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Mechanisms and therapeutic implications of hypermutation in gliomas

A high tumour mutational burden (hypermutation) is observed in some gliomas (1–5); 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...

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Autores principales: Touat, Mehdi, Li, Yvonne Y., Boynton, Adam N., Spurr, Liam F., Iorgulescu, J. Bryan, Bohrson, Craig L., Cortes-Ciriano, Isidro, Birzu, Cristina, Geduldig, Jack E., Pelton, Kristine, Lim-Fat, Mary Jane, Pal, Sangita, Ferrer-Luna, Ruben, Ramkissoon, Shakti H., Dubois, Frank, Bellamy, Charlotte, Currimjee, Naomi, Bonardi, Juliana, Qian, Kenin, Ho, Patricia, Malinowski, Seth, Taquet, Leon, Jones, Robert, Shetty, Aniket, Chow, Kin-Hoe, Sharaf, Radwa, Pavlick, Dean, Albacker, Lee A., Younan, Nadia, Baldini, Capucine, Verreault, Maïté, Giry, Marine, Guillerm, Erell, Ammari, Samy, Beuvon, Frédéric, Mokhtari, Karima, Alentorn, Agusti, Dehais, Caroline, Houillier, Caroline, Laigle-Donadey, Florence, Psimaras, Dimitri, Lee, Eudocia Q., Nayak, Lakshmi, McFaline-Figueroa, J. Ricardo, Carpentier, Alexandre, Cornu, Philippe, Capelle, Laurent, Mathon, Bertrand, Barnholtz-Sloan, Jill S., Chakravarti, Arnab, Bi, Wenya Linda, Chiocca, E. Antonio, Fehnel, Katie Pricola, Alexandrescu, Sanda, Chi, Susan, Haas-Kogan, Daphne, Batchelor, Tracy T., Frampton, Garrett M., Alexander, Brian M., Huang, Raymond Y., Ligon, Azra H., Coulet, Florence, Delattre, Jean-Yves, Hoang-Xuan, Khê, Meredith, David M., Santagata, Sandro, Duval, Alex, Sanson, Marc, Cherniack, Andrew, Wen, Patrick Y., Reardon, David A., Marabelle, Aurélien, Park, Peter J., Idbaih, Ahmed, Beroukhim, Rameen, Bandopadhayay, Pratiti, Bielle, Franck, Ligon, Keith L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235024/
https://www.ncbi.nlm.nih.gov/pubmed/32322066
http://dx.doi.org/10.1038/s41586-020-2209-9
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author Touat, Mehdi
Li, Yvonne Y.
Boynton, Adam N.
Spurr, Liam F.
Iorgulescu, J. Bryan
Bohrson, Craig L.
Cortes-Ciriano, Isidro
Birzu, Cristina
Geduldig, Jack E.
Pelton, Kristine
Lim-Fat, Mary Jane
Pal, Sangita
Ferrer-Luna, Ruben
Ramkissoon, Shakti H.
Dubois, Frank
Bellamy, Charlotte
Currimjee, Naomi
Bonardi, Juliana
Qian, Kenin
Ho, Patricia
Malinowski, Seth
Taquet, Leon
Jones, Robert
Shetty, Aniket
Chow, Kin-Hoe
Sharaf, Radwa
Pavlick, Dean
Albacker, Lee A.
Younan, Nadia
Baldini, Capucine
Verreault, Maïté
Giry, Marine
Guillerm, Erell
Ammari, Samy
Beuvon, Frédéric
Mokhtari, Karima
Alentorn, Agusti
Dehais, Caroline
Houillier, Caroline
Laigle-Donadey, Florence
Psimaras, Dimitri
Lee, Eudocia Q.
Nayak, Lakshmi
McFaline-Figueroa, J. Ricardo
Carpentier, Alexandre
Cornu, Philippe
Capelle, Laurent
Mathon, Bertrand
Barnholtz-Sloan, Jill S.
Chakravarti, Arnab
Bi, Wenya Linda
Chiocca, E. Antonio
Fehnel, Katie Pricola
Alexandrescu, Sanda
Chi, Susan
Haas-Kogan, Daphne
Batchelor, Tracy T.
Frampton, Garrett M.
Alexander, Brian M.
Huang, Raymond Y.
Ligon, Azra H.
Coulet, Florence
Delattre, Jean-Yves
Hoang-Xuan, Khê
Meredith, David M.
Santagata, Sandro
Duval, Alex
Sanson, Marc
Cherniack, Andrew
Wen, Patrick Y.
Reardon, David A.
Marabelle, Aurélien
Park, Peter J.
Idbaih, Ahmed
Beroukhim, Rameen
Bandopadhayay, Pratiti
Bielle, Franck
Ligon, Keith L.
author_facet Touat, Mehdi
Li, Yvonne Y.
Boynton, Adam N.
Spurr, Liam F.
Iorgulescu, J. Bryan
Bohrson, Craig L.
Cortes-Ciriano, Isidro
Birzu, Cristina
Geduldig, Jack E.
Pelton, Kristine
Lim-Fat, Mary Jane
Pal, Sangita
Ferrer-Luna, Ruben
Ramkissoon, Shakti H.
Dubois, Frank
Bellamy, Charlotte
Currimjee, Naomi
Bonardi, Juliana
Qian, Kenin
Ho, Patricia
Malinowski, Seth
Taquet, Leon
Jones, Robert
Shetty, Aniket
Chow, Kin-Hoe
Sharaf, Radwa
Pavlick, Dean
Albacker, Lee A.
Younan, Nadia
Baldini, Capucine
Verreault, Maïté
Giry, Marine
Guillerm, Erell
Ammari, Samy
Beuvon, Frédéric
Mokhtari, Karima
Alentorn, Agusti
Dehais, Caroline
Houillier, Caroline
Laigle-Donadey, Florence
Psimaras, Dimitri
Lee, Eudocia Q.
Nayak, Lakshmi
McFaline-Figueroa, J. Ricardo
Carpentier, Alexandre
Cornu, Philippe
Capelle, Laurent
Mathon, Bertrand
Barnholtz-Sloan, Jill S.
Chakravarti, Arnab
Bi, Wenya Linda
Chiocca, E. Antonio
Fehnel, Katie Pricola
Alexandrescu, Sanda
Chi, Susan
Haas-Kogan, Daphne
Batchelor, Tracy T.
Frampton, Garrett M.
Alexander, Brian M.
Huang, Raymond Y.
Ligon, Azra H.
Coulet, Florence
Delattre, Jean-Yves
Hoang-Xuan, Khê
Meredith, David M.
Santagata, Sandro
Duval, Alex
Sanson, Marc
Cherniack, Andrew
Wen, Patrick Y.
Reardon, David A.
Marabelle, Aurélien
Park, Peter J.
Idbaih, Ahmed
Beroukhim, Rameen
Bandopadhayay, Pratiti
Bielle, Franck
Ligon, Keith L.
author_sort Touat, Mehdi
collection PubMed
description A high tumour mutational burden (hypermutation) is observed in some gliomas (1–5); 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.
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spelling pubmed-82350242021-06-26 Mechanisms and therapeutic implications of hypermutation in gliomas Touat, Mehdi Li, Yvonne Y. Boynton, Adam N. Spurr, Liam F. Iorgulescu, J. Bryan Bohrson, Craig L. Cortes-Ciriano, Isidro Birzu, Cristina Geduldig, Jack E. Pelton, Kristine Lim-Fat, Mary Jane Pal, Sangita Ferrer-Luna, Ruben Ramkissoon, Shakti H. Dubois, Frank Bellamy, Charlotte Currimjee, Naomi Bonardi, Juliana Qian, Kenin Ho, Patricia Malinowski, Seth Taquet, Leon Jones, Robert Shetty, Aniket Chow, Kin-Hoe Sharaf, Radwa Pavlick, Dean Albacker, Lee A. Younan, Nadia Baldini, Capucine Verreault, Maïté Giry, Marine Guillerm, Erell Ammari, Samy Beuvon, Frédéric Mokhtari, Karima Alentorn, Agusti Dehais, Caroline Houillier, Caroline Laigle-Donadey, Florence Psimaras, Dimitri Lee, Eudocia Q. Nayak, Lakshmi McFaline-Figueroa, J. Ricardo Carpentier, Alexandre Cornu, Philippe Capelle, Laurent Mathon, Bertrand Barnholtz-Sloan, Jill S. Chakravarti, Arnab Bi, Wenya Linda Chiocca, E. Antonio Fehnel, Katie Pricola Alexandrescu, Sanda Chi, Susan Haas-Kogan, Daphne Batchelor, Tracy T. Frampton, Garrett M. Alexander, Brian M. Huang, Raymond Y. Ligon, Azra H. Coulet, Florence Delattre, Jean-Yves Hoang-Xuan, Khê Meredith, David M. Santagata, Sandro Duval, Alex Sanson, Marc Cherniack, Andrew Wen, Patrick Y. Reardon, David A. Marabelle, Aurélien Park, Peter J. Idbaih, Ahmed Beroukhim, Rameen Bandopadhayay, Pratiti Bielle, Franck Ligon, Keith L. Nature Article A high tumour mutational burden (hypermutation) is observed in some gliomas (1–5); 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. 2020-04-15 2020-04 /pmc/articles/PMC8235024/ /pubmed/32322066 http://dx.doi.org/10.1038/s41586-020-2209-9 Text en http://www.nature.com/authors/editorial_policies/license.html#termsUsers may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Touat, Mehdi
Li, Yvonne Y.
Boynton, Adam N.
Spurr, Liam F.
Iorgulescu, J. Bryan
Bohrson, Craig L.
Cortes-Ciriano, Isidro
Birzu, Cristina
Geduldig, Jack E.
Pelton, Kristine
Lim-Fat, Mary Jane
Pal, Sangita
Ferrer-Luna, Ruben
Ramkissoon, Shakti H.
Dubois, Frank
Bellamy, Charlotte
Currimjee, Naomi
Bonardi, Juliana
Qian, Kenin
Ho, Patricia
Malinowski, Seth
Taquet, Leon
Jones, Robert
Shetty, Aniket
Chow, Kin-Hoe
Sharaf, Radwa
Pavlick, Dean
Albacker, Lee A.
Younan, Nadia
Baldini, Capucine
Verreault, Maïté
Giry, Marine
Guillerm, Erell
Ammari, Samy
Beuvon, Frédéric
Mokhtari, Karima
Alentorn, Agusti
Dehais, Caroline
Houillier, Caroline
Laigle-Donadey, Florence
Psimaras, Dimitri
Lee, Eudocia Q.
Nayak, Lakshmi
McFaline-Figueroa, J. Ricardo
Carpentier, Alexandre
Cornu, Philippe
Capelle, Laurent
Mathon, Bertrand
Barnholtz-Sloan, Jill S.
Chakravarti, Arnab
Bi, Wenya Linda
Chiocca, E. Antonio
Fehnel, Katie Pricola
Alexandrescu, Sanda
Chi, Susan
Haas-Kogan, Daphne
Batchelor, Tracy T.
Frampton, Garrett M.
Alexander, Brian M.
Huang, Raymond Y.
Ligon, Azra H.
Coulet, Florence
Delattre, Jean-Yves
Hoang-Xuan, Khê
Meredith, David M.
Santagata, Sandro
Duval, Alex
Sanson, Marc
Cherniack, Andrew
Wen, Patrick Y.
Reardon, David A.
Marabelle, Aurélien
Park, Peter J.
Idbaih, Ahmed
Beroukhim, Rameen
Bandopadhayay, Pratiti
Bielle, Franck
Ligon, Keith L.
Mechanisms and therapeutic implications of hypermutation in gliomas
title Mechanisms and therapeutic implications of hypermutation in gliomas
title_full Mechanisms and therapeutic implications of hypermutation in gliomas
title_fullStr Mechanisms and therapeutic implications of hypermutation in gliomas
title_full_unstemmed Mechanisms and therapeutic implications of hypermutation in gliomas
title_short Mechanisms and therapeutic implications of hypermutation in gliomas
title_sort mechanisms and therapeutic implications of hypermutation in gliomas
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235024/
https://www.ncbi.nlm.nih.gov/pubmed/32322066
http://dx.doi.org/10.1038/s41586-020-2209-9
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