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 Vortmeyer, Kaya Bilguvar, Katsuhito Yasuno, Lisa M. DeAngelis, Joachim M. Baehring, Jennifer Moliterno & 1 others Murat Günel

Research output: Contribution to journalArticle

7 Citations (Scopus)

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

Fingerprint

Glioma
Exome
Therapeutics
Glioblastoma
Survival
Genomics
Brain Neoplasms
Neoplasms
Radiotherapy
Clone Cells
Genome
Pressure
Recurrence
Drug Therapy

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)

Cite this

Erson-Omay, E. Z., Henegariu, O., Omay, S. B., Harmanci, A. S., Youngblood, M. W., Mishra-Gorur, K., ... 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

Longitudinal analysis of treatment-induced genomic alterations in gliomas. / Erson-Omay, E. Zeynep; Henegariu, Octavian; Omay, S. Bülent; Harmanci, Akdes Serin; Youngblood, Mark W.; Mishra-Gorur, Ketu; Li, Jie; Özduman, Koray; Carrión-Grant, Geneive; Clark, Victoria E.; Çağlar, Caner; Bakircioğlu, Mehmet; Pamir, M. Necmettin; Tabar, Viviane; Vortmeyer, Alexander; Bilguvar, Kaya; Yasuno, Katsuhito; DeAngelis, Lisa M.; Baehring, Joachim M.; Moliterno, Jennifer; Günel, Murat.

In: Genome Medicine, Vol. 9, No. 1, 12, 02.02.2017.

Research output: Contribution to journalArticle

Erson-Omay, EZ, Henegariu, O, Omay, SB, Harmanci, AS, Youngblood, MW, Mishra-Gorur, K, Li, J, Özduman, K, Carrión-Grant, G, Clark, VE, Çağlar, C, Bakircioğlu, M, Pamir, MN, Tabar, V, Vortmeyer, A, Bilguvar, K, Yasuno, K, DeAngelis, LM, Baehring, JM, Moliterno, J & Günel, M 2017, 'Longitudinal analysis of treatment-induced genomic alterations in gliomas', Genome Medicine, vol. 9, no. 1, 12. https://doi.org/10.1186/s13073-017-0401-9
Erson-Omay EZ, Henegariu O, Omay SB, Harmanci AS, Youngblood MW, Mishra-Gorur K et al. Longitudinal analysis of treatment-induced genomic alterations in gliomas. Genome Medicine. 2017 Feb 2;9(1). 12. https://doi.org/10.1186/s13073-017-0401-9
Erson-Omay, E. Zeynep ; Henegariu, Octavian ; Omay, S. Bülent ; Harmanci, Akdes Serin ; Youngblood, Mark W. ; Mishra-Gorur, Ketu ; Li, Jie ; Özduman, Koray ; Carrión-Grant, Geneive ; Clark, Victoria E. ; Çağlar, Caner ; Bakircioğlu, Mehmet ; Pamir, M. Necmettin ; Tabar, Viviane ; Vortmeyer, Alexander ; Bilguvar, Kaya ; Yasuno, Katsuhito ; DeAngelis, Lisa M. ; Baehring, Joachim M. ; Moliterno, Jennifer ; Günel, Murat. / Longitudinal analysis of treatment-induced genomic alterations in gliomas. In: Genome Medicine. 2017 ; Vol. 9, No. 1.
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AU - Erson-Omay, E. Zeynep

AU - Henegariu, Octavian

AU - Omay, S. Bülent

AU - Harmanci, Akdes Serin

AU - Youngblood, Mark W.

AU - Mishra-Gorur, Ketu

AU - Li, Jie

AU - Özduman, Koray

AU - Carrión-Grant, Geneive

AU - Clark, Victoria E.

AU - Çağlar, Caner

AU - Bakircioğlu, Mehmet

AU - Pamir, M. Necmettin

AU - Tabar, Viviane

AU - Vortmeyer, Alexander

AU - Bilguvar, Kaya

AU - Yasuno, Katsuhito

AU - DeAngelis, Lisa M.

AU - Baehring, Joachim M.

AU - Moliterno, Jennifer

AU - Günel, Murat

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N2 - 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.

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