Gene Amplification and Deletion in Pancreatic Cancer

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胰腺癌的发展至关重要。 用于早期发现以及机械性治疗策略的强大的临床分析。从长远来看 本研究的目的是确定胰腺癌中致病基因的扩增和缺失。 并对潜在的癌基因和肿瘤抑制基因进行功能鉴定。 胰腺癌细胞系的阵列比较基因组杂交(阵列CGH) 先前未知的DNA扩增和缺失，含有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，它们的拷贝发生了变化 数量和表达可能与胰腺癌有关：调节TGFp信号的SMURF1， 和DKK3，可能参与WNT信号转导。这项提案的一个主要目标是描述 SMURF1和DKK3在胰腺癌发生发展中的作用 细胞培养和小鼠体内。第二个主要目标是将阵列CGH研究扩展到原发性胰腺肿瘤， 从而发现更多的胰腺癌候选基因。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，特别是与TGFp和 WNT途径，可能为治疗干预提供新的策略。 这一建议的具体科学目标是：(1)表征基因扩增在 胰腺癌的发病机制，重点是TGFp信号的调节者SMURF1；(2)特征 基因缺失在胰腺癌发生发展中的作用--以潜在调节因子DKK3为中心 以及(3)在胰腺癌中鉴定其他新的DNA扩增和缺失， 对胰腺原发肿瘤进行阵列式CGH分析。

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 SMURF1and 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.