Longitudinal analysis of treatment-induced genomic alterations in gliomas
E Zeynep Erson-Omay1,2, Octavian Henegariu1,2,3,4,5, S Bülent Omay1,2
1Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT, USA.
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.
Insights
Longitudinal whole-exome sequencing (WES) guided treatment of glioblastoma multiforme (GBM) revealed dynamic molecular changes. Genomics-guided therapy extended survival over 5 years, highlighting the importance of adaptive precision medicine for brain tumors.
Area of Science:
- Neuro-oncology
- Genomics
- Precision Medicine
Background:
- Glioblastoma multiforme (GBM) is an aggressive brain tumor with poor prognosis.
- Standard treatments (surgery, radiation, chemotherapy) show variable efficacy due to tumor heterogeneity.
- Whole-exome sequencing (WES) offers insights into the molecular basis of treatment resistance.
Observation:
- A patient with primary GBM and two recurrences underwent WES-guided treatment.
- Longitudinal analysis tracked dynamic genomic evolution under therapeutic pressure.
- Chromothripsis and mismatch repair deficiency emerged as significant genomic events.
Findings:
- Targeted therapies selected for resistant clones, often driven by chromothripsis.
- Genomic profiling identified acquired mismatch repair deficiency.
- Personalized treatment, informed by WES, extended patient survival beyond 5 years.
- The patient responded favorably to immune checkpoint inhibition after developing mismatch repair deficiency.
Implications:
- Longitudinal genomic profiling is crucial for adapting precision therapies.
- Understanding dynamic molecular changes can overcome treatment resistance in GBM.
- WES-guided adaptive treatment strategies can significantly improve outcomes for brain tumor patients.
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