Mechanisms and therapeutic implications of hypermutation in gliomas.

in Nature by 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, Sangita Pal, Ruben Ferrer-Luna, Shakti H Ramkissoon, Frank Dubois, Charlotte Bellamy, Naomi Currimjee, Juliana Bonardi, Kenin Qian, Patricia Ho, Seth Malinowski, Leon Taquet, Robert E Jones, Aniket Shetty, Kin-Hoe Chow, Radwa Sharaf, Dean Pavlick, Lee A Albacker, Nadia Younan, Capucine Baldini, Maïté Verreault, Marine Giry, Erell Guillerm, Samy Ammari, Frédéric Beuvon, Karima Mokhtari, Agusti Alentorn, Caroline Dehais, Caroline Houillier, Florence Laigle-Donadey, Dimitri Psimaras, Eudocia Q Lee, Lakshmi Nayak, J Ricardo McFaline-Figueroa, Alexandre Carpentier, Philippe Cornu, Laurent Capelle, Bertrand Mathon, Jill S Barnholtz-Sloan, Arnab Chakravarti, Wenya Linda Bi, E Antonio Chiocca, Katie Pricola Fehnel, Sanda Alexandrescu, Susan N Chi, Daphne Haas-Kogan, Tracy T Batchelor, Garrett M Frampton, Brian M Alexander, Raymond Y Huang, Azra H Ligon, Florence Coulet, Jean-Yves Delattre, Khê Hoang-Xuan, David M Meredith, Sandro Santagata, Alex Duval, Marc Sanson, Andrew D Cherniack, Patrick Y Wen, David A Reardon, Aurélien Marabelle, Peter J Park, Ahmed Idbaih, Rameen Beroukhim, Pratiti Bandopadhayay, Franck Bielle, Keith L Ligon

TLDR

  • The study looked at how mutations happen in brain tumors called gliomas. They found that there are two main ways that mutations happen: one way is that there are problems with the genes that help make DNA, and the other way is that the tumor becomes resistant to treatment and then gets more mutations. The study also found that the mutations in the tumors didn't always show up in tests, but they were still there. The study also found that the mutations in the tumors didn't always mean that the tumor would respond to a certain treatment. The study also found that chemotherapy can cause the tumor to get more mutations, but it doesn't always mean that the tumor will respond to a certain treatment. The study also found that the mutations in the tumors can be used to diagnose the tumor.

Abstract

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

Overview

  • The study aims to comprehensively analyze the molecular determinants of mutational burden and signatures in 10,294 gliomas to understand the mechanisms by which hypermutation develops and whether it predicts the response to immunotherapy. The study delineates 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. The study experimentally recapitulates the mutational signature of post-treatment hypermutated gliomas by temozolomide-induced damage in cells with MMR deficiency. The study identifies that MMR-deficient gliomas are 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. The study also shows 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.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions detailed in the study. The study identifies two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and 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. The study experimentally recapitulates the mutational signature of post-treatment hypermutated gliomas by temozolomide-induced damage in cells with MMR deficiency. The study identifies that MMR-deficient gliomas are 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. The study also shows 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.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice. The study identifies two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and 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. The study experimentally recapitulates the mutational signature of post-treatment hypermutated gliomas by temozolomide-induced damage in cells with MMR deficiency. The study identifies that MMR-deficient gliomas are 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. The study also shows 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. Future research directions could include further investigation of the mechanisms underlying the development of hypermutation in gliomas, the role of MMR defects in acquired resistance to chemotherapy, and the potential of targeting MMR defects in the treatment of gliomas.
Read Full Article