Longitudinal analysis of treatment-induced genomic alterations in gliomas Journal Article
| Authors: | Erson-Omay, E. Z.; Henegariu, O.; Omay, S. B.; Harmanci, A. S.; Youngblood, M. W.; Mishra-Gorur, K.; Li, J.; Özduman, K.; Carrión-Grant, G.; Clark, V. E.; Çağlar, C.; Bakircioğlu, M.; Pamir, M. N.; Tabar, V.; Vortmeyer, A. O.; Bilguvar, K.; Yasuno, K.; DeAngelis, L. M.; Baehring, J. M.; Moliterno, J.; Günel, M. |
| Article Title: | Longitudinal analysis of treatment-induced genomic alterations in gliomas |
| 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 genome-sequenced 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. © 2017 The Author(s). |
| Keywords: | glioma; mismatch repair deficiency; tumor evolution; genomics-guided precision medicine; immune checkpoint inhibition; longitudinal genomic analysis |
| Journal Title: | Genome Medicine |
| Volume: | 9 |
| ISSN: | 1756-994X |
| Publisher: | Biomed Central Ltd |
| Date Published: | 2017-02-02 |
| Start Page: | 12 |
| Language: | English |
| DOI: | 10.1186/s13073-017-0401-9 |
| PROVIDER: | scopus |
| PMCID: | PMC5290635 |
| PUBMED: | 28153049 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 March 2017 -- Source: Scopus |
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