Mutational Analysis Reveals the Origin and Therapy-driven Evolution of Recurrent Glioma

By Brett E. Johnson, T. Mazor, C. Hong, Michael R. Barnes, Koki Aihara, Cory Y. McLean, S. Fouse, Shogo Yamamoto, Hiroki R. Ueda, K. Tatsuno and 24 more. Science, 2013

1,210 citations recorded by the source corpus.

Back with a Vengeance After surgery, gliomas (a type of brain tumor) recur in nearly all patients and often in a more aggressive form. Johnson et al. (p. 189, published online 12 December 2013) used exome sequencing to explore whether recurrent tumors harbor different mutations than the primary tumors and whether the mutational profile in the recurrences is influenced by postsurgical treatment of patients with temozolomide (TMZ), a chemotherapeutic drug known to damage DNA. In more than 40% of cases, at least half of the mutations in the initial glioma were undetected at recurrence. The recurrent tumors in many of the TMZ-treated patients bore the signature of TMZ-induced mutagenesis and appeared to follow an evolutionary path to high-grade glioma distinct from that in untreated patients. Primary brain tumors and their recurrences can exhibit vastly different mutational profiles. 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 in TP53, 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.

Subfields: Cancer Research, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/6665a8443517e0479f7073f3a940b313af35d12a

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Citations in the corpus

Glioma Subclassifications and Their Clinical Significance (2017, background): “A second group of IDH1/IDH2 mutated and DNA hypermethylated tumors have intact 1p/19q, and these instead carry alterations in ATRX and TP53, corresponding to molecular astrocytomas.”
Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. (2015, background): “Modes of Tumor Evolution and Cooperation between Tumor Subclones Longitudinal (Johnson et al., 2014; Mullighan et al., 2008; Shah et al., 2009), spatial (Aerts et al., 2014; Bashashati et al., 2013; Campbell et al., 2010; Gerlinger et al., 2012, 2014; Haffner et al., 2013; Navin et al., 2010, 2011;…”
Artificial intelligence in Cancer Imaging: Clinical Challenges and Applications (2019, background): “63,65 ITH analysis has indicated that, although targetable somatic alterations may appear to be clonal in a single tumor biopsy, they may be entirely absent in additional biopsies from different regions of the same tumor.”
Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future. (2017, positive): “Indeed, the most notable outliers with regard to high subclonal mutational burden, but low clonal burden, are low-grade gliomas that recur as glioblastomas after treatment with the alkylating agent temozolomide (Johnson et al., 2014; Kim et al., 2015).”
Targeting Metabolism for Cancer Therapy (2017, background): “, 2009), raising the possibility that IDH mutations are important for tumor initiation, but accumulation of additional oncogenic mutations renders GBM tumors less dependent on constitutive expression of mutant IDH for tumor proliferation and progression (Johnson et al., 2014; Wakimoto et al., 2014).”
Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab (2017, background): “…has been reported following other cancer therapies such as cytotoxic treatments in glioblastoma (GBM) and chronic lymphocytic leukemia, and our observation of CDKN2A loss in four patients with PD agrees with reported changes in GBM tumors at progression (Johnson et al., 2014; Landau et al., 2015).”