小柯机器人

近日，美国哈佛医学院Peter J. Park等研究人员合作发现，ERα相关的易位是乳腺癌中肿瘤基因扩增的基础。2023年5月17日，《自然》杂志在线发表了这项成果。

研究人员表明，乳腺癌的病灶扩增经常来自于一种机制，被称为易位桥扩增，其涉及染色体间的易位，导致双着丝粒染色体桥的形成和断裂。在780个乳腺癌基因组中，研究人员观察到病灶扩增经常通过其边界的染色体间易位相互连接。随后的分析表明了以下模型：致癌基因邻域在G1中易位，形成一个双着丝粒染色体，然后双着丝粒染色体被复制，随着双着丝粒姐妹染色体在有丝分裂过程中的分离，形成染色体桥，然后断裂，片段常常在染色体外DNA中环化。这个模型解释了关键致癌基因的扩增，包括ERBB2和CCND1。复发性扩增边界和重排热点与乳腺癌细胞中的雌激素受体结合相关。

在实验中，雌激素处理诱导雌激素受体靶区的DNA双链断裂，这些断裂通过易位修复，这表明雌激素在产生最初的易位中起作用。一项泛癌分析揭示了启动病灶扩增机制的组织特异性偏差，断裂-融合-架桥循环在一些组织中普遍存在，而易位-架桥扩增则在其他组织中普遍存在，这可能是由于DNA断裂修复的时间不同。这些结果确定了一种常见的肿瘤基因扩增模式，并提出雌激素是其在乳腺癌中的机制来源。

据介绍，局部拷贝数扩增是一种致癌事件。尽管最近的研究揭示了肿瘤基因扩增的复杂结构和演化轨迹，但对其起源仍知之甚少。

附：英文原文

Title: ERα-associated translocations underlie oncogene amplifications in breast cancer

Author: Lee, Jake June-Koo, Jung, Youngsook Lucy, Cheong, Taek-Chin, Espejo Valle-Inclan, Jose, Chu, Chong, Gulhan, Doga C., Ljungstrm, Viktor, Jin, Hu, Viswanadham, Vinayak V., Watson, Emma V., Corts-Ciriano, Isidro, Elledge, Stephen J., Chiarle, Roberto, Pellman, David, Park, Peter J.

Issue&Volume: 2023-05-17

Abstract: Focal copy-number amplification is an oncogenic event. Although recent studies have revealed the complex structure1,2,3 and the evolutionary trajectories4 of oncogene amplicons, their origin remains poorly understood. Here we show that focal amplifications in breast cancer frequently derive from a mechanism—which we term translocation–bridge amplification—involving inter-chromosomal translocations that lead to dicentric chromosome bridge formation and breakage. In 780 breast cancer genomes, we observe that focal amplifications are frequently connected to each other by inter-chromosomal translocations at their boundaries. Subsequent analysis indicates the following model: the oncogene neighbourhood is translocated in G1 creating a dicentric chromosome, the dicentric chromosome is replicated, and as dicentric sister chromosomes segregate during mitosis, a chromosome bridge is formed and then broken, with fragments often being circularized in extrachromosomal DNAs. This model explains the amplifications of key oncogenes, including ERBB2 and CCND1. Recurrent amplification boundaries and rearrangement hotspots correlate with oestrogen receptor binding in breast cancer cells. Experimentally, oestrogen treatment induces DNA double-strand breaks in the oestrogen receptor target regions that are repaired by translocations, suggesting a role of oestrogen in generating the initial translocations. A pan-cancer analysis reveals tissue-specific biases in mechanisms initiating focal amplifications, with the breakage–fusion–bridge cycle prevalent in some and the translocation–bridge amplification in others, probably owing to the different timing of DNA break repair. Our results identify a common mode of oncogene amplification and propose oestrogen as its mechanistic origin in breast cancer.

DOI: 10.1038/s41586-023-06057-w

Source: https://www.nature.com/articles/s41586-023-06057-w

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
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