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

Brett E. Johnson, Tali Mazor, Chibo Hong, Michael Barnes, Koki Aihara, Cory Y. McLean, Shaun D. Fouse, Shogo Yamamoto, Hiroki Ueda, Kenji Tatsuno, Saurabh Asthana, Llewellyn E. Jalbert, Sarah J. Nelson, Andrew W. Bollen, W. Clay Gustafson, Elise Charron, William A. Weiss, Ivan V. Smirnov, Jun S. Song, Adam B. OlshenSoonmee Cha, Yongjun Zhao, Richard A. Moore, Andrew J. Mungall, Steven J.M. Jones, Martin Hirst, Marco A. Marra, Nobuhito Saito, Hiroyuki Aburatani, Akitake Mukasa, Mitchel S. Berger, Susan M. Chang, Barry S. Taylor, Joseph F. Costello

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)189-193
Number of pages5
JournalScience
Volume343
Issue number6167
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • General

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    Johnson, B. E., Mazor, T., Hong, C., Barnes, M., Aihara, K., McLean, C. Y., Fouse, S. D., Yamamoto, S., Ueda, H., Tatsuno, K., Asthana, S., Jalbert, L. E., Nelson, S. J., Bollen, A. W., Gustafson, W. C., Charron, E., Weiss, W. A., Smirnov, I. V., Song, J. S., ... Costello, J. F. (2014). Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science, 343(6167), 189-193. https://doi.org/10.1126/science.1239947