Comprehensive High-throughput Mapping of Cancer Genomes

项目描述（申请人提供）：本项目旨在发展全面、快速、经济的癌症复发性染色体畸变检测方法。该方法将允许以Kbp分辨率水平检测数百个小（< 1000个细胞）标本中的复发性染色体畸变，包括由平衡重排引起的小缺失和异常连接。该开发项目采用下一代技术和方法，对大规模基因组测序和制图至关重要。为了使非基因组学专家的基础科学家和临床医生能够对结果数据进行分析，这些方法将得到Genboree的支持，Genboree是在BCM人类基因组测序中心的基因组测绘项目背景下开发的一个可在线访问的信息系统。复发性重排具有生物学和临床意义：1)它们与癌症进展的致病事件有关，2)它们可作为高信息诊断和预后标记，3)它们可作为治疗靶点。多种转化细胞系和原发肿瘤样本的全面高分辨率基因组图谱将揭示新的生物学和临床意义显著的复发性染色体畸变。复发性染色体畸变在白血病、淋巴瘤和肉瘤中最为常见。然而，最近的证据表明，癌症也包含生物学上重要的高度复发性重排，我们的目标是使用所提出的方法发现。由于肿瘤中重排结构的复杂性和细胞群的异质性，使用当前的细胞遗传学方法只能部分检测到复发性重排。对高度重排的基因组的研究，如在乳腺癌和其他癌症中发现的基因组的研究，将特别受益于比现有技术更高的分辨率。该项目将开发一种新技术，用于识别参与乳腺癌进展的基因畸变，乳腺癌是女性中最常见的癌症，以及其他实体肿瘤的进展。通过应用该技术获得的关于特定基因畸变的知识将有助于开发新的高度靶向癌症治疗方法。

DESCRIPTION (provided by applicant): This project aims to develop comprehensive, rapid, and economical methods for detecting recurrent chromosomal aberrations in cancer. The methods will allow detection of recurrent chromosomal aberrations in hundreds of small (< 1000 cells) specimens at the Kbp level of resolution, including small deletions and aberrant joins induced by balanced rearrangements. This development project employs next-generation technologies and methodologies essential for large-scale genome sequencing and mapping .To enable analyses of resulting data by basic scientists and clinicians who are not experts in genomics, the methods will be supported by Genboree, a turnkey web- accessible informatic system developed in the context of genome mapping projects at the BCM Human Genome Sequencing Center. Recurrent rearrangements have both biological and clinical importance: 1) they have been implicated as causative events in cancer progression, 2) they can be used as highly informative diagnostic and prognostic markers, and 3) they have served as therapeutic targets. Comprehensive high-resolution mapping of genomes in multiple transformed cell lines and primary tumor samples will reveal novel biologically and clinically significant recurrent chromosomal aberrations. Recurrent chromosomal aberrations are best understood in leukemias, lymphomas, and sarcomas. However, recent evidence suggests that carcinomas also contain biologically important highly recurrent rearrangements, which we aim to discover using the proposed methods. Due to the more complex structure of rearrangements and heterogeneity of cell populations in carcinomas, recurrent rearrangements are only partially detectable using current cytogenetic methods. The study of highly rearranged genomes such as those found in breast cancer and other carcinomas will particularly benefit from an increase in resolution beyond currently available technologies. This project will develop a novel technology for identifying gene aberrations that are involved in the progression of breast cancer, the most common cancer among women, and in the progression of other solid tumors. The knowledge about specific gene aberrations gained through the application of the technology will enable development of novel highly targeted cancer therapies.