2025年12月22日出版的《自然—遗传学》杂志发表了加拿大科学家的一项最新研究成果。来自亚瑟和索尼娅·拉巴特脑肿瘤研究中心的Uri Tabori小组研制了错配修复缺陷胶质瘤的高突变形态、肿瘤发生模式和免疫治疗反应。

为了研究驱动突变出现的机制及其对胶质瘤形成和患者预后的影响，研究人员分析了162例priMMRD-HGG的基因组和临床数据。

在这里，课题组确定了由复制DNA聚合酶或IDH1的次要驱动突变定义的三个亚组。这些亚群通过基因组不稳定性产生机制的不同组合聚集在胶质瘤驱动因子上，显示出点突变和拷贝数改变之间的负相关。MMRD特征驱动TP53和IDH1特异性突变的出现，特别是排除了常见的小儿胶质瘤驱动因素。全局低甲基化将priMMRD-HGG分层成一个独特的甲基化表。DNA聚合体priMMRD-HGG表现出超突变、免疫热微环境和免疫治疗反应性，而IDH1mut priMMRD-HGG则表现出免疫冷和免疫治疗耐药。MMRD驱动的胶质瘤发生定义了非随机突变模式在癌症发展中的作用，为靶向和免疫治疗提供了框架。

研究人员表示，原发性错配修复缺陷高级别胶质瘤（priMMRD-HGG）是一种致死性肿瘤，其特点是高突变、对放化疗有耐药性和对免疫治疗的不同反应。

附：英文原文

Title: Patterns of hypermutation shape tumorigenesis and immunotherapy response in mismatch-repair-deficient glioma

Author: Fernandez, Nicholas R., Chang, Yuan, Nunes, Nuno M., Dimayacyac, Jose R., Levine, Adrian, Ringel, Amit, Negm, Logine, Ercan, Ayse Bahar, Hess, Julian M., Ahmad, Olfat, Lee, Caitlin, Stengs, Lucie, Bianchi, Vanessa, Edwards, Melissa, Doherty, Sheradan, Chung, Jiil, Nobre, Liana, Bennett, Julie, Dodgshun, Andrew J., Jones, David T. W., Pfister, Stefan M., Villani, Anita, Malkin, David, Ramaswamy, Vijay, Huang, Annie, Bouffet, Eric, Aronson, Melyssa, Dirks, Peter B., Shlien, Adam, Getz, Gad, Maruvka, Yosef E., Ertl-Wagner, Birgit, Hawkins, Cynthia, Das, Anirban, Tabori, Uri

Issue&Volume: 2025-12-22

Abstract: Primary mismatch-repair-deficient high-grade gliomas (priMMRD-HGG) are lethal tumors characterized by hypermutation, resistance to chemoradiation and variable response to immunotherapy. To investigate the mechanisms governing the emergence of driver mutations and their impact on gliomagenesis and patient outcomes, we analyzed genomic and clinical data from 162 priMMRD-HGG. Here we identified three subgroups defined by secondary driver mutations in replicative DNA polymerases or IDH1. These subgroups converge on glioma drivers through distinct combinations of genomic instability–generating mechanisms, displaying an inverse correlation between point mutations and copy number alterations. MMRD signatures drive the emergence of specific mutations in TP53 and IDH1, notably excluding common pediatric glioma drivers. Global hypomethylation stratifies priMMRD-HGG into a unique methylation cluster. DNA-polymerasemut priMMRD-HGG exhibit ultrahypermutation, an immune-hot microenvironment and immunotherapy responsiveness, whereas IDH1mut priMMRD-HGG are immune-cold and immunotherapy resistant. MMRD-driven gliomagenesis defines the role of nonrandom mutagenesis patterns in cancer development, providing frameworks for targeted and immune-therapeutics.

DOI: 10.1038/s41588-025-02420-x

Source: https://www.nature.com/articles/s41588-025-02420-x