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: 8464660
• 负责人: SCOTT E KERN
• 金额: $ 32.93万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8464660
• 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 Profile; 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; Publications; Publishing; RNA; 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; tumorigenic; 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.

对癌症机理的理解主要依赖于突变的基因。这些基因包括引起家族性肿瘤易感性的基因、控制复制保真度的基因和存在于调节途径中的基因。 胰腺癌是一个异常有效的系统，可以识别独特的突变靶点，我们的研究小组对此做出了重大贡献。这种成功部分归因于纯合缺失的高度信息化结构模式以及该肿瘤类型中基因组维持突变（特别是影响同源重组的突变）的较高发生率。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通过已知的突变来解释，并且大多数具有CIN（染色体不稳定性）的癌症尚未与分子原因机械地联系起来。例如，新基因中的隐性突变目前被发现的速度比注释其功能意义的速度要快。 我们最近探索并发表了新的关键技术突破和特殊肿瘤细胞资源，可以快速加速这一研究。强大的高通量测序技术正在进行中，以帮助这些研究，但需要通过我们正在开发的癌症基因组战略结构分析的路线图来补充。 我们的具体目标是找到新突变基因的有希望的位点。对于具有一些现有功能线索的基因，我们可以使用可用的测定来评估突变的影响。对于真正的新基因，几乎没有关于其功能的线索，我们可以使用我们开发的体细胞同源重组技术实现错义突变或基因破坏，通过基因特异性测定和原位异种移植完成表型评估。对于具有未知功能分配和远距离进化保守性的基因，将使用基因损伤的斑马鱼模型来调查 发育线索的功能和能力，以增加斑马鱼胰腺肿瘤的发生。后一种技术似乎令人惊讶，但似乎为新基因的分类提供了巨大的效率。 我们的长期目标是为胰腺癌的家族易感性、信号通路中断和基因组不稳定性的未来研究提供更完整的基础。