학술논문
Longitudinal analysis of treatment-induced genomic alterations in gliomas.
Document Type
Article
Author
Erson-Omay, E. Zeynep; Henegariu, Octavian; Omay, S. Bülent; Harmancı, Akdes Serin; Youngblood, Mark W.; Mishra-Gorur, Ketu; Jie Li; Özduman, Koray; Carrión-Grant, Geneive; Clark, Victoria E.; Çağlar, Caner; Bakırcıoğlu, Mehmet; Pamir, M. Necmettin; Tabar, Viviane; Vortmeyer, Alexander O.; Bilguvar, Kaya; Katsuhito Yasuno; DeAngelis, Lisa M.; Baehring, Joachim M.; Moliterno, Jennifer
Source
Subject
*NERVOUS system tumors
*GLIOBLASTOMA multiforme
*RADIOTHERAPY
*ELECTROTHERAPEUTICS
*OLIGODENDROGLIOMAS
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Language
ISSN
1756-994X
Abstract
Background: Glioblastoma multiforme (GBM) constitutes nearly half of all malignant brain tumors and has a median survival of 15 months. The standard treatment for these lesions includes maximal resection, radiotherapy, and chemotherapy; however, individual tumors display immense variability in their response to these approaches. Genomic techniques such as whole-exome sequencing (WES) provide an opportunity to understand the molecular basis of this variability. Methods: Here, we report WES-guided treatment of a patient with a primary GBM and two subsequent recurrences, demonstrating the dynamic nature of treatment-induced molecular changes and their implications for clinical decision-making. We also analyze the Yale-Glioma cohort, composed of 110 whole exome- or whole genomesequenced tumor-normal pairs, to assess the frequency of genomic events found in the presented case. Results: Our longitudinal analysis revealed how the genomic profile evolved under the pressure of therapy. Specifically targeted approaches eradicated treatment-sensitive clones while enriching for resistant ones, generated due to chromothripsis, which we show to be a frequent event in GBMs based on our extended analysis of 110 gliomas in the Yale-Glioma cohort. Despite chromothripsis and the later acquired mismatch-repair deficiency, genomics-guided personalized treatment extended survival to over 5 years. Interestingly, the case displayed a favorable response to immune checkpoint inhibition after acquiring mismatch repair deficiency. Conclusions: Our study demonstrates the importance of longitudinal genomic profiling to adjust to the dynamic nature of treatment-induced molecular changes to improve the outcomes of precision therapies. [ABSTRACT FROM AUTHOR]