Mechanisms of gene amplification in human cancers

人类癌症基因扩增的机制

• 批准号: 10241284
• 负责人: Hisashi Tanaka
• 金额: $ 36.34万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241284
• 关键词: 17q12; 17q21; 8q24; Attention; BRCA2 gene; Breast; ChIP-seq; Characteristics; Chromosome Structures; Chromosome abnormality; Chromosomes; Complex; Conflict (Psychology); Cytogenetics; DNA; DNA biosynthesis; DNA replication fork; Data; Defect; Development; Double Minutes; ERBB2 gene; Etiology; Event; Evolution; Freezing; Funding; Genetic Transcription; Genome; Genomic Segment; Genomic approach; Genomics; Goals; Growth; Human; Human Genome; Hybrids; Knowledge; Lead; Lesion; MYC gene; Malignant Neoplasms; Mammary Neoplasms; Medical center; Methods; Modeling; Molecular; Molecular Target; Monitor; Movement; Mus; Oncogenes; Oncoproteins; Outcome; Polymerase; Predisposition; Process; Proteins; RNA; Rad30 protein; Recurrence; Research; Resources; Role; Signal Pathway; Site; Stress; Structural Chromosomal Abnormality; Structural defect; Structure; System; Testing; Therapeutic; Time; Translating; Travel; Untranslated RNA; anticancer research; cancer cell; chromatin immunoprecipitation; fitness; gel electrophoresis; genome sequencing; genomic locus; histone modification; insight; neoplastic cell; novel; novel strategies; overexpression; premalignant; recruit; replication stress; therapeutic target; tumor; tumorigenesis; whole genome

PROJECT SUMMARY The goal of our proposed study is to determine the mechanisms underlying structural chromosome abnormalities and genomic amplification in human tumors. Genomic (gene) amplification is one of the key drivers of tumor development and progression. There are several, recurrently amplified oncogene loci in the genome. Enormous efforts have been directed to antagonizing the outcomes of oncogene amplification, such as overexpressed proteins and downstream signaling pathways. So far, little attention has been paid to the translational potential of the underlying amplification mechanisms. Our long-term goal is to translate the knowledge from genomic amplification mechanisms for controlling aggressive tumors. A genomic segment harboring an oncogene can accumulate either within chromosomes or extrachromosomally in the form of circular minichromosomes. Therefore, identifying a single molecular process for controlling genomic amplification appears challenging. We have shown that a defect in DNA replication is a crucial initiating event for genomic amplification. To faithfully duplicate the large human genome, replication machinery (forks) must travel a long distance and overcome a number of natural obstacles, such as DNA secondary structures and collisions with transcription machinery. Tumor cells and pre-cancerous lesions often fail to protect replication forks at these obstacles, and as a result, forks stall and collapse (replication stress). Collapsed forks become broken forks with recombinogenic DNA ends, which can lead to chromosomal abnormalities and genomic amplification. Although we now recognize the crucial role of replication stress, molecular mechanisms from stalled/collapsed forks to recurrent genomic amplification remain elusive. Such information is essential to identify new targets to control genomic amplification. For recurrent genomic amplification to occur, there must be a natural obstacle near an oncogene that repeatedly impedes replication fork movements. We hypothesize that locus-specific, natural genomic stress impedes replication fork movements and escorts collapsed forks into recurrent genomic amplification. We have identified candidate obstacles in two recurrently-amplified genomic loci, 8q24 with MYC oncogene (AIM1) and 17q12-21 with ERBB2 oncogene (AIM2), and will investigate molecular mechanisms step-by-step from stalled/collapsed forks to genomic amplification. Our results will reveal a specific interaction between amplification mechanisms and local genomic context, which may provide us a novel mechanistic insight with therapeutic potential.

项目概要 我们提出的研究的目标是确定结构染色体的潜在机制 人类肿瘤中的异常和基因组扩增。基因组（基因）扩增是关键之一 肿瘤发生和进展的驱动因素。有几个反复扩增的癌基因位点 基因组。人们付出了巨大的努力来对抗癌基因扩增的结果，例如 作为过度表达的蛋白质和下游信号通路。到目前为止，还很少有人关注 潜在放大机制的转化潜力。我们的长期目标是翻译 来自控制侵袭性肿瘤的基因组扩增机制的知识。 含有癌基因的基因组片段可以在染色体内积累，也可以在染色体内积累。 在染色体外以圆形微型染色体的形式存在。因此，识别单个分子过程 控制基因组扩增似乎具有挑战性。我们已经证明 DNA 复制的缺陷是 基因组扩增的关键起始事件。为了忠实地复制大型人类基因组，复制 机器（叉子）必须行驶很长的距离并克服许多自然障碍，例如 DNA 二级结构以及与转录机制的碰撞。肿瘤细胞和癌前病变经常 无法在这些障碍处保护复制分叉，结果导致分叉停滞和崩溃（复制压力）。 塌陷的叉变成带有重组 DNA 末端的断裂叉，这可能导致染色体 异常和基因组扩增。 尽管我们现在认识到复制应激的关键作用，但停滞/崩溃的分子机制 反复基因组扩增的分叉仍然难以捉摸。这些信息对于确定新目标至关重要 控制基因组扩增。对于反复发生的基因组扩增，必须存在天然障碍 靠近反复阻碍复制叉运动的癌基因。我们假设位点特异性， 自然基因组应激阻碍复制叉运动并护送塌陷的复制叉进入循环基因组 放大。我们已经在两个反复扩增的基因组位点（8q24 和 MYC）中确定了候选障碍 癌基因 (AIM1) 和 17q12-21 与 ERBB2 癌基因 (AIM2)，并将研究分子机制 逐步从停滞/崩溃的叉子到基因组扩增。我们的结果将揭示特定的相互作用 放大机制和局部基因组背景之间的关系，这可能为我们提供一种新的机制 具有治疗潜力的洞察力。