High-throughput analysis of pancreatic cancer mutations

描述（由申请人提供）：对癌症的机械理解在很大程度上依赖于突变基因。突变基因包括显性致癌基因和隐性抑制基因，它们在机体上发生突变以驱动肿瘤发生。从历史上看，胰腺癌是一个非常有效的系统，可以识别重要的突变基因，创造了我们研究小组贡献的一系列发现。这一成功部分是由于纯合缺失的高信息结构模式以及正常/肿瘤样本的良好匹配对，其中肿瘤细胞扩增为细胞系和异种移植物，以使其丰富，否则会污染基质细胞。因此，重要的突变被有效地识别出来，然后在原始组织中得到确认。我们最近发表了高通量遗传分析技术，迅速加快了这方面的研究。高通量测序技术将需要其他补充性的初级分析以及基于初级分析结果的后续遗传研究来补充。我们的具体目标是找到新的体细胞突变基因的有希望的位点。纯合缺失基因将被明确定位，并与鉴定的突变基因整合图谱。我们将辨别出具有灭活突变（针对肿瘤抑制基因和基因组维持基因）和激活突变（针对致癌基因）模式的体细胞突变的复发模式。这种综合的方法将使我们能够识别和更好地表征肿瘤发生中发生突变的关键信号通路。我们的长期目标是为未来胰腺癌肿瘤发生、信号通路中断和治疗靶点的研究提供更完整的基础。

DESCRIPTION (provided by applicant): A mechanistic understanding of cancer rests heavily upon the mutated genes. Mutated genes include the dominant oncogenes and recessive suppressor genes that are mutated somatically to drive tumorigenesis. Pancreatic cancer has historically been an unusually efficient system in which to identify the important mutated genes, creating a portfolio of discoveries to which our research group has contributed. This success is due in part to highly informative structural patterns of homozygous deletions as well as well-matched pairs of normal/tumor samples where the tumor cells are expanded as cell lines and xenografts to enrich them over the otherwise contaminating stromal cells. Important mutations are thus efficiently identified and then confirmed in the original tissues. We recently published high-throughput genetic analysis techniques that quickly accelerate this line of study. High-throughput sequencing techniques will need to be complemented by other complementary primary analyses as well as followup genetic studies based upon the findings from the primary analyses. Our specific aims will locate promising sites of new somatically mutated genes. Homozygously deleted genes will be specifically targeted and the maps integrated with the identified mutated genes. We will discern the recurrent patterns of somatic mutations having patterns of inactivating mutations (for the tumor-suppressor genes and genome-maintenance genes) and of activating mutations (for the oncogenes). This comprehensive approach will enable us to identify and better characterize the key signaling pathways mutated in tumorigenesis. Our long-term goal is to provide a more complete foundation for future studies of tumorigenesis, disrupted signaling pathways, and therapeutic targets in pancreatic cancer. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is a genetic disease caused by mutations. We identified frequent mutations in the p16, SMAD4, BRCA2, and other genes, and this line of research is now reaching a period of rapid development, for the advanced tools to explore these new mutations are now available.