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Mechanisms and therapeutic implications of hypermutation in gliomas

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Listed:
  • Mehdi Touat

    (Harvard Medical School
    Broad Institute of Harvard and MIT
    Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin)

  • Yvonne Y. Li

    (Broad Institute of Harvard and MIT
    Harvard Medical School)

  • Adam N. Boynton

    (Broad Institute of Harvard and MIT
    Dana-Farber/Boston Children’s Cancer and Blood Disorders Center)

  • Liam F. Spurr

    (Broad Institute of Harvard and MIT
    Harvard Medical School)

  • J. Bryan Iorgulescu

    (Harvard Medical School
    Brigham & Women’s Hospital, Boston)

  • Craig L. Bohrson

    (Harvard Medical School
    Harvard Medical School)

  • Isidro Cortes-Ciriano

    (Wellcome Genome Campus)

  • Cristina Birzu

    (Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin)

  • Jack E. Geduldig

    (Harvard Medical School)

  • Kristine Pelton

    (Harvard Medical School)

  • Mary Jane Lim-Fat

    (Harvard Medical School
    Harvard Medical School)

  • Sangita Pal

    (Broad Institute of Harvard and MIT
    Harvard Medical School)

  • Ruben Ferrer-Luna

    (Broad Institute of Harvard and MIT
    Harvard Medical School
    Foundation Medicine Inc.)

  • Shakti H. Ramkissoon

    (Foundation Medicine Inc.
    Wake Forest School of Medicine)

  • Frank Dubois

    (Broad Institute of Harvard and MIT
    Harvard Medical School)

  • Charlotte Bellamy

    (Harvard Medical School)

  • Naomi Currimjee

    (Harvard Medical School)

  • Juliana Bonardi

    (Harvard Medical School)

  • Kenin Qian

    (Dana-Farber/Boston Children’s Cancer and Blood Disorders Center)

  • Patricia Ho

    (Dana-Farber/Boston Children’s Cancer and Blood Disorders Center)

  • Seth Malinowski

    (Harvard Medical School)

  • Leon Taquet

    (Harvard Medical School)

  • Robert E. Jones

    (Harvard Medical School)

  • Aniket Shetty

    (Dana-Farber Cancer Institute)

  • Kin-Hoe Chow

    (Dana-Farber Cancer Institute)

  • Radwa Sharaf

    (Foundation Medicine Inc.)

  • Dean Pavlick

    (Foundation Medicine Inc.)

  • Lee A. Albacker

    (Foundation Medicine Inc.)

  • Nadia Younan

    (Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin)

  • Capucine Baldini

    (Gustave Roussy)

  • Maïté Verreault

    (Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière)

  • Marine Giry

    (Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière)

  • Erell Guillerm

    (Unité fonctionnelle d’Oncogénétique et Angiogénétique Moléculaire, Département de génétique, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix)

  • Samy Ammari

    (Gustave Roussy
    IR4M (UMR8081), Université Paris-Sud, Centre National de la Recherche Scientifique)

  • Frédéric Beuvon

    (AP-HP, Université Paris Descartes, Hôpital Cochin, Service d’Anatomie et Cytologie Pathologiques)

  • Karima Mokhtari

    (Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neuropathologie Laboratoire Escourolle)

  • Agusti Alentorn

    (Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin)

  • Caroline Dehais

    (Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin)

  • Caroline Houillier

    (Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin)

  • Florence Laigle-Donadey

    (Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin)

  • Dimitri Psimaras

    (Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin)

  • Eudocia Q. Lee

    (Harvard Medical School
    Harvard Medical School)

  • Lakshmi Nayak

    (Harvard Medical School
    Harvard Medical School)

  • J. Ricardo McFaline-Figueroa

    (Harvard Medical School
    Harvard Medical School)

  • Alexandre Carpentier

    (Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurochirurgie)

  • Philippe Cornu

    (Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurochirurgie)

  • Laurent Capelle

    (Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurochirurgie)

  • Bertrand Mathon

    (Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurochirurgie)

  • Jill S. Barnholtz-Sloan

    (Case Western Reserve University School of Medicine)

  • Arnab Chakravarti

    (Arthur G. James Hospital/Ohio State Comprehensive Cancer Center)

  • Wenya Linda Bi

    (Harvard Medical School)

  • E. Antonio Chiocca

    (Harvard Medical School)

  • Katie Pricola Fehnel

    (Harvard Medical School)

  • Sanda Alexandrescu

    (Harvard Medical School)

  • Susan N. Chi

    (Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
    Harvard Medical School)

  • Daphne Haas-Kogan

    (Harvard Medical School)

  • Tracy T. Batchelor

    (Harvard Medical School
    Harvard Medical School)

  • Garrett M. Frampton

    (Foundation Medicine Inc.)

  • Brian M. Alexander

    (Foundation Medicine Inc.
    Harvard Medical School)

  • Raymond Y. Huang

    (Harvard Medical School)

  • Azra H. Ligon

    (Brigham & Women’s Hospital, Boston)

  • Florence Coulet

    (Unité fonctionnelle d’Oncogénétique et Angiogénétique Moléculaire, Département de génétique, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix)

  • Jean-Yves Delattre

    (Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin
    Institut du Cerveau et de la Moelle épinière, ICM)

  • Khê Hoang-Xuan

    (Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin)

  • David M. Meredith

    (Harvard Medical School
    Brigham & Women’s Hospital, Boston)

  • Sandro Santagata

    (Harvard Medical School
    Brigham & Women’s Hospital, Boston
    Harvard Medical School
    Harvard Medical School)

  • Alex Duval

    (Sorbonne Université, Inserm, UMR 938, Centre de Recherche Saint Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer)

  • Marc Sanson

    (Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin
    Institut du Cerveau et de la Moelle épinière, ICM)

  • Andrew D. Cherniack

    (Broad Institute of Harvard and MIT
    Harvard Medical School)

  • Patrick Y. Wen

    (Harvard Medical School
    Harvard Medical School)

  • David A. Reardon

    (Harvard Medical School)

  • Aurélien Marabelle

    (Gustave Roussy)

  • Peter J. Park

    (Harvard Medical School)

  • Ahmed Idbaih

    (Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin)

  • Rameen Beroukhim

    (Broad Institute of Harvard and MIT
    Harvard Medical School
    Harvard Medical School)

  • Pratiti Bandopadhayay

    (Broad Institute of Harvard and MIT
    Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
    Harvard Medical School)

  • Franck Bielle

    (Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neuropathologie Laboratoire Escourolle)

  • Keith L. Ligon

    (Harvard Medical School
    Broad Institute of Harvard and MIT
    Brigham & Women’s Hospital, Boston
    Dana-Farber Cancer Institute)

Abstract

A high tumour mutational burden (hypermutation) is observed in some gliomas1–5; 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.

Suggested Citation

  • 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 , 2020. "Mechanisms and therapeutic implications of hypermutation in gliomas," Nature, Nature, vol. 580(7804), pages 517-523, April.
  • Handle: RePEc:nat:nature:v:580:y:2020:i:7804:d:10.1038_s41586-020-2209-9
    DOI: 10.1038/s41586-020-2209-9
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    Cited by:

    1. Xing Cheng & Jing An & Jitong Lou & Qisheng Gu & Weimin Ding & Gaith Nabil Droby & Yilin Wang & Chenghao Wang & Yanzhe Gao & Jay Ramanlal Anand & Abigail Shelton & Andrew Benson Satterlee & Breanna Ma, 2024. "Trans-lesion synthesis and mismatch repair pathway crosstalk defines chemoresistance and hypermutation mechanisms in glioblastoma," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Xiaojing Wang & Anne-Marie Langevin & Peter J. Houghton & Siyuan Zheng, 2022. "Genomic disparities between cancers in adolescent and young adults and in older adults," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Shannon Coy & Shu Wang & Sylwia A. Stopka & Jia-Ren Lin & Clarence Yapp & Cecily C. Ritch & Lisa Salhi & Gregory J. Baker & Rumana Rashid & Gerard Baquer & Michael Regan & Prasidda Khadka & Kristina A, 2022. "Single cell spatial analysis reveals the topology of immunomodulatory purinergic signaling in glioblastoma," Nature Communications, Nature, vol. 13(1), pages 1-24, December.
    4. Yanming Ren & Zongyao Huang & Lingling Zhou & Peng Xiao & Junwei Song & Ping He & Chuanxing Xie & Ran Zhou & Menghan Li & Xiangqun Dong & Qing Mao & Chao You & Jianguo Xu & Yanhui Liu & Zhigang Lan & , 2023. "Spatial transcriptomics reveals niche-specific enrichment and vulnerabilities of radial glial stem-like cells in malignant gliomas," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    5. Verena Turco & Kira Pfleiderer & Jessica Hunger & Natalie K. Horvat & Kianush Karimian-Jazi & Katharina Schregel & Manuel Fischer & Gianluca Brugnara & Kristine Jähne & Volker Sturm & Yannik Streibel , 2023. "T cell-independent eradication of experimental glioma by intravenous TLR7/8-agonist-loaded nanoparticles," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    6. Jianxing Yin & Xiefeng Wang & Xin Ge & Fangshu Ding & Zhumei Shi & Zehe Ge & Guang Huang & Ningwei Zhao & Dongyin Chen & Junxia Zhang & Sameer Agnihotri & Yuandong Cao & Jing Ji & Fan Lin & Qianghu Wa, 2023. "Hypoxanthine phosphoribosyl transferase 1 metabolizes temozolomide to activate AMPK for driving chemoresistance of glioblastomas," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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