High-throughput analysis of pancreatic cancer mutations

胰腺癌突变的高通量分析

• 批准号: 8193244
• 负责人: SCOTT E KERN
• 金额: $ 24.76万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8193244
• 关键词: Activins; Advanced Development; Affect; Algorithms; Allelotyping; BRAF gene; 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; KRAS2 gene; Loss of Heterozygosity; MADH4 gene; MAP Kinase Gene; MDM2 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; 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

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）：对癌症的机制性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制基因，它们在体细胞上发生突变以驱动肿瘤发生。胰腺癌在历史上一直是一个非常有效的系统，可以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。这种成功部分归因于纯合缺失的高度信息化的结构模式以及良好匹配的正常/肿瘤样品对，其中肿瘤细胞作为细胞系和异种移植物扩增以使它们富集在否则污染的基质细胞上。因此，重要的突变被有效地鉴定，然后在原始组织中被确认。我们最近发表了高通量遗传分析技术，可以快速加速这一研究。高通量测序技术需要得到其他补充性初步分析以及基于初步分析结果的后续遗传研究的补充。我们的具体目标将定位新的体细胞突变基因的有希望的网站。同源性缺失的基因将被特异性靶向，并且图谱与鉴定的突变基因整合。我们将辨别体细胞突变的重复模式，其具有失活突变模式（对于肿瘤抑制基因和基因组维持基因）和激活突变模式（对于癌基因）。这种全面的方法将使我们能够识别和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。我们在p16、SMAD 4、BRCA 2和其他基因中发现了频繁的突变，这一研究领域现在正处于快速发展时期，因为现在已经有了探索这些新突变的先进工具。