失。