Multimodal iterative sequencing of cancer genomes and single tumor cells

癌症基因组和单个肿瘤细胞的多模式迭代测序

基本信息

批准号：
10363694
负责人：
Hanlee P Ji
金额：
$ 37.66万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-03 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10363694
关键词：
Address Alleles Alternative Splicing Bar Codes Biological Assay Biological Models Biopsy Biopsy Specimen Blood Cells Cancer Patient Cancer cell line Cells Cellularity Clinical Clinical Research Consumption DNA DNA Resequencing DNA Sequence Alteration Data Data Set Development Diagnostic tests Epigenetic Process Event Gene Expression Gene Fusion Genes Genetic Genomics Goals Gold Libraries Lymphocyte Malignant Neoplasms Measures Methods Minor Modality Molecular Molecular Analysis Nucleic Acids Patients Performance Polymerase Precision therapeutics Primary Neoplasm Primer Extension Protein Isoforms RNA Reaction Research Personnel Residual Tumors Resources Sampling Solid Source Technology Testing Time Tissue Sample Tissues Transcript Validation Variant anticancer research base biomarker identification cancer cell cancer diagnosis cancer genome cancer genomics cell free DNA clinical material epigenetic marker experimental analysis experimental study genetic variant genome sequencing genomic aberrations genomic biomarker improved individual patient interest multimodality neoplastic cell novel novel diagnostics novel therapeutics outcome prediction preservation programs research study single cell analysis targeted treatment therapy outcome therapy resistant transcriptome transcriptome sequencing transcriptomics translational cancer research tumor tumor DNA variant detection

项目摘要

ABSTRACT Genome sequencing technology has been transformative in the analysis of cancer. From genomic, transcriptomic, and epigenetic data, researchers are making new discoveries about the mechanisms of cancer development that are leading to new therapies and diagnostic tests. Accelerating these discoveries, genomic analysis is being applied to a wide variety of analytes such as cell-free DNA and single cells from tissue biopsies. However, given the increasing range of available genomic sequencing assays available for cancer genomic studies, a major challenge comes from the limited amounts of clinical tumor samples. Tissue biopsies and samples oftentimes provide a small amount of genomic analyte. As a result, only one or two genomic sequencing experiments can be performed, which leads to a less than complete picture of features of a patient tumor. To address this issue, we developed and validated a technology called APEX – this sequencing technology enables repeated use of the same nucleic acid analytes derived from a variety of clinical samples relevant for cancer translational research and clinical studies. As a result, researchers have the opportunity to conduct many types of genomic analyses on the same sample and genomic material. APEX technology is based on the covalent attachment of nucleic acid analytes to a solid support, so that the original genomic material is permanently retained, can be subject to a variety of sequencing assays and as a result, can be analyzed through many iterations. The use of multiple iterations also offers an opportunity to improve the delineations of critical genomic aberrations that occur in only a small fraction of the tumor cells. We propose the development of APEX for integrated multi-modal and iterative genomic analyses of primary cancer biopsies and cell free DNA from patients. Aim 1 focuses on cell-free DNA analytes, and Aim 2 focuses on single-cell transcriptome sequencing. Overall, our proposed APEX technology will broadly impact the field of translational cancer research by providing a new platform whereby clinical samples can be used as a renewable resource for subsequent genomic sequencing. It removes constraints afforded by limited amounts of tissue samples from translational clinical studies. With these improvements, APEX will improve the assessment of somatic genomic alterations in cancer cells, integration of multi-modal sequencing technologies, and offer personalized molecular analyses for each cancer patient.

抽象的基因组测序技术在癌症分析中发生了变革。通过转录组和表观遗传学数据，研究人员正在对癌症机制做出新发现基因组学的发展正在加速新疗法和诊断测试的发展。分析适用于多种分析，例如游离 DNA 和组织活检中的单细胞。然而，鉴于可用于癌症基因组的基因组测序测定的范围不断增加研究中，一个主要挑战来自有限的临床肿瘤样本和组织活检。样本通常提供少量基因组分析，因此仅进行一两个基因组测序。可以进行实验，这会导致对患者肿瘤特征的了解不完整。为了解决这个问题，我们开发并验证了一种名为 APEX 的技术——这种测序技术能够重复使用源自各种相关临床样本的相同核酸分析物因此，研究人员有机会进行许多癌症转化研究和临床研究。对同一样本和基因组材料进行不同类型的基因组分析基于 APEX 技术。将核酸分析物共价连接到固相支持物上，从而使原始基因组材料永久保留，可以接受各种测序分析，结果可以通过以下方式进行分析多次迭代的使用还提供了改进关键描述的机会。我们建议开发 APEX。用于原发性癌症的集成多模式和迭代基因组分析活检和无细胞 DNA 目标 1 专注于无细胞 DNA 分析，目标 2 专注于单细胞转录组测序。总体而言，我们提出的 APEX 技术将通过以下方式广泛影响转化癌症研究领域：提供一个新的平台，使临床样本可以用作后续基因组的可再生资源它消除了转化临床中有限的组织样本所带来的限制。通过这些改进，APEX 将改进癌症体细胞基因组改变的评估。细胞、多模式测序技术的整合，并为每种细胞提供个性化的分子分析癌症患者。