Discovery and Evaluation of Prioritized Mutations in Pancreatic Cancer

胰腺癌优先突变的发现和评估

• 批准号: 7651546
• 负责人: SCOTT E KERN
• 金额: $ 29.12万
• 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: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7651546
• 关键词: Activins; Adult; Affect; Alternative Splicing; Apoptosis; Apoptotic; BRCA2 gene; Binding; Biological Assay; Cancer Family; Cell Cycle; Cells; Characteristics; Chromosomal Instability; Chromosome Mapping; Classification; Cloning; Complement; Complex; Consensus; Databases; Deletion Mutation; Development; Distant; Dominant Genes; Drug or chemical Tissue Distribution; Evaluation; Event; Exhibits; Follow-Up Studies; Foundations; Funding; Funding Agency; Future; Gene Expression; Gene Proteins; Gene Targeting; Genes; Genome; Genomic Instability; Goals; Hereditary Disease; Human; Impairment; In Situ; In Vitro; Incidence; Knock-out; Knowledge; Libraries; MADH4 gene; Maintenance; Malignant Neoplasms; Malignant neoplasm of pancreas; Maps; Mediating; Methods; Missense Mutation; Modeling; Molecular; Mutate; Mutation; Neoplasm Metastasis; Neoplasms; Oncogenes; Organ; PAWR protein; Pancreas; Pattern; Predisposition; Principal Investigator; Publications; Publishing; RNA Splicing; Recessive Genes; Recombinants; Regulatory Pathway; Research; Resources; Rest; Role; Seeds; Signal Pathway; Site; Small Interfering RNA; Somatic Cell; Somatic Mutation; Source; Specific qualifier value; Specificity; Surveys; System; Techniques; Technology; Tertiary Protein Structure; Tissues; Transcript; Transforming Growth Factor beta; Triage; Tumor Suppressor Genes; United States National Institutes of Health; Variant; Xenograft procedure; Zebrafish; cancer cell; cancer genome; cellular engineering; density; disease-causing mutation; experience; genome-wide; high risk; homologous recombination; human tissue; in vivo; loss of function mutation; mutant; neoplastic; neoplastic cell; new technology; novel; pancreatic neoplasm; pancreatic tumorigenesis; polyclonal antibody; protein function; receptor; research study; success; tool; transcription factor; tumor; tumorigenesis; zebrafish development

A mechanistic understanding of cancer rests heavily upon the mutated genes. These include genes causing familial tumor susceptibilities, governing replication fidelity, and residing in regulatory pathways. Pancreatic cancer is an unusually efficient system in which to identify distinctive mutational targets, discoveries to which our research group has contributed heavily. This success is due in part to highly informative structural patterns of homozygous deletions as well as a higher incidence of genome- maintenance mutations (especially those affecting homologous recombination) in this tumor type. Indications are that many recessive genes and perhaps additional dominant genes remain to be discovered in pancreatic cancer. Most of the high-risk pancreatic cancer families remain unexplained by known mutations, and most cancers having CIN (chromosomal instability) are not yet tied mechanistically to a molecular cause. Recessive mutations in novel genes, for example, are currently being discovered more rapidly than can be annotated for their functional significance. We recently explored and published key technical breakthroughs and special tumor cell resources that are newly available and can quickly accelerate this line of study. Powerful high-throughput sequencing techniques are underway to aid such studies, but will need to be complemented by a roadmap derived from a strategic structural analysis of the cancer genome such as we are developing. Our specific aims will locate promising sites of new mutant genes. For genes having some existing functional clues, we can assess the effects of mutation using available assays. For truly novel genes having few clues as to their function, we can achieve missense mutations or gene disruption using technologies we developed for homologous recombination in somatic cells, with phenotypic assessment accomplished both by gene-specific assays and by orthotopic xenografting. For genes having unknown functional assignment and distant evolutionary conservation, a zebrafish model of gene impairment will be used to survey for developmental clues to function and for an ability to augment zebrafish pancreatic tumorigenesis. This latter technique seems surprising, but appears to offer immense efficiency for classifying novel genes. Our long-term goal is to provide a more complete foundation for future studies of familial susceptibility, disrupted signaling pathways, and genome instability in pancreatic cancer. RELEVANCE (Seeinstructions): Pancreatic cancer is a genetic disease caused by mutations. We identified frequent mutations in the p16, SMAD4, BRCA2, and other genes, explaining the causes of many cases of familial forms of pancreatic cancer. We now need to efficiently survey large numbers of mutated genes arising through new technologies. These genes and techniques will be explored in this project

对癌症机理的理解主要依赖于突变的基因。其中包括基因 引起家族性肿瘤易感性，控制复制保真度，并存在于调节途径中。 胰腺癌是一个异常有效的系统，可以识别独特的突变靶点， 我们的研究小组对这些发现做出了很大贡献。这一成功的部分原因是， 纯合缺失的信息结构模式以及基因组- 维持突变（尤其是影响同源重组的突变）。 有迹象表明，许多隐性基因，也许还有额外的显性基因有待发现 在胰腺癌中。大多数高危胰腺癌家族仍然无法解释已知的 突变，并且大多数具有CIN（染色体不稳定性）的癌症还没有在机械上与突变联系在一起。 分子原因例如，新基因的隐性突变目前正在被发现， 比可以解释其功能意义的速度更快。 我们最近探索并发表了关键技术突破和特殊肿瘤细胞资源， 是最近才出现的，可以迅速加速这一研究方向。强大的高通量测序 技术正在进行中，以帮助这些研究，但需要补充的路线图，来自 我们正在开发的癌症基因组的战略结构分析。 我们的具体目标是找到新突变基因的有希望的位点。对于基因， 功能线索，我们可以评估突变的影响，使用现有的分析。对于真正新颖的基因， 关于其功能的线索很少，我们可以使用我们所使用的技术来实现错义突变或基因破坏。 开发用于体细胞中的同源重组，表型评估完成了 通过基因特异性测定和原位异种移植。对于具有未知功能分配的基因 和远距离进化保护，斑马鱼模型的基因损伤将用于调查 发育线索的功能和能力，以增加斑马鱼胰腺肿瘤的发生。后一 这项技术似乎令人惊讶，但似乎提供了巨大的效率分类新基因。 我们的长期目标是为未来的家族易感性研究提供一个更完整的基础， 破坏的信号通路和胰腺癌中的基因组不稳定性。 相关性（参见说明）： 胰腺癌是一种由基因突变引起的遗传性疾病。我们发现了p16基因的频繁突变， SMAD 4、BRCA 2和其他基因，解释了许多家族性胰腺癌病例的原因。 癌我们现在需要有效地调查大量的突变基因， 技术.这些基因和技术将在本项目中进行探索