NEW GENETIC MARKERS FOR PANCREATIC CANCER

大多数人类恶性肿瘤是由于突变的积累， 激活癌基因和抑癌基因。胰腺 癌症，有限数量的基因改变是已知的，但很明显， 还有许多其他的有待发现。在过去，技术问题 破坏了这些基因研究我们最近组织了一个新颖的小组， 100例人胰腺癌，通过在裸细胞中作为异种移植物繁殖而扩增 小鼠这个资源，第一次，允许这样的问题， 有效回答。尖端技术的最新发展 也加速了这种肿瘤的基因解剖。因为 肿瘤的生物学特征与潜在的遗传因素有关。 变化，对这些关系的了解应该能够促进 胰腺癌的治疗方法 我们认识到，这项建议的一些目标并不直接 翻译然而，RFA指出，“因为基础研究， 胰腺癌落后于其他主要实体瘤， 胰腺癌的基础研究有更大的回旋余地。" 此外，我们的初步研究已经确定了关键标志物，包括 胰腺癌p16基因和BRCA 2基因座的改变 癌症，已经在遗传形式的癌症中看到了临床应用， 胰腺癌和乳腺癌。 在初步研究中，详细的等位基因分型已经确定了候选基因。 胰腺癌中疑似新型肿瘤抑制基因的区域。 我们证实了K-ras基因突变的高发生率（>90%），建立了一个高的 p53突变的种族（70%），确定了共同的失活的p16 基因（>80%），从一个新的热点克隆了肿瘤抑制基因DPC 4， 18 q上的纯合缺失，并使用代表性差异 分析，以提供BRCA 2基因的精细定位，通过我们的 在BRCA 2基因座上鉴定一个小的纯合缺失， 家族性乳腺癌背景下出现的胰腺癌。 具体而言，该项目旨在继续开展这项工作，以确定新的 肿瘤抑制基因，识别激活的癌基因，并使用这些基因 了解胰腺癌发生的临床环境的线索 和传播。

Most human malignancies result from the accumulation of mutations which activate oncogenes and inactivate tumor-suppressor genes. For pancreatic cancer, a limited number of genetic alterations are known, but it is clear that many others remain to be discovered. In the past, technical problems impaired these genetic studies. We recently assembled a novel panel of over 100 human pancreatic cancers, expanded by propagation as xenografts in nude mice. This resource, for the first time, allows such questions to be efficiently answered. Recent developments of sophisticated technologies have also accelerated the genetic dissection of this tumor. Because the biologic characteristics of the tumor are tied to the underlying genetic changes, knowledge of these relationships should enable advances in the understanding and management of pancreatic cancer. We realize that some of the aims of this proposal are not directly translational. However, the RFA states, "Because basic research in pancreatic cancer has lagged behind that of the other major solid tumors, greater leeway is given for basic research studies on pancreatic cancer." Furthermore, our preliminary studies have identified key markers, including the alterations of the p16 gene and of the BRCA2 locus in pancreatic cancer, which already have seen clinical application in inherited forms of pancreatic and breast cancer. In preliminary studies, detailed allelotyping has identified candidate regions for suspected novel tumor-suppressor genes in pancreatic cancer. We confirmed the high rate of K-ras mutations (>90%), established a high race of p53 mutations (70%), identified the common inactivation of the p16 gene (>80%), cloned the tumor-suppressor DPC4 from a novel hotspot of homozygous deletion on 18q, and used the representational difference analysis to provide the fine localization of the BRCA 2 gene through our identification of a small homozygous deletion at the BRCA2 locus in a pancreatic cancer arising in a setting of familial breast cancer. Specifically, this project aims to continue this work to identify new tumor-suppressor genes, identify activated oncogenes, and use these genetic clues to understand the clinical settings in which pancreatic cancer arises and spreads.