1. Mechanisms and therapeutic implications of hypermutation in gliomas
- Author
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Florence Coulet, Jill S. Barnholtz-Sloan, Marc Sanson, Adam Boynton, Aniket Shetty, Yvonne Y. Li, Tracy T. Batchelor, Marine Giry, Garrett M. Frampton, Alexandre Carpentier, Peter J. Park, Franck Bielle, Eudocia Q. Lee, Khê Hoang-Xuan, Jean-Yves Delattre, Leon Taquet, Philippe Cornu, Erell Guillerm, Andrew D. Cherniack, Liam F. Spurr, Robert E. Jones, Mehdi Touat, Rameen Beroukhim, Patrick Y. Wen, J. Bryan Iorgulescu, David Meredith, Kristine Pelton, Caroline Dehais, Radwa Sharaf, Sandro Santagata, Alex Duval, Kenin Qian, Nadia Younan, Florence Laigle-Donadey, Patricia Ho, J Ricardo McFaline-Figueroa, Juliana Bonardi, Mary Jane Lim-Fat, David A. Reardon, Capucine Baldini, Naomi Currimjee, Shakti H. Ramkissoon, Caroline Houillier, Katie Pricola Fehnel, Seth Malinowski, Dimitri Psimaras, Cristina Birzu, Charlotte Bellamy, Isidro Cortes-Ciriano, Keith L. Ligon, Jack Geduldig, Karima Mokhtari, Maite Verreault, Lee A. Albacker, Pratiti Bandopadhayay, Bertrand Mathon, Susan N. Chi, E. Antonio Chiocca, Agusti Alentorn, Dean Pavlick, Frank Dubois, Sangita Pal, Samy Ammari, Brian M. Alexander, Arnab Chakravarti, Azra H. Ligon, Sanda Alexandrescu, Ahmed Idbaih, Frédéric Beuvon, Lakshmi Nayak, Laurent Capelle, Aurélien Marabelle, Daphne A. Haas-Kogan, Raymond Y. Huang, Craig L. Bohrson, Wenya Linda Bi, Ruben Ferrer-Luna, and Kin-Hoe Chow
- Subjects
Male ,0301 basic medicine ,Genome instability ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,Somatic hypermutation ,Biology ,DNA Mismatch Repair ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Gene Frequency ,Cancer immunotherapy ,Glioma ,Temozolomide ,medicine ,Animals ,Humans ,Antineoplastic Agents, Alkylating ,Multidisciplinary ,Brain Neoplasms ,Genome, Human ,Microsatellite instability ,Cancer ,Sequence Analysis, DNA ,Prognosis ,medicine.disease ,Xenograft Model Antitumor Assays ,Phenotype ,030104 developmental biology ,Mutagenesis ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,DNA mismatch repair ,Immunotherapy ,Microsatellite Repeats ,medicine.drug - 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. Temozolomide therapy seems to lead to mismatch repair deficiency and hypermutation in gliomas, but not to an increase in response to immunotherapy.
- Published
- 2020