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Mechanisms of gene amplification in human cancers

人类癌症基因扩增的机制

基本信息

批准号：
10466882
负责人：
Hisashi Tanaka
金额：
$ 35.61万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10466882
关键词：
17q12 17q21 8q24 Attention BRCA2 gene Breast ChIP-seq Characteristics 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 translational potential tumor tumorigenesis whole genome

项目摘要

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.

项目摘要我们的研究目标是确定结构染色体的机制异常和人类肿瘤中的基因组扩增。基因组（基因）扩增是关键之一肿瘤发展和进展的驱动因素。有几个，复发扩增的癌基因位点，在基因组巨大的努力已经指向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，很少有人注意到潜在的放大机制的翻译潜力。我们的长期目标是将基因组扩增机制的知识，用于控制侵袭性肿瘤。携带癌基因的基因组片段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，确定单个分子过程控制基因组扩增似乎是一个挑战。我们已经证明，DNA复制中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，机器（叉子）必须走很长的距离，并克服一些自然障碍，如DNA 二级结构和与转录机制的碰撞。肿瘤细胞和癌前病变通常无法在这些障碍处保护复制分叉，因此，分叉停止并崩溃（复制压力）。折叠的分叉变成断裂的分叉，带有重组DNA末端，这可能导致染色体断裂。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，但分子机制陷入停滞/崩溃重复基因组扩增的分叉仍然难以捉摸。这些信息对于确定新的目标至关重要，控制基因组扩增。要发生反复的基因组扩增，在一个癌基因附近，反复阻碍复制叉的运动。我们假设基因座特异性，自然的基因组压力阻碍复制叉的运动，并护送崩溃的叉进入复发的基因组。放大我们在两个反复扩增的基因组位点，8 q24与MYC，癌基因（AIM 1）和17 q12 -21与ERBB 2癌基因（AIM 2），并将研究分子机制从停滞/崩溃的分叉到基因组扩增的一步一步。我们的结果将揭示一种特定的相互作用扩增机制和局部基因组背景之间的联系，这可能为我们提供一种新的机制，具有治疗潜力的洞察力。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mutant POLQ and POLZ/REV3L DNA polymerases may contribute to the favorable survival of patients with tumors with POLE mutations outside the exonuclease domain.

突变的 POLQ 和 POLZ/REV3L DNA 聚合酶可能有助于外切核酸酶结构域外具有 POLE 突变的肿瘤患者的良好生存。

DOI：
10.1186/s12881-020-01089-9
发表时间：
2020
期刊：
BMC medical genetics
影响因子：
0
作者：
Huang,Fangjin;Tanaka,Hisashi;Knudsen,BeatriceS;Rutgers,JoanneK
通讯作者：
Rutgers,JoanneK

A common copy-number breakpoint of ERBB2 amplification in breast cancer colocalizes with a complex block of segmental duplications.

DOI：
10.1186/bcr3362
发表时间：
2012-11-26
期刊：
Breast cancer research : BCR
影响因子：
0
作者：
Marotta M;Chen X;Inoshita A;Stephens R;Budd GT;Crowe JP;Lyons J;Kondratova A;Tubbs R;Tanaka H
通讯作者：
Tanaka H

The Applications of Plasma Cell-free DNA in Cancer Detection: Implications in the Management of Breast Cancer Patients.