小柯机器人

德国霍普儿童癌症中心Matthias A. Karajannis研究组介绍了多层菊形团样胚胎性肿瘤（ETMR）诊断和复发的分子基础。相关论文2019年12月4日在线发表在《自然》上。

研究人员收集了193个原发性ETMR和23个与之匹配的复发样本，以研究这种独特肿瘤类型的基因组图谱。研究人员发现患有肿瘤的患者中，驱动器C19MC未被频繁扩增，而DICER1或其它与microRNA相关的畸变（例如miR-17-92的体细胞扩增，也称为MIR17HG）具有种系突变。全基因组测序显示，肿瘤的单核苷酸变异（SNV）总体复发率较低，但广泛存在的R环结构导致了普遍的基因组不稳定。该研究表明，R环相关的染色体不稳定性可能使由DICER1功能丧失引起的。比较原发瘤和相匹配的复发样本显示出保守性很强的结构变异，但SNV的保守性很低。此外，许多新获得的SNV与顺铂治疗产生的突变特征相关。最后，研究人员证明使用拓扑异构酶和PARP抑制剂靶向R环可能是治疗这种致命疾病的有效策略。

研究人员表示，ETMR是恶性程度高的小儿胚胎脑肿瘤，预后普遍较差。

附：英文原文

Title: The molecular landscape of ETMR at diagnosis and relapse

Author: Sander Lambo, Susanne N. Grbner, Tobias Rausch, Sebastian M. Waszak, Christin Schmidt, Aparna Gorthi, July Carolina Romero, Monika Mauermann, Sebastian Brabetz, Sonja Krausert, Ivo Buchhalter, Jan Koster, Danny A. Zwijnenburg, Martin Sill, Jens-Martin Hbner, Norman Mack, Benjamin Schwalm, Marina Ryzhova, Volker Hovestadt, Simon Papillon-Cavanagh, Jennifer A. Chan, Pablo Landgraf, Ben Ho, Till Milde, Olaf Witt, Jonas Ecker, Felix Sahm, David Sumerauer, David W. Ellison, Brent A. Orr, Anna Darabi, Christine Haberler, Dominique Figarella-Branger, Pieter Wesseling, Jens Schittenhelm, Marc Remke, Michael D. Taylor, Maria J. Gil-da-Costa, Maria astowska, Wiesawa Grajkowska, Martin Hasselblatt, Peter Hauser, Torsten Pietsch, Emmanuelle Uro-Coste, Franck Bourdeaut, Julien Masliah-Planchon, Valrie Rigau, Sanda Alexandrescu, Stephan Wolf, Xiao-Nan Li, Ulrich Schller, Matija Snuderl, Matthias A. Karajannis

Issue&Volume: 2019-12-04

Abstract: Embryonal tumours with multilayered rosettes (ETMRs) are aggressive paediatric embryonal brain tumours with a universally poor prognosis1. Here we collected 193 primary ETMRs and 23 matched relapse samples to investigate the genomic landscape of this distinct tumour type. We found that patients with tumours in which the proposed driver C19MC24 was not amplified frequently had germline mutations in DICER1 or other microRNA-related aberrations such as somatic amplification of miR-17-92 (also known as MIR17HG). Whole-genome sequencing revealed that tumours had an overall low recurrence of single-nucleotide variants (SNVs), but showed prevalent genomic instability caused by widespread occurrence of R-loop structures. We show that R-loop-associated chromosomal instability can be induced by the loss of DICER1 function. Comparison of primary tumours and matched relapse samples showed a strong conservation of structural variants, but low conservation of SNVs. Moreover, many newly acquired SNVs are associated with a mutational signature related to cisplatin treatment. Finally, we show that targeting R-loops with topoisomerase and PARP inhibitors might be an effective treatment strategy for this deadly disease. Analyses of primary and relapse samples of embryonal tumours with multilayered rosettes provide insights into the molecular mechanisms that underlie the development and opportunities for the treatment of this deadly disease.

DOI: 10.1038/s41586-019-1815-x

Source:https://www.nature.com/articles/s41586-019-1815-x

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
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