Genomic Evolution of Breast Cancer

乳腺癌的基因组进化

• 批准号: 9238749
• 负责人: AREND SIDOW
• 金额: $ 65.39万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9238749
• 关键词: Algorithms; Alleles; Aneuploidy; Archives; Biological Assay; Carcinoma; Cell Lineage; Cells; Characteristics; Copy Number Polymorphism; DNA; Diagnostic; Disease; ERBB2 gene; Event; Evolution; Gene Expression; Gene Frequency; Genetic; Genome; Genomics; Lesion; Libraries; Light; Malignant Neoplasms; Maps; Methodology; Mitotic; Molecular Evolution; Molecular Profiling; Mutation; Neoplasms; Normal Cell; Normal tissue morphology; Nucleotides; Oncogenes; PIK3CA gene; Pathologic; Patients; Phenotype; Phylogenetic Analysis; Pilot Projects; Plant Roots; Point Mutation; Prevention strategy; Recording of previous events; Resolution; Role; Sampling; Site; Somatic Mutation; Structure; Testing; Time; Tissue Sample; Tissues; Trees; Validation; Variant; Work; base; comparative; drug development; falls; gene function; genome sequencing; improved; insight; malignant breast neoplasm; molecular phenotype; neoplastic; neuronal cell body; overexpression; public health relevance; reconstruction; targeted sequencing; treatment strategy; tumor; tumor progression; tumorigenesis; whole genome; zygote

DESCRIPTION (provided by applicant): Every cell present in our bodies is related to every other cell by mitotic division, and the history of each of our somas is a bifurcating cell lineage tree whose root is the zygote. We will use this concept to establish lineage relationships among neoplastic lesions and carcinomas from each of 100 HER2-positive breast cancer cases. We will accomplish this by sequencing the genomes of several distinct tissue samples (normal, neoplastic, carcinoma) from each case and by performing expression profiling. The somatic variation we will identify (single nucleotide variants, structural variants, and aneuploidies) willbe used to build lineage trees that serve as roadmaps to determine when during evolution genomic driver events (HER2 overexpression and/or amplification, aneuploidies, and mutations in key cancer genes) and gene expression changes occurred. Several additional neoplastic samples that are too small for whole-genome sequencing will be identified and typed by targeted PCR and sequencing, for 192 of the identified somatic mutations from each case. These additional samples will substantially broaden the phylogenetic tree and facilitate finer resolution as to which types of mutations and other genomic changes happen first during neoplastic evolution. They will also allow us to determine if there are mutations that recur within the same case. Remarkably, in our previous work we have shown, on the basis of such tree analyses, that H1047R in PIK3CA has arisen multiple times within several patients. We will identify additional such mutations, if they exist. Our proposed work is distinct from other studies of tumor evolution, which have so far focused exclusively on within-tumor subclone evolution or metastatic changes, and which cannot order the earliest driver changes. Our study will distinguish drivers of the initial proliferative phenotype from those that cause a full-blown carcinoma. This can only be done by comparative analyses of early neoplasias with normal tissue and with carcinomas. We note that this concept is well-established in species phylogenetics and evolution, where past events are routinely inferred by comparison among extant species, and which have broadly facilitated insight into both gene function and evolutionary mechanisms. Just like evolving species, cells in our somas are governed by inheritance, change, and divergence, and our understanding of the origins and evolution of neoplasias towards tumors will benefit from a phylogenetic and evolutionary perspective. Our proposed study is one of the first that is dedicated to examining cancer in the light of evolution. We believe that a fuller understanding of mutational mechanisms, the order of driver changes during progression, and the role of hypermutable sites, will be essential for improving diagnostics, prediction, and drug development of this fundamentally evolutionary disease.

描述（由申请人提供）：我们体内存在的每个细胞都通过有丝分裂与其他每个细胞相关，并且我们每个体细胞的历史都是一棵分叉的细胞谱系树，其根是受精卵。我们将利用这一概念来建立 100 例 HER2 阳性乳腺癌病例中每例肿瘤病变和癌之间的谱系关系。我们将通过对每个病例​​的几个不同组织样本（正常、肿瘤、癌）的基因组进行测序并进行表达谱来实现这一目标。我们将识别的体细胞变异（单核苷酸变异、结构变异和非整倍体）将用于构建谱系树，作为路线图，以确定进化过程中何时发生基因组驱动事件（HER2 过度表达和/或扩增、非整倍体和关键癌症的突变）基因）和基因表达发生变化。另外几个对于全基因组测序而言太小的肿瘤样本将通过靶向 PCR 和测序进行鉴定和分型，每个病例中已鉴定出 192 种体细胞突变。这些额外的样本将大大拓宽系统发育树，并有助于更精细地确定在肿瘤进化过程中首先发生哪些类型的突变和其他基因组变化。它们还将使我们能够确定同一病例中是否重复出现突变。值得注意的是，在我们之前的工作中，基于此类树分析，我们已经表明 PIK3CA 中的 H1047R 在几名患者中多次出现。如果存在的话，我们将识别更多此类突变。我们提出的工作与其他肿瘤进化研究不同， 迄今为止，它们仅专注于肿瘤内亚克隆进化或转移变化，并且无法订购最早的驱动程序变化。我们的研究将区分最初增殖表型的驱动因素和导致成熟癌症的驱动因素。这只能通过早期肿瘤与正常组织和癌的比较分析来完成。我们注意到，这个概念在物种系统发育和进化中得到了很好的确立，过去的事件通常是通过现有物种之间的比较来推断的，并且广泛促进了对基因功能和进化机制的深入了解。就像进化的物种一样，我们体细胞中的细胞受到遗传、变化和分化的控制，我们对肿瘤向肿瘤的起源和进化的理解将从系统发生和进化的角度受益。我们提出的研究是第一个致力于从进化角度研究癌症的研究之一。我们相信，更全面地了解突变机制、进展过程中驱动变化的顺序以及高突变位点的作用，对于改善这种根本性进化疾病的诊断、预测和药物开发至关重要。