The origins of chromosome rearrangement in the cancer genome

癌症基因组中染色体重排的起源

• 批准号: 9223946
• 负责人: JOHN MACIEJOWSKI
• 金额: $ 11.98万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-14 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9223946
• 关键词: Algorithms; Aneuploidy; Bioinformatics; Biological Assay; Biology; Cancer Etiology; Cancer Patient; Cell Cycle Checkpoint; Cell Death; Cell Line; Cell division; Chemicals; Chromosome Segregation; Chromosomes; Chronic Lymphocytic Leukemia; Cicatrix; Clinical; Clinical Research; Clonal Evolution; Complex; Cytidine Deaminase; DNA Repair Pathway; DNA Sequence; DNA Sequence Alteration; Data; Defect; Development; Diagnosis; Diagnostic Neoplasm Staging; Dicentric chromosome; Disease; Disease Progression; Ensure; Environment; Enzymes; Event; Evolution; Failure; Foundations; Frequencies; Functional disorder; Genes; Genetic; Genetic Variation; Genome; Genomic Instability; Genomic approach; Genomics; Goals; Growth; Human; In Vitro; Incidence; Institution; Interdisciplinary Study; Karyotype; Laboratories; Link; Malignant Neoplasms; Mathematics; Mentors; Methods; Mitosis; Mitotic Chromosome; Modeling; Molecular; Mutation; Outcome; Pathology; Patients; Phase; Phenotype; Play; Positioning Attribute; Process; Proteins; Protocols documentation; Reading; Research; Research Personnel; Research Project Summaries; Resources; Role; Sampling; Scientist; Sequence Analysis; Solid; Solid Neoplasm; Staging; Structure; System; TP53 gene; TREX1 gene; Technology; Tetraploidy; Training; Universities; Variant; Work; base; cancer genome; cancer genomics; career; career development; chromothripsis; clinical practice; computerized tools; genetic variant; genome sequencing; human tissue; improved; insight; malignant breast neoplasm; mouse model; novel; nuclease; outcome forecast; overexpression; prognostic value; research study; screening; telomere; tenure track; tissue culture; tool; tumor; tumor progression; tumorigenesis; whole genome

Project Summary Research Advances in DNA sequencing have revealed that cancer genomes harbor chromosome rearrangements of unexpected frequency and staggering complexity. Despite the recognition that these variations can enable cancer development by inducing pro-growth genetic change and facilitating clonal evolution, the instigating factors and mechanisms behind rearrangement are often unknown. This proposal aims to identify the underlying causes of cancer-associated chromosome rearrangements by focusing on errors during mitosis, especially in the context of dicentric chromosome formation. Telomere fusions, which occur during human tumorigenesis when critically short telomeres become dysfunctional, generate dicentric chromosomes. This stage of telomere fusion, genomic instability, and frequent cell death is known as telomere crisis (TC). Dr. John Maciejowski's previous work has shown that the dicentric chromosomes formed during TC are resolved after attack by the cytoplasmic nuclease, TREX1, yielding chromothripsis (chromosome shattering) and kataegis (clustered hypermutation). Here, Dr. Maciejowski will use his established, genetically tractable model of TC to determine if enzymatic attack is directly responsible for observed genomic variants (Aim 1). This approach will utilize whole genome sequencing to assess rearrangement and mutation phenotypes associated with loss of a specific gene. In addition, he will develop novel assays to detect prior TC in cancer genomes (Aim 2) with the overall goal of defining the role of TC in cancer etiology (Aim 3). Finally, he will use his previously developed karyotype-based rearrangement screening and whole genome sequencing pipeline to identify additional causes of genome rearrangement by defining the genomic changes associated with dysfunction of the spindle assembly checkpoint, a cell cycle checkpoint that ensures high fidelity chromosome segregation during mitosis and is often dysregulated in cancer (Aim 4). Collectively, this proposal combines the versatility of mammalian tissue culture genetics and the power of whole genome sequencing with the aim to provide deep insights into a key aspect of tumorigenesis: the genome rearrangements that spur cancer progression and tumor evolution. Candidate Dr. Maciejowski's long-term goal is to understand the impact of errors in chromosome segregation on chromosome rearrangement, aneuploidy, and cancer development. He plans to use whole genome sequencing to assess genomic instability after the introduction of chemical or genetic perturbations in chromosome segregation or DNA repair pathways. His background in Mathematics and extensive training in chromosomal biology, the mechanisms of mitotic chromosome segregation, and human tissue culture systems provide him a solid foundation to achieve this goal. During the K99/Mentored Phase, Dr. Maciejowski will be trained in bioinformatic methods with applications in whole genome sequencing analysis. This will be critical for his future research and help launch his career as an independent investigator. Environment During the K99/Mentored Phase, Dr. Maciejowski will be supported by an outstanding group of scientists: Dr. Titia de Lange is an expert in the consequences of telomere dysfunction and will serve as primary mentor. Dr. Marcin Imielinski is a computational biologist with expertise in developing algorithms to probe cancer genome structure. Collaborators will include Dr. Peter J. Campbell, a leader in cancer genomics, and Dr. Achim Jungbluth, an expert in pathology. Together, this group comprises a strong multidisciplinary research team that will successfully execute the proposed experiments and advance a training plan that will help Dr. Maciejowski transition to an independent academic position. Dr. Maciejowski will be trained in advanced sequencing approaches including: paired end sequencing, inferring copy number from read depth, and identifying rearrangements and mutations. Career development will also be emphasized. Research will primarily be performed at The Rockefeller University, which offers unsurpassed resources, established mechanisms for career development, and a collegial academic environment. Given the strong support of his mentoring team and the excellent environment at RU, Dr. Maciejowski expects to identify and transition to an independent tenure track position at an institution supportive of his R00/Independent Phase research goals. !

项目摘要 研究 DNA测序的进步表明，癌症基因组携带染色体重排 出乎意料的频率和惊人的复杂性。尽管认识到这些变化可以启用 通过诱导促进增长的遗传变化和促进克隆进化，促进癌症的发展 重排背后的因素和机制通常未知。该建议旨在确定 通过关注有丝分裂期间的错误，与癌症相关的染色体重排的根本原因 尤其是在折叠染色体形成的背景下。在人类期间发生的端粒融合 肿瘤发生时，当急性短端粒发生功能失调时，会产生肉体染色体。这 端粒融合，基因组不稳定性和频繁的细胞死亡的阶段称为端粒危机（TC）。约翰博士 Maciejowski以前的工作表明，在TC期间形成的二含染色体在 细胞质核酸酶，Trex1的攻击，产生染色体（染色体破碎）和kataegis （聚集超成名）。在这里，Maciejowski博士将使用他已建立的遗传性TC模型来 确定酶促攻击是否直接负责观察到的基因组变体（AIM 1）。这种方法会 利用整个基因组测序来评估与损失相关的重排和突变表型 特定基因。此外，他还将开发新的测定法，以检测癌症基因组中的先验TC（AIM 2） 定义TC在癌症病因中的作用的总体目标（AIM 3）。最后，他将使用他以前开发的 基于核型的重排筛查和整个基因组测序管道，以识别其他 通过定义与主轴功能障碍相关的基因组变化来导致基因组重排的原因 组装检查点，一个细胞周期检查点，可确保有丝分裂期间高保真染色体隔离 并且通常在癌症中失调（AIM 4）。总的来说，该提案结合了哺乳动物的多功能性 组织培养遗传学和整个基因组测序的力量，目的是深入了解 肿瘤发生的主要方面：刺激癌症进展和肿瘤进化的基因组重排。 候选人 Maciejowski博士的长期目标是了解染色体隔离中错误的影响 染色体重排，非整倍性和癌症发展。他计划使用整个基因组 在引入化学或遗传扰动之后评估基因组不稳定性的测序 染色体分离或DNA修复途径。他在数学和广泛培训方面的背景 染色体生物学，有丝分裂染色体分离的机制和人体组织培养系统 为他提供实现这一目标的坚实基础。在K99/指导阶段，Maciejowski博士将 接受了生物信息学方法的培训，并在整个基因组测序分析中应用。这对 他的未来研究并帮助他成为独立调查员的职业。 环境 在K99/指导阶段，Maciejowski博士将得到一群杰出的科学家的支持： Titia de Lange是端粒功能障碍后果的专家，并将作为主要导师。博士 Marcin Imielinski是一名计算生物学家，在开发算法以探测癌症基因组方面具有专业知识 结构。合作者将包括癌症基因组学领导者Peter J. Campbell博士和Achim博士 Jungbluth，病理学专家。该小组一起组成了一个强大的多学科研究团队 将成功执行拟议的实验并制定培训计划，以帮助Maciejowski博士 过渡到独立的学术职位。 Maciejowski博士将接受高级测序培训 方法在内，包括：配对的终端测序，从读取深度推断拷贝数以及识别 重排和突变。职业发展也将被强调。研究主要是 在洛克菲勒大学（Rockefeller University 职业发展和大学学术环境。鉴于他的指导团队的大力支持 Maciejowski博士希望在Ru的绝佳环境中识别并过渡到独立 统治轨道位置在机构中支持其R00/独立阶段研究目标。 呢