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Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma

Tumor recurrence is a leading cause of cancer mortality. Therapies for recurrent disease may fail, at least in part, because the genomic alterations driving the growth of recurrences are distinct from those in the initial tumor. To explore this hypothesis, we sequenced the exomes of 23 initial low-grade gliomas and recurrent tumors resected from the same patients. In 43% of cases, at least half of the mutations in the initial tumor were undetected at recurrence, including driver mutations inTP53, ATRX, SMARCA4, and BRAF; this suggests that recurrent tumors are often seeded by cells derived from the initial tumor at a very early stage of their evolution. Notably, tumors from 6 of 10 patients treated with the chemotherapeutic drug temozolomide (TMZ) followed an alternative evolutionary path to high-grade glioma. At recurrence, these tumors were hypermutated and harbored driver mutations in the RB (retinoblastoma) and Akt-mTOR (mammalian target of rapamycin) pathways that bore the signature of TMZ-induced mutagenesis.

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Dataset ID Description Technology Samples
EGAD00001000714 102
Publications Citations
Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma.
Science 343: 2014 189-193
812
Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment.
Acta Neuropathol 129: 2015 597-607
100
DNA Methylation and Somatic Mutations Converge on the Cell Cycle and Define Similar Evolutionary Histories in Brain Tumors.
Cancer Cell 28: 2015 307-317
157
Clonal evolution of glioblastoma under therapy.
Nat Genet 48: 2016 768-776
400
Between-region genetic divergence reflects the mode and tempo of tumor evolution.
Nat Genet 49: 2017 1015-1024
77
Comprehensive Analysis of Hypermutation in Human Cancer.
Cell 171: 2017 1042-1056.e10
386
Clonal replacement and heterogeneity in breast tumors treated with neoadjuvant HER2-targeted therapy.
Nat Commun 10: 2019 657
29
MGMT promoter methylation level in newly diagnosed low-grade glioma is a predictor of hypermutation at recurrence.
Neuro Oncol 22: 2020 1580-1590
45
DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells.
Cancer Discov 11: 2021 1176-1191
31
Mutations in the RAS/MAPK Pathway Drive Replication Repair-Deficient Hypermutated Tumors and Confer Sensitivity to MEK Inhibition.
Cancer Discov 11: 2021 1454-1467
17
Pathway-based classification of glioblastoma uncovers a mitochondrial subtype with therapeutic vulnerabilities.
Nat Cancer 2: 2021 141-156
122
Pharmacogenomic profiling reveals molecular features of chemotherapy resistance in IDH wild-type primary glioblastoma.
Genome Med 15: 2023 16
3