High-throughput analysis of pancreatic cancer mutations

胰腺癌突变的高通量分析

基本信息

批准号：
7842654
负责人：
SCOTT E KERN
金额：
$ 25.52万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7842654
关键词：
Activins Advanced Development Affect Algorithms Allelotyping BRCA2 gene Cell Line Cloning Code Complement Consensus Copy Number Polymorphism DNA Detection Development Dominant Genes Dominant-Negative Mutation Follow-Up Studies Foundations Frequencies Funding Future Gene Deletion Gene Mutation Genes Genetic Genome Germ-Line Mutation Goals Growth Factor Hereditary Disease Homo Human Judgment Loss of Heterozygosity MADH4 gene Maintenance Malignant Neoplasms Malignant neoplasm of pancreas Maps Methods Mining Mutate Mutation Mutation Spectra Oncogenes Pathway interactions Pattern Phosphotransferases Play Proteins Publications Publishing Recessive Genes Recurrence Research Resolution Rest Role Sampling Signal Pathway Site Somatic Mutation Source Stromal Cells Suppressor Genes System TP53 gene Techniques Tissues Transcript Transforming Growth Factor beta Tumor Suppressor Genes United States National Institutes of Health Variant Xenograft procedure base deletion analysis density design disease-causing mutation experience gene function genetic analysis high throughput analysis insertion/deletion mutation interest neoplastic cell novel pancreatic neoplasm public health relevance receptor success therapeutic target tool tumor tumorigenesis tumorigenic

项目摘要

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.

描述（由申请人提供）：对癌症机制的理解很大程度上取决于突变基因。突变基因包括显性癌基因和隐性抑制基因，它们发生体细胞突变以驱动肿瘤发生。胰腺癌历来是一个异常有效的系统，可以识别重要的突变基因，创造了我们的研究小组做出贡献的一系列发现。这一成功部分归因于纯合缺失的信息丰富的结构模式以及良好匹配的正常/肿瘤样本对，其中肿瘤细胞作为细胞系和异种移植物进行扩增，以富集它们而不是污染的基质细胞。因此，重要的突变可以被有效地识别出来，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，可以迅速加速这一研究方向。高通量测序技术需要由其他互补的初步分析以及基于初步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。将专门针对纯合删除的基因，并将图谱与已识别的突变基因整合。我们将辨别具有失活突变（对于肿瘤抑制基因和基因组维持基因）和激活突变（对于癌基因）模式的体细胞突变的重复模式。这种综合方法将使我们能够识别并更好地表征肿瘤发生中突变的关键信号通路。我们的长期目标是为胰腺癌的肿瘤发生、信号通路中断和治疗靶点的未来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性疾病。我们发现了p16、SMAD4、BRCA2等基因的频繁突变，目前这一领域的研究正处于快速发展阶段，探索这些新突变的先进工具现已可用。