Frequency and consequences of chromosome missegregation in breast cancer

项目摘要 Research.染色体不稳定性（CIN）-在100多年前被观察到是第一个癌症标志- 以通过不正常的细胞分裂而持续地丢失和获得整个染色体为特征。这个过程 导致非整倍性，即染色体数目不正确的状态，这存在于超过70%的 实体瘤，其中一些显示非整倍体的复发模式。持续的“错误隔离” 染色体异常与更差的患者预后和晚期临床特征相关。这归因于 通过不同非整倍体的广泛分布，具有增加的基因组多样性的肿瘤的适应性增加 克隆在较高的错误分离率下，它似乎会导致细胞死亡和肿瘤抑制。的发生 CIN也被认为使肿瘤对CIN诱导的化疗如紫杉烷敏感。尽管中国的长期 历史，其作为紫杉烷功效的预后标志物和生物标志物的临床用途是不可访问的，因为目前 定量染色体错误分离率的方法在组织中不可行， 信息量大和/或劳动密集型。该提案的一个关键目标是将联合收割机随机计算 用肿瘤的单细胞测序对细胞分裂进行建模， 肿瘤内染色体错误分离率。此外，染色体后的细胞过程 作为核型选择基础的错误分离还没有被探索。我们假设- 错误分离转录过程阻止或允许克隆的繁殖， 特定的非整倍体染色体组合。我们将随机产生许多组合， 转化和非转化细胞系中的染色体拷贝数改变，并分析急性 在单细胞分辨率下的转录改变和克隆组成。总的来说，长期目标是 一项提案旨在解决染色体错误分离与乳腺癌之间的复杂关系 关于其在人类乳腺肿瘤中的发病率和下游转录水平的进展 肿瘤演变的基础。这项工作在方法上是创新的， 提高我们对肿瘤演变的理解以及如何评估患者的CIN。 训练通过完成建议的研究，我将发展我的技能，在设计和实施 高影响力和严谨的科学研究。通过课程作业和与实验室成员的互动， 合作者，我将开发细胞生物学和基因组学/转录组学的多学科专业知识 实验和分析方法。我将磨练专业技能，在科学交流，公众 参与，并通过提供给我的许多机会与我互动，并提出我的网络 研究合作者，现场专家，立法者和社区成员。独特的，多学科的 这里提出的培训将使我在以下领域成为一名独立调查员 癌症基因组学在学术或联邦研究机构。

PROJECT SUMMARY Research. Chromosomal instability (CIN) – observed as the first cancer hallmark over 100 years ago – is characterized by the persistent loss and gain of whole chromosomes through abnormal cell division. This process results in aneuploidy, the state of having an incorrect number of chromosomes, which is present in over 70% of solid tumors, some of which display recurring patterns of aneuploidy. Persistent ‘missegregation’ of chromosomes is associated with worse patient prognosis and advanced clinical features. This is attributed to the increased adaptability of a tumor having increased genomic diversity via a broad landscape of different aneuploid clones. At higher rates of missegregation it appears to cause cell death and tumor inhibition. The occurrence of CIN is also theorized to sensitize tumors to CIN-inducing chemotherapies like taxanes. Despite CIN’s long history, its clinical use as a prognostic marker and biomarker for taxane efficacy is inaccessible as current methods of quantifying rates of chromosome missegregation are either infeasible in tissue, insufficiently informative and/or labor intensive. A critical goal for this proposal to combine stochastic computational modeling of cell division with single cell sequencing of tumors in order to allow for the quantification of intratumoral rates of chromosome missegregation. Additionally, cellular processes after chromosome missegregation that underlie karyotypic selection have not been explored. We hypothesize that post- missegregation transcriptional processes either preclude or permit the propagation of clones with specific aneuploid chromosome combinations. We will stochastically generate many combinations of chromosome copy number alterations in transformed and non-transformed cell lines and analyze the acute transcriptional alterations and clonal composition at single cell resolution. Overall, the long-term goal for this proposal is to resolve the complex relationship between chromosome missegregation and breast cancer progression with respect to its incidence in human breast tumors and downstream transcriptional consequences that underlie tumor evolution. This work is innovative in its approach and will significantly improve our understanding of tumor evolution and how to evaluate CIN in patients. Training. Through completion of the proposed research, I will develop my skills in the design and implementation of high impact and rigorous scientific studies. Through coursework and interactions with lab members and collaborators, I will develop multi-disciplinary expertise in cell biological and genomics/transcriptomics experimental and analytical methods. I will hone professional skills in scientific communication, public engagement, and networking through the many opportunities afforded to me to interact with and present my research to collaborators, field-experts, legislators, and community members. The unique, multi-disciplinary training proposed here will position me well for a career as an independent investigator in the field of cancer genomics at an academic or federal research institution.