Longitudinal analysis of treatment-induced genomic alterations in gliomas

E. Zeynep Erson-Omay, Octavian Henegariu, S. Bülent Omay, Akdes Serin Harmanci, Mark W. Youngblood, Ketu Mishra-Gorur, Jie Li, Koray Özduman, Geneive Carrión-Grant, Victoria E. Clark, Caner Çağlar, Mehmet Bakircioğlu, M. Necmettin Pamir, Viviane Tabar, Alexander O. Vortmeyer, Kaya Bilguvar, Katsuhito Yasuno, Lisa M. DeAngelis, Joachim M. Baehring, Jennifer MoliternoMurat Günel

Research output: Contribution to journalArticle

7 Scopus citations

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.

Original languageEnglish (US)
Article number12
JournalGenome Medicine
Volume9
Issue number1
DOIs
StatePublished - Feb 2 2017
Externally publishedYes

Keywords

  • Genomics-guided precision medicine
  • Glioma
  • Immune checkpoint inhibition
  • Longitudinal genomic analysis
  • Mismatch repair deficiency
  • Tumor evolution

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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  • Cite this

    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., ... Günel, M. (2017). Longitudinal analysis of treatment-induced genomic alterations in gliomas. Genome Medicine, 9(1), [12]. https://doi.org/10.1186/s13073-017-0401-9