Gene Amplification and Deletion in Pancreatic Cancer

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分析以及机械治疗策略至关重要。本研究的长期目标是确定胰腺癌的致病基因扩增和缺失，并从功能上表征潜在的癌基因和肿瘤抑制基因。基于阵列的比较基因组杂交（array CGH）在胰腺癌细胞系上定义了先前未被识别的DNA扩增和缺失，包含新的候选癌基因和肿瘤抑制基因。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信号的SMURF1和可能参与WNT信号传导的DKK3。本研究的主要目标是通过研究细胞培养和小鼠肿瘤生长来表征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，从而发现更多的候选胰腺癌基因。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TGFp和WNT通路，并可能为治疗干预提供新的策略。本提案的具体科学目的是：(1)表征基因扩增在胰腺癌发病机制中的作用，重点研究TGFp信号调节因子SMURF1；(2)研究基因缺失在胰腺癌发生发展中的作用，重点关注WNT信号的潜在调节剂DKK3；(3)通过阵列CGH分析原发性胰腺肿瘤，确定胰腺癌中其他新的DNA扩增和缺失。

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.