Abstract
BackgroundGlioblastoma 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.MethodsHere, 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.ResultsOur 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.ConclusionsOur 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.
Highlights
Glioblastoma multiforme (GBM) constitutes nearly half of all malignant brain tumors and has a median survival of 15 months
The case displayed a favorable response to immune checkpoint inhibition after acquiring mismatch repair deficiency
Detailed analysis of the Copy number variation (CNV) and Structural variation (SV) revealed segments on chromosomes 7p.11 and 1q.32, with more than 20 copies overlapping with the EGFR and Mdm2-like P53-binding protein (MDM4) genes, respectively (Fig. 2a)
Summary
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; 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. Erson-Omay et al Genome Medicine (2017) 9:12 resistance The results of this analysis helped to guide personalized, precise treatment of the patient despite having two therapeutically adverse events with two recurrences, chromothripsis and mismatch repair (MMR) deficiency. The case displayed a favorable response to immune checkpoint inhibition after acquiring mismatch repair deficiency With this clinical approach, the patient survived more than 5 years despite the two recurrences (Fig. 1). Our observations emphasize the necessity of genomic profiling and comparative analyses for each clinical recurrence or progression
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