美国哈佛医学院David M. Meredith等课题组的最新研究发现神经胶质瘤高突变的机制及其治疗意。2020年4月15日出版的《自然》杂志发表了该项成果。
他们全面分析10294胶质瘤的突变负荷和特征的分子决定因素。他们描述了超突变的两个主要途径：与DNA聚合酶和错配修复（MMR）基因的结构缺陷相关的从头途径；以及与化疗敏感性神经胶质瘤中，MMR缺陷驱动的获得性耐药相关的更常见的后处理途径，这种胶质瘤中化疗药物替莫唑胺治疗后复发。
实验上，替莫唑胺对MMR缺乏的细胞造成的损伤可以概括治疗后高突变神经胶质瘤的突变特征。MMR缺陷型神经胶质瘤的特点是：缺乏突出的T细胞浸润，广泛的肿瘤内异质性，患者存活率差以及对PD-1阻断的反应率低。
此外，尽管大量分析未检测到MMR缺陷型神经胶质瘤中的微卫星不稳定性，但对治疗后突变的神经胶质瘤细胞进行单细胞全基因组测序分析，发现了微卫星突变。这些结果表明，化疗可以驱动超突变群体的获得，而不会促进对PD-1阻滞的反应，并支持对癌症中突变负荷和特征的诊断使用。
据了解，在某些神经胶质瘤中观察到很高的肿瘤突变负荷（高突变）；然而，人们对超突变发展的机制及其是否预测免疫疗法的反应知之甚少。
附：英文原文
Title: Mechanisms and therapeutic implications of hypermutation in gliomas
Author: Mehdi Touat, Yvonne Y. Li, Adam N. Boynton, Liam F. Spurr, J. Bryan Iorgulescu, Craig L. Bohrson, Isidro Cortes-Ciriano, Cristina Birzu, Jack E. Geduldig, Kristine Pelton, Mary Jane Lim-Fat, Sangita Pal, Ruben Ferrer-Luna, Shakti H. Ramkissoon, Frank Dubois, Charlotte Bellamy, Naomi Currimjee, Juliana Bonardi, Kenin Qian, Patricia Ho, Seth Malinowski, Leon Taquet, Robert E. Jones, Aniket Shetty, Kin-Hoe Chow, Radwa Sharaf, Dean Pavlick, Lee A. Albacker, Nadia Younan, Capucine Baldini, Mat Verreault, Marine Giry, Erell Guillerm, Samy Ammari, Frdric Beuvon, Karima Mokhtari, Agusti Alentorn, Caroline Dehais, Caroline Houillier, Florence Laigle-Donadey, Dimitri Psimaras, Eudocia Q. Lee, Lakshmi Nayak, J. Ricardo McFaline-Figueroa, Alexandre Carpentier, Philippe Cornu, Laurent Capelle, Bertrand Mathon, Jill S. Barnholtz-Sloan, Arnab Chakravarti, Wenya Linda Bi, E. Antonio Chiocca, Katie Pricola Fehnel, Sanda Alexandrescu, Susan N. Chi, Daphne Haas-Kogan, Tracy T. Batchelor, Garrett M. Frampton, Brian M. Alexander, Raymond Y. Huang, Azra H. Ligon, Florence Coulet, Jean-Yves Delattre, Kh Hoang-Xuan, David M. Meredith
Issue&Volume: 2020-04-15
Abstract: A high tumour mutational burden (hypermutation) is observed in some gliomas1,2,3,4,5; however, the mechanisms by which hypermutation develops and whether it predicts the response to immunotherapy are poorly understood. Here we comprehensively analyse the molecular determinants of mutational burden and signatures in 10,294 gliomas. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and mismatch repair (MMR) genes, and a more common post-treatment pathway, associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas that recur after treatment with the chemotherapy drug temozolomide. Experimentally, the mutational signature of post-treatment hypermutated gliomas was recapitulated by temozolomide-induced damage in cells with MMR deficiency. MMR-deficient gliomas were characterized by a lack of prominent T cell infiltrates, extensive intratumoral heterogeneity, poor patient survival and a low rate of response to PD-1 blockade. Moreover, although bulk analyses did not detect microsatellite instability in MMR-deficient gliomas, single-cell whole-genome sequencing analysis of post-treatment hypermutated glioma cells identified microsatellite mutations. These results show that chemotherapy can drive the acquisition of hypermutated populations without promoting a response to PD-1 blockade and supports the diagnostic use of mutational burden and signatures in cancer.
DOI: 10.1038/s41586-020-2209-9
Source: https://www.nature.com/articles/s41586-020-2209-9
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/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
