Center for the Comprehensive Analysis of Cancer Somatic Copy-Number Alterations, Rearrangements, and Long-Read Sequencing Data

癌症体细胞拷贝数改变、重排和长读长测序数据综合分析中心

• 批准号: 10491146
• 负责人: RAMEEN BEROUKHIM
• 金额: $ 37.63万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10491146
• 关键词: Address; Admixture; Algorithms; Automobile Driving; Cancer Diagnostics; Cells; Chromosome Structures; Chromosome abnormality; Chromosomes; Classification Scheme; Clinical; Clinical Trials; Communities; Competence; Complex; Custom; DNA; DNA Repair; DNA Sequence Rearrangement; DNA analysis; Data; Development; Diagnosis; Event; Evolution; Genome; Genome Data Analysis Center; Genome Data Analysis Network; Genomics; Genotype; Haplotypes; Heterogeneity; Human; Human Resources; Immersion; Inflammatory Infiltrate; International; Leadership; Link; Malignant Neoplasms; Methods; Methylation; Molecular; Mutation; Mutation Analysis; Patients; Pattern; Phase; Physicians; Play; Ploidies; RNA; Recording of previous events; Recurrence; Repetitive Sequence; Research; Resolution; Role; SNP genotyping; Sampling; Scientist; Shapes; Structure; The Cancer Genome Atlas; Therapeutic; Variant; Visualization software; Work; admixture mapping; arm; base; cancer genome; cancer subtypes; cell free DNA; chromothripsis; circulating DNA; exome; experience; genome sequencing; genome wide association study; genomic locus; improved; innovation; insight; molecular subtypes; nanopore; novel therapeutic intervention; reconstruction; repaired; single cell analysis; tool; tumor; whole genome; working group

Abstract We propose to continue our established Genomics Data Analysis Center for the analysis of structural variants in cancer, including somatic copy-number alterations (SCNAs) and rearrangements, addressing the Copy Number competency required by GDAN. We also add capabilities to analyze long- and linked-read data, addressing a second competency. We led SCNA analyses throughout The Cancer Genome Atlas (TCGA) and the first iteration of the Genomics Data Analysis Network (GDAN). We also co-led the Structural Variations Working Group of the International Cancer Genome Consortium Pan-Cancer Analysis of Whole Genomes (PCAWG). For these efforts, we have developed a large suite of tools and deep expertise covering all aspects of analysis of SVs in cancer. Specifically, we will accomplish five Aims: In Aims 1 and 2, we will determine SCNA and rearrangement profiles from either short-read (whole exome or whole genome) or long-/linked-read sequencing data, and determine germline genotypes, parental haplotypes, and ancestry groups. The haplotype information will be used to improve our copy-number resolution. In Aim 3, we reconstruct the tumor genome and its evolutionary history. We evaluate sample heterogeneity including tumor purity, ploidy, and subclonal alterations, and phase rearrangements to homologous chromosomes—determining somatic distances between all pairs of loci. Using these data, we determine mechanisms of DNA damage and repair and infer the events that occurred over tumor evolution. In Aim 4, we integrate data across samples to identify SVs and genomic loci that impact tumor evolution, detect associations with other molecular and clinical features, and evaluate potential SCNA-determined subclasses. Moreover, we perform association and admixture analyses with the germline genotypes detected in Aim 1. In Aim 5, we indicate ways in which we will immerse ourselves within the GDAN and disseminate our analysis results both within the GDAN and to the wider community. Within this, we offer secondary competencies in single-cell and circulating DNA analysis. Our GDAC will provide a comprehensive analysis of the roles of structural variations in cancer development and progression through treatment among GDAN samples. We will also optimize interactions with the wider GDAN and scientific community to make maximal use of these data.

摘要 我们建议继续我们已建立的基因组数据分析中心进行分析 癌症中的结构变异，包括体细胞拷贝数改变(SCNAs)和 重新安排，解决GDAN要求的副本数量能力。我们还添加了 分析长时间和链接读取数据的能力，满足第二项能力。我们领先 整个癌症基因组图谱(TCGA)和第一次迭代的SCNA分析 基因组数据分析网络(GDAN)。我们还共同领导了结构变化的工作 国际癌症基因组联合会泛癌全基因组分析小组 (PCAWG)。为了这些努力，我们开发了一套大型工具和深厚的专业知识 涵盖癌症中SVS分析的方方面面。具体来说，我们将实现五个目标： 目标1和2，我们将从短读(完整)中确定SCNA和重排配置文件 外显子组或全基因组)或长/连锁读取测序数据，并确定胚系 基因类型、亲本单倍型和祖先群体。单倍型信息将用于 提高我们的复印数分辨率。在目标3中，我们重建了肿瘤基因组及其 进化史。我们评估样本的异质性，包括肿瘤纯度、倍体和 亚克隆改变和同源染色体的阶段重排--测定 所有基因座对之间的体细胞距离。利用这些数据，我们确定了DNA的作用机制 损伤和修复，并推断在肿瘤进化过程中发生的事件。在目标4中，我们集成了 跨样本数据识别影响肿瘤进化的SVS和基因组基因座，检测 与其他分子和临床特征的相关性，以及由SCNA确定的评估潜力 子类。此外，我们还对该生殖系进行了关联和混合分析 在目标1中检测到的基因类型。在目标5中，我们指出了我们将沉浸其中的方式 并在GDAN内部和更广泛的范围内传播我们的分析结果 社区。在这方面，我们提供单细胞和循环DNA方面的次要能力 分析。我们的GDAC将全面分析结构变化在 GDAN样本中癌症的发展和通过治疗的进展。我们还将 优化与更广泛的GDAN和科学界的互动，以最大限度地利用这些 数据。