Longitudinal analysis of treatment-induced genomic alterations in gliomas.

Erson-Omay EZ1,2, Henegariu O1,2,3,4,5, Omay SB1,2, Harmancı AS1,2, Youngblood MW1,2,3, Mishra-Gorur K1,2,3,4,5, Li J6, Özduman K7, Carrión-Grant G1,2, Clark VE1,2,3, Çağlar C1,2, Bakırcıoğlu M1,2, Pamir MN7, Tabar V8, Vortmeyer AO6, Bilguvar K1,3,5,9, Yasuno K1,2, DeAngelis LM10, Baehring JM2,11,12, Moliterno J1,2,12, Günel M13,14,15,16,17,18,19,20.

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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.