美国加州大学圣地亚哥分校Lukas Chavez团队近期取得重要工作进展，他们研究发现，环状染色体外DNA促进高危髓母细胞瘤的肿瘤异质性。相关研究成果2023年11月9日在线发表于《自然—遗传学》杂志上。

据介绍，患者肿瘤中的环状染色体外DNA（ecDNA）是致癌基因表达、耐药性演变和不良患者预后的重要驱动因素。

在465名患者的481例髓母细胞瘤肿瘤的回顾性队列中，应用计算方法检测和重建ecDNA，研究人员在82名患者（18%）中发现了环状ecDNA。ecDNA阳性髓母细胞瘤患者在诊断后5年内复发的可能性是原来的两倍多，死亡的可能性是以前的三倍。肿瘤的一个子集包含多个ecDNA谱系，每个谱系都包含不同的扩增致癌基因。髓母细胞瘤模型中的多模式测序、成像和CRISPR抑制实验揭示了每个细胞ecDNA拷贝数的肿瘤内异质性，以及ecDNA上频繁的假定“增强子重新布线”事件。

总之，这项研究揭示了髓母细胞瘤中ecDNA的频率和多样性，分为分子亚群，并表明拷贝数异质性和增强子重新布线是ecDNA的致癌特征。

附：英文原文

Title: Circular extrachromosomal DNA promotes tumor heterogeneity in high-risk medulloblastoma

Author: Chapman, Owen S., Luebeck, Jens, Sridhar, Sunita, Wong, Ivy Tsz-Lo, Dixit, Deobrat, Wang, Shanqing, Prasad, Gino, Rajkumar, Utkrisht, Pagadala, Meghana S., Larson, Jon D., He, Britney Jiayu, Hung, King L., Lange, Joshua T., Dehkordi, Siavash R., Chandran, Sahaana, Adam, Miriam, Morgan, Ling, Wani, Sameena, Tiwari, Ashutosh, Guccione, Caitlin, Lin, Yingxi, Dutta, Aditi, Lo, Yan Yuen, Juarez, Edwin, Robinson, James T., Korshunov, Andrey, Michaels, John-Edward A., Cho, Yoon-Jae, Malicki, Denise M., Coufal, Nicole G., Levy, Michael L., Hobbs, Charlotte, Scheuermann, Richard H., Crawford, John R., Pomeroy, Scott L., Rich, Jeremy N., Zhang, Xinlian, Chang, Howard Y., Dixon, Jesse R., Bagchi, Anindya, Deshpande, Aniruddha J., Carter, Hannah, Fraenkel, Ernest, Mischel, Paul S., Wechsler-Reya, Robert J., Bafna, Vineet, Mesirov, Jill P., Chavez, Lukas

Issue&Volume: 2023-11-09

Abstract: Circular extrachromosomal DNA (ecDNA) in patient tumors is an important driver of oncogenic gene expression, evolution of drug resistance and poor patient outcomes. Applying computational methods for the detection and reconstruction of ecDNA across a retrospective cohort of 481 medulloblastoma tumors from 465 patients, we identify circular ecDNA in 82 patients (18%). Patients with ecDNA-positive medulloblastoma were more than twice as likely to relapse and three times as likely to die within 5 years of diagnosis. A subset of tumors harbored multiple ecDNA lineages, each containing distinct amplified oncogenes. Multimodal sequencing, imaging and CRISPR inhibition experiments in medulloblastoma models reveal intratumoral heterogeneity of ecDNA copy number per cell and frequent putative ‘enhancer rewiring’ events on ecDNA. This study reveals the frequency and diversity of ecDNA in medulloblastoma, stratified into molecular subgroups, and suggests copy number heterogeneity and enhancer rewiring as oncogenic features of ecDNA. Circular extrachromosomal DNA in high-risk medulloblastoma contributes to tumor heterogeneity and associates with relapse and survival. Enhancer rewiring events involving known oncogenes are frequent events, affecting transcription and proliferation.

DOI: 10.1038/s41588-023-01551-3

Source: https://www.nature.com/articles/s41588-023-01551-3