@article {1532784, title = {Mechanisms and therapeutic implications of hypermutation in gliomas}, journal = {Nature}, volume = {580}, number = {7804}, year = {2020}, month = {2020 04}, pages = {517-523}, 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.}, keywords = {Animals, Antineoplastic Agents, Alkylating, Brain Neoplasms, DNA Mismatch Repair, Gene Frequency, Genome, Human, Glioma, Humans, Male, Mice, Microsatellite Repeats, Mutagenesis, Mutation, Phenotype, Prognosis, Programmed Cell Death 1 Receptor, Sequence Analysis, DNA, Temozolomide, Xenograft Model Antitumor Assays}, issn = {1476-4687}, doi = {10.1038/s41586-020-2209-9}, author = {Touat, Mehdi and Li, Yvonne Y and Boynton, Adam N and Spurr, Liam F and Iorgulescu, J Bryan and Bohrson, Craig L and Cortes-Ciriano, Isidro and Birzu, Cristina and Geduldig, Jack E and Pelton, Kristine and Lim-Fat, Mary Jane and Pal, Sangita and Ferrer-Luna, Ruben and Ramkissoon, Shakti H and Dubois, Frank and Bellamy, Charlotte and Currimjee, Naomi and Bonardi, Juliana and Qian, Kenin and Ho, Patricia and Malinowski, Seth and Taquet, Leon and Jones, Robert E and Shetty, Aniket and Chow, Kin-Hoe and Sharaf, Radwa and Pavlick, Dean and Albacker, Lee A and Younan, Nadia and Baldini, Capucine and Verreault, Ma{\"\i}t{\'e} and Giry, Marine and Guillerm, Erell and Ammari, Samy and Beuvon, Fr{\'e}d{\'e}ric and Mokhtari, Karima and Alentorn, Agusti and Dehais, Caroline and Houillier, Caroline and Laigle-Donadey, Florence and Psimaras, Dimitri and Lee, Eudocia Q and Nayak, Lakshmi and McFaline-Figueroa, J Ricardo and Carpentier, Alexandre and Cornu, Philippe and Capelle, Laurent and Mathon, Bertrand and Barnholtz-Sloan, Jill S and Chakravarti, Arnab and Bi, Wenya Linda and Chiocca, E Antonio and Fehnel, Katie Pricola and Sanda Alexandrescu and Chi, Susan N and Haas-Kogan, Daphne and Batchelor, Tracy T and Frampton, Garrett M and Alexander, Brian M and Huang, Raymond Y and Ligon, Azra H and Coulet, Florence and Delattre, Jean-Yves and Hoang-Xuan, Kh{\^e} and Meredith, David M and Santagata, Sandro and Duval, Alex and Sanson, Marc and Cherniack, Andrew D and Wen, Patrick Y and Reardon, David A and Marabelle, Aur{\'e}lien and Park, Peter J and Idbaih, Ahmed and Beroukhim, Rameen and Bandopadhayay, Pratiti and Bielle, Franck and Ligon, Keith L} }