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ERα-related chromothripsis enhances concordant gene transcription on chromosome 17q11.1-q24.1 in luminal breast cancer.
BMC Medical Genomics ( IF 2.1 ) Pub Date : 2020-05-14 , DOI: 10.1186/s12920-020-0729-7
Chun-Lin Lin , Xi Tan , Meizhen Chen , Meena Kusi , Chia-Nung Hung , Chih-Wei Chou , Ya-Ting Hsu , Chiou-Miin Wang , Nameer Kirma , Chun-Liang Chen , Ching-Hung Lin , Kate I. Lathrop , Richard Elledge , Virginia G. Kaklamani , Kohzoh Mitsuya , Tim H.-M. Huang

BACKGROUND Chromothripsis is an event of genomic instability leading to complex chromosomal alterations in cancer. Frequent long-range chromatin interactions between transcription factors (TFs) and targets may promote extensive translocations and copy-number alterations in proximal contact regions through inappropriate DNA stitching. Although studies have proposed models to explain the initiation of chromothripsis, few discussed how TFs influence this process for tumor progression. METHODS This study focused on genomic alterations in amplification associated regions within chromosome 17. Inter-/intra-chromosomal rearrangements were analyzed using whole genome sequencing data of breast tumors in the Cancer Genome Atlas (TCGA) cohort. Common ERα binding sites were defined based on MCF-7, T47D, and MDA-MB-134 breast cancer cell lines using univariate K-means clustering methods. Nanopore sequencing technology was applied to validate frequent rearrangements detected between ATC loci on 17q23 and an ERα hub on 20q13. The efficacy of pharmacological inhibition of a potentially druggable target gene on 17q23 was evaluated using breast cancer cell lines and patient-derived circulating breast tumor cells. RESULTS There are five adjoining regions from 17q11.1 to 17q24.1 being hotspots of chromothripsis. Inter-/intra-chromosomal rearrangements of these regions occurred more frequently in ERα-positive tumors than in ERα-negative tumors. In addition, the locations of the rearrangements were often mapped within or close to dense ERα binding sites localized on these five 17q regions or other chromosomes. This chromothriptic event was linked to concordant upregulation of 96 loci that predominantly regulate cell-cycle machineries in advanced luminal tumors. Genome-editing analysis confirmed that an ERα hub localized on 20q13 coordinately regulates a subset of these loci localized on 17q23 through long-range chromosome interactions. One of these loci, Tousled Like Kinase 2 (TLK2) known to participate in DNA damage checkpoint control, is an actionable target using phenothiazine antipsychotics (PTZs). The antiproliferative effect of PTZs was prominent in high TLK2-expressing cells, compared to low expressing cells. CONCLUSION This study demonstrates a new approach for identifying tumorigenic drivers from genomic regions highly susceptible to ERα-related chromothripsis. We found a group of luminal breast tumors displaying 17q-related chromothripsis for which antipsychotics can be repurposed as treatment adjuncts.

中文翻译:


ERα 相关的染色体碎裂增强管腔乳腺癌中染色体 17q11.1-q24.1 上的一致基因转录。



背景技术染色体碎裂是一种基因组不稳定事件,导致癌症中复杂的染色体改变。转录因子 (TF) 和靶标之间频繁的长程染色质相互作用可能会通过不适当的 DNA 拼接促进近端接触区域的广泛易位和拷贝数改变。尽管研究提出了模型来解释染色质碎裂的起始,但很少有人讨论 TF 如何影响肿瘤进展的这一过程。方法本研究重点关注 17 号染色体内扩增相关区域的基因组改变。使用癌症基因组图谱 (TCGA) 队列中乳腺肿瘤的全基因组测序数据分析染色体间/染色体内重排。使用单变量 K 均值聚类方法根据 MCF-7、T47D 和 MDA-MB-134 乳腺癌细胞系定义常见 ERα 结合位点。应用纳米孔测序技术来验证 17q23 上的 ATC 位点和 20q13 上的 ERα 中心之间检测到的频繁重排。使用乳腺癌细胞系和患者来源的循环乳腺肿瘤细胞评估了 17q23 上潜在可药物靶基因的药理抑制效果。结果从17q11.1到17q24.1有五个​​相邻区域是染色体碎裂的热点。这些区域的染色体间/染色体内重排在 ERα 阳性肿瘤中比在 ERα 阴性肿瘤中更频繁地发生。此外,重排的位置通常位于这五个 17q 区域或其他染色体上的密集 ERα 结合位点内或附近。这种染色体碎裂事件与 96 个基因座的一致上调有关,这些基因座主要调节晚期管腔肿瘤中的细胞周期机制。 基因组编辑分析证实,位于 20q13 上的 ERα 中枢通过远程染色体相互作用协调调节位于 17q23 上的这些基因座的子集。其中一个位点,Tousled Like Kinase 2 (TLK2),已知参与 DNA 损伤检查点控制,是使用吩噻嗪抗精神病药 (PTZ) 的可操作靶点。与低表达细胞相比,PTZ 的抗增殖作用在高 TLK2 表达细胞中更为显着。结论 这项研究展示了一种从对 ERα 相关染色体碎裂高度敏感的基因组区域识别致瘤驱动因素的新方法。我们发现了一组表现出 17q 相关染色体碎裂的管腔乳腺肿瘤,抗精神病药物可以重新用作治疗辅助药物。
更新日期:2020-05-14
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