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。突变基因包括显性癌基因和隐性抑癌基因，它们通过体细胞突变来驱动肿瘤的发生。在历史上，胰腺癌一直是一个异常有效的系统，可以在其中识别重要的突变基因，创造了一系列发现，我们的研究小组对此做出了贡献。这一成功在一定程度上是由于纯合缺失的高度信息量的结构模式，以及匹配良好的正常/肿瘤样本对，其中肿瘤细胞作为细胞系和异种移植进行扩张，以丰富它们，使其覆盖原本受到污染的基质细胞。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的基因分析技术，迅速加速了这一研究路线。高通量测序技术将需要得到其他补充初步分析以及基于初步分析结果的后续遗传研究的补充。我们的特定目标将定位新的体细胞突变基因的有希望的位置。纯合缺失的基因将被特定定位，并将图谱与已识别的突变基因整合在一起。我们将辨别体细胞突变的重复模式，该模式具有失活突变(针对肿瘤抑制基因和基因组维持基因)和激活突变(针对癌基因)的模式。这种综合的方法将使我们能够识别和更好地描述在肿瘤发生中突变的关键信号通路。我们的长期目标是为未来胰腺癌的肿瘤发生、干扰的信号通路和治疗靶点的研究提供更完整的基础。 公共卫生相关性：胰腺癌是一种由突变引起的遗传病。我们发现了p16、Smad4、BRCA2和其他基因的频繁突变，这一系列研究现在正进入快速发展期，因为现在可以使用先进的工具来探索这些新的突变。

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.