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研究揭示成人弥漫性胶质瘤的纵向分子轨迹
2019-11-21 12:48

美国杰克逊基因组医学实验室Roel G. W. Verhaak课题组的最新研究,揭示了成人弥漫性胶质瘤的纵向分子轨迹。相关论文11月20日在线发表在《自然》上。

研究人员分析了按时间分离的DNA测序数据,并为222名成人神经胶质瘤患者匹配了相应的临床注释。通过分析弥漫性胶质瘤的三种主要亚型的突变和拷贝数,研究人员发现在疾病初期检测到的驱动基因可以保留到其复发,而很少有证据表明复发特异性基因的改变。烷化剂治疗导致了不同发生率的神经胶质瘤亚型超变体产生,而超变体与总生存期的差异无关。在复发性神经胶质瘤中经常检测到获得性非整倍,其特征在于IDH突变,但没有同时缺失1p/19q染色体臂,并且进一步与细胞周期的获得性改变和不良预后吻合。随着时间的流逝,每个肿瘤的克隆结构仍然相似,但是亚克隆的选择性与存活率降低有关。最后,初始和复发的神经胶质瘤之间的免疫编辑水平没有差异。总的来说,该研究结果表明,最强的选择压力发生在神经胶质瘤的早期发展过程中,在很大程度上,目前疗法对于这种选择性的作用是随机的。

据了解,目前尚不清楚成人弥漫性神经胶质瘤患者中普遍抗药机制的进化过程。

附:英文原文

Title: Longitudinal molecular trajectories of diffuse glioma in adults

Author: Floris P. Barthel, Kevin C. Johnson, Frederick S. Varn, Anzhela D. Moskalik, Georgette Tanner, Emre Kocakavuk, Kevin J. Anderson, Olajide Abiola, Kenneth Aldape, Kristin D. Alfaro, Donat Alpar, Samirkumar B. Amin, David M. Ashley, Pratiti Bandopadhayay, Jill S. Barnholtz-Sloan, Rameen Beroukhim, Christoph Bock, Priscilla K. Brastianos, Daniel J. Brat, Andrew R. Brodbelt, Alexander F. Bruns, Ketan R. Bulsara, Aruna Chakrabarty, Arnab Chakravarti, Jeffrey H. Chuang, Elizabeth B. Claus, Elizabeth J. Cochran, Jennifer Connelly, Joseph F. Costello, Gaetano Finocchiaro, Michael N. Fletcher, Pim J. French, Hui K. Gan, Mark R. Gilbert, Peter V. Gould, Matthew R. Grimmer, Antonio Iavarone, Azzam Ismail, Michael D. Jenkinson, Mustafa Khasraw, Hoon Kim, Mathilde C. M. Kouwenhoven, Peter S. LaViolette, Meihong Li, Peter Lichter, Keith L. Ligon, Allison K. Lowman, Tathiane M. Malta, Tali Mazor, Kerrie L. McDonald, Annette M. Molinaro, Do-Hyun Nam, Naema Nayyar, Ho Keung Ng, Chew Yee Ngan, Simone P. Niclou, Johanna M. Niers, Houtan Noushmehr, Javad Noorbakhsh, D. Ryan Ormond, Chul-Kee Park, Laila M. Poisson, Raul Rabadan, Bernhard Radlwimmer, Ganesh Rao, Guido Reifenberger, Jason K. Sa, Michael Schuster, Brian L. Shaw, Susan C. Short, Peter A. Sillevis Smitt, Andrew E. Sloan, Marion Smits, Hiromichi Suzuki, Ghazaleh Tabatabai, Erwin G. Van Meir, Colin Watts, Michael Weller, Pieter Wesseling, Bart A. Westerman, Georg Widhalm

Issue&Volume: 2019-11-20

Abstract: The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear1,2. Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of diffuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, whereas there was little evidence of recurrence-specific gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at different rates across the glioma subtypes, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner. The GLASS Consortium studies the evolutionary trajectories of 222 patients with a diffuse glioma to aid in our understanding of tumour progression and treatment failure

DOI: 10.1038/s41586-019-1775-1

Source:https://www.nature.com/articles/s41586-019-1775-1

 

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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