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<p>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 <i>IDH1</i>. 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 <i>TP53</i> and <i>IDH1</i>, notably excluding common pediatric glioma drivers. Global hypomethylation stratifies priMMRD-HGG into a unique methylation cluster. DNA-polymerase<sup>mut</sup> priMMRD-HGG exhibit ultrahypermutation, an immune-hot microenvironment and immunotherapy responsiveness, whereas IDH1<sup>mut</sup> 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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年12月22日

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

摘要

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.