Dres-08. Clinical Significance of Hypermutation in Gliomas
Year: 2019
Type: conference-abstract
Abstract: BACKGROUND Hypermutation is an emerging biomarker for predicting response to immunotherapy in cancer patients, however its clinical value in gliomas is not established. We sought to assess the determinants of hypermutation in gliomas, and its value for predicting response to standard of care and immune checkpoint blockade (ICB). METHODS We performed comprehensive genomic characterization of 2,420 clinically annotated gliomas. We assessed the clinical and molecular characteristics associated with hypermutation and relationships between hypermutation and response to cancer treatments. RESULTS Hypermutation occurred predominantly as an adaptive resistance mechanism to temozolomide in gliomas and was most prevalent in recurrent gliomas with MGMTpromoter methylation (33.8%), IDH1/2mutation (41.0%) or 1p/19q co-deletion (59.5%). Hypermutation was almost always associated with molecular defects in DNA mismatch repair (MMR), and was associated with shorter survival after its appearance based on multivariate analysis (hazard ratio 1.91; 95% CI 1.24–2.94; P=0.004). The molecular mechanisms whereby gliomas undergo hypermutation during therapy with alkylating agents were dissected using patient-derived glioma models in vitro and in vivo. Outcomes of hypermutated gliomas treated with immune checkpoint blockade or with standard of care agents will be presented at the conference. CONCLUSIONS Using the largest set of hypermutated gliomas described to date, this study establishes that mutational burden and mutation signatures are clinically and biologically significant biomarkers that can be used to predict therapy response and guide treatment decisions in gliomas
Source: Neuro-Oncology
Authors: Mehdi Touat, Yvonne Li, Adam Boynton, Liam Spurr, Bryan Iorgulescu, Christina Birzu, Sangita Pal, Ruben Ferrer-Luna, Jack Geduldig, Charlotte Bellamy, Nadia Younan, Capucine Baldini, Maite Verreault, Erell Guillerm, Samy Ammari, Frederic Beuvon, Karima Mokhtari, Agusti Alentorn, Caroline Dehais, Caroline Houiller, Florence Laigle-Donadey, Eudocia Lee, Lakshmi Nayak, Alexandre Carpentier, Philippe Cornu, Bertrand mathon, Wenya Bi, Ennio Chiocca, Sanda Alexandrescu, Susan Chi, Daphne Haas-Kogan, Brian Alexander, Raymond Huang, Azra Ligon, Florence Coulet, Jean-Yves Delattre, Khe Hoang-Xuan, David Meredith, Sandro Santagata, Alex Duval, Marc Sanson, Andrew Cherniack, Patrick Wen, David Reardon, Aurelien Marabelle, Ahmed Idbaih, Rameen Beroukhim, Pratiti Bandopadhayay, Franck Bielle, Keith Ligon
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2988734677