Abstract 5705: Mechanisms and therapeutic implications of hypermutation in gliomas

Abstract

High tumor mutational burden (hypermutation) is observed in some gliomas; however, its mechanisms of development and whether it predicts immunotherapy response are poorly understood. Here, we comprehensively analyze the molecular determinants of mutational burden and signatures in 10,294 gliomas including AACR Project GENIE and institutional datasets. 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 temozolomide treatment. Experimentally, the mutational signature of post-treatment hypermutated gliomas was only recapitulated by temozolomide-induced damage in cells harboring MMR deficiency. MMR-deficient gliomas exhibited unique features including the lack of prominent T-cell infiltrates, extensive intratumoral heterogeneity, poor survival and low response rate to PD-1 blockade. Moreover, while microsatellite instability in MMR-deficient gliomas was not detected by bulk analyses, single-cell whole-genome sequencing of post-treatment hypermutated glioma cells demonstrated microsatellite mutations. This study shows that chemotherapy can drive acquisition of hypermutated populations without promoting response to PD-1 blockade and supports diagnostic use of mutational burden and signatures in cancer. Citation Format: Mehdi Touat, Yvonne Y. Li, Adam N. Boynton, Liam F. Spurr, Bryan Iorgulescu, Craig L. Bohrson, Isidro Cortes-Ciriano, Jack E. Geduldig, Kristine Pelton, Mary J. Lim-Fat, Sangita Pal, Shakti H. Ramkissoon, Frank Dubois, Charlotte Bellamy, Naomi Currimjee, Kenin Qian, Seth Malinowski, Aniket Shetty, Kin-Hoe Chow, Maïté Verreault, Erell Guillerm, Samy Ammari, Frédéric Beuvon, Karima Mokhtari, Agusti Alentorn, Caroline Dehais, Caroline Houillier, Florence Laigle-Donadey, Dimitri Psimaras, Alexandre Carpentier, Philippe Cornu, Laurent Capelle, Bertrand Mathon, Jill S. Barnholtz-Sloan, Arnab Chakravarti, Wenya L. Bi, Garrett M. Frampton, Marc Sanson, Brian M. Alexander, Andrew Cherniack, Patrick Y. Wen, David A. Reardon, Aurelien Marabelle, Peter J. Park, Ahmed Idbaih, Rameen Beroukhim, Pratiti Bandopadhayay, Franck Bielle, Keith L. Ligon. Mechanisms and therapeutic implications of hypermutation in gliomas [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5705.

Longitudinal analysis of diffuse glioma reveals cell state dynamics at recurrence associated with changes in genetics and the microenvironment

“…This finding across both subtypes suggests that hypermutation may represent a pan-glioma treatment resistance mechanism. Hypermutation did not associate with patient survival in the GLASS dataset but has been found more frequently in distant recurrences and linked to reduced survival following high-grade progression in low-grade IDH-mutant tumors (Barthel et al, 2019;Touat et al, 2020;Yu et al, 2021). Given these findings, our data highlights methods to predict treatment-induced hypermutation represent a previously unrecognized unmet clinical need in the field.…”

“…Approximately 20% of gliomas recur with a hypermutated phenotype following treatment with alkylating agents, a standard-of-care chemotherapy (Barthel et al, 2019;Touat et al, 2020). This 10 phenotype has been associated with disease progression and distant recurrence (Yu et al, 2021).…”

Association Between Tumor Mutation Burden and Prognosis in Lower-Grade Glioma: An Exploratory Study 

“…Besides, temozolomide was shown to induce damage in cells with MMR de ciency driving the acquisition of hypermutated populations without promoting a response to PD-1 blockade [24] . Moreover, immunohistochemistry for MMR serves as a screening test for hypermutated gliomas [25] .…”

Glutaminolysis dynamics during astrocytoma progression correlates with tumor aggressiveness

“…The proneural subtype characterized by the presence of IDH mutation has been associated with a better prognosis [9], while the mesenchymal subtype with NF1 or RB1 mutations has presented the worst outcome, with an average overall survival of 8-11 months [10]. More recently, an impact of the mutational landscape on the response to immunotherapy and on the acquired resistance to temozolomide (TMZ) has been demonstrated in gliomas [11].…”