Longitudinal analysis of treatment-induced genomic alterations in gliomas.
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.



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.



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.



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.
Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
E Zeynep
EZ
Erson-Omay
Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.|Department of Genetics, Yale School of Medicine, New Haven, CT, USA.|Department of Neurobiology, Yale School of Medicine, New Haven, CT, USA.|Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT, USA.
Octavian
O
Henegariu
Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
S Bülent
SB
Omay
Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
Akdes Serin
AS
Harmancı
Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.|Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
Mark W
MW
Youngblood
Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.|Department of Genetics, Yale School of Medicine, New Haven, CT, USA.|Department of Neurobiology, Yale School of Medicine, New Haven, CT, USA.|Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT, USA.
Ketu
K
Mishra-Gorur
Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
Jie
J
Li
Department of Neurosurgery, Acıbadem University School of Medicine, Istanbul, Turkey.
Koray
K
Özduman
Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
Geneive
G
Carrión-Grant
Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.|Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
Victoria E
VE
Clark
Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
Caner
C
Çağlar
Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
Mehmet
M
Bakırcıoğlu
Department of Neurosurgery, Acıbadem University School of Medicine, Istanbul, Turkey.
M Necmettin
MN
Pamir
Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Viviane
V
Tabar
Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
Alexander O
AO
Vortmeyer
Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT, USA.|Department of Genetics, Yale School of Medicine, New Haven, CT, USA.|Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT, USA.|Yale Center for Genome Analysis, Yale School of Medicine, Orange, CT, USA.
Kaya
K
Bilguvar
Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
Katsuhito
K
Yasuno
Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Lisa M
LM
DeAngelis
Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.|Department of Neurology, Yale School of Medicine, New Haven, CT, USA.|Yale Brain Tumor Center, Yale School of Medicine, New Haven, CT, USA.
Joachim M
JM
Baehring
Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.|Yale Brain Tumor Center, Yale School of Medicine, New Haven, CT, USA.
Jennifer
J
Moliterno
Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT, USA. murat.gunel@yale.edu.|Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA. murat.gunel@yale.edu.|Department of Genetics, Yale School of Medicine, New Haven, CT, USA. murat.gunel@yale.edu.|Department of Neurobiology, Yale School of Medicine, New Haven, CT, USA. murat.gunel@yale.edu.|Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT, USA. murat.gunel@yale.edu.|Yale Brain Tumor Center, Yale School of Medicine, New Haven, CT, USA. murat.gunel@yale.edu.|Yale Comprehensive Cancer Center, Yale School of Medicine, New Haven, CT, USA. murat.gunel@yale.edu.|Yale Neurosurgery, PO Box 208082, New Haven, CT, 06520-8082, USA. murat.gunel@yale.edu.
Murat
M
Günel
D000970:Antineoplastic Agents / Q000627:therapeutic use; D002869:Chromosome Aberrations; D003131:Combined Modality Therapy; D053843:DNA Mismatch Repair; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm; D018450:Disease Progression; D059472:Exome; D005260:Female; D013502:General Surgery; D015894:Genome, Human; D023281:Genomics; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007167:Immunotherapy; D008137:Longitudinal Studies; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D057285:Precision Medicine; D011878:Radiotherapy; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm
Genomics-guided precision medicine; Glioma; Immune checkpoint inhibition; Longitudinal genomic analysis; Mismatch repair deficiency; Tumor evolution