Recurrent gliomas genetically diverge from the initial tumor following surgical resection.

  • Major finding: Recurrent gliomas genetically diverge from the initial tumor following surgical resection.

  • Clinical relevance: Temozolomide may promote high-grade glioma recurrence by inducing oncogenic mutations.

  • Impact: Mutational analysis of gliomas at diagnosis may not predict therapeutic targets in recurrent tumors.

A large proportion of low-grade gliomas recur following surgical resection, and some progress to a more malignant state. To better understand the malignant progression of recurrent low-grade gliomas after surgery and determine the role of chemotherapy in tumor recurrence, Johnson and colleagues compared the mutational profiles of grade II gliomas at diagnosis and recurrence and the effects of adjuvant chemotherapy with temozolomide (TMZ) on the genetic landscape of residual disease. Exome sequencing of 23 grade II astrocytic gliomas and their recurrences revealed that only an average of 54% of somatic coding mutations in the initial tumors were detected in the recurrent tumors. Genetic variation between initial and recurrent tumors suggests that seeding of recurrent tumors can occur throughout the evolution of the initial tumor. Although sequencing of multiple geographic regions revealed intratumoral heterogeneity within initial and recurrent tumors, many mutations were shared, suggesting that intratumoral heterogeneity could not completely explain the genetic divergence between initial and recurrent tumors. To understand whether mutagenic chemotherapies can promote genetic variance in recurrent disease, the authors sequenced initial and recurrent tumors from patients treated with the alkylating agent TMZ. A hypermutated phenotype not present in the initial samples was observed in the recurrent gliomas of 6 out of 10 patients treated with TMZ. Moreover, hypermutated recurrent tumors progressed to malignant glioblastoma and were found to harbor TMZ-associated oncogenic mutations in driver genes previously linked with high-grade gliomas in the RB and AKT–mTOR signaling pathways. Together, these findings suggest that recurrent gliomas diverge from the initial tumor early in their evolution and that adjuvant chemotherapy can dramatically amplify the genetic diversity, which can, in some but not all cases, accelerate malignant progression.

Johnson BE, Mazor T, Hong C, Barnes M, Aihara K, McLean CY, et al. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science 2014;343:189–93.

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