Journal Article

Longitudinal analysis of treatment-induced genomic alterations in gliomas

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

2017

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V
• Subject: Antineoplastic Agents - therapeutic use / Bioinformatics / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer Research / Care and treatment / Chemotherapy / Chromosome Aberrations / Combined Modality Therapy / Disease Progression / DNA Mismatch Repair / DNA Mutational Analysis / DNA, Neoplasm / Exome / Exome sequencing / Female / General Surgery / Genome, Human / Genomics / Glioblastoma - genetics / Glioblastoma - pathology / Glioblastoma - therapy / Glioblastoma multiforme / Human Genetics / Humans / Immunotherapy / Longitudinal Studies / Medicine/Public Health / Metabolomics / Middle Aged / Mutation / Neoplasm Recurrence, Local / Precision cancer medicine / Precision Medicine / Radiotherapy / Risk factors / Systems Biology / Treatment Outcome