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

Brett Johnson(University of California, San Francisco), Tali Mazor(University of California, San Francisco), Chibo Hong(University of California, San Francisco), Michael J. Barnes(University of California, San Francisco), Koki Aihara(Bunkyo University), Cory Y. McLean(University of California, San Francisco), Shaun D. Fouse(University of California, San Francisco), Shogo Yamamoto(Tokyo University of Science), Hiroki Ueda(Tokyo University of Science), Kenji Tatsuno(Tokyo University of Science), Saurabh Asthana(University of California, San Francisco), Llewellyn E. Jalbert(University of California, San Francisco), Sarah J. Nelson(University of California, San Francisco), Andrew W. Bollen(University of California, San Francisco), W. Clay Gustafson(University of California, San Francisco), Elise Charron(University of California, San Francisco), William A. Weiss(University of California, San Francisco), Ivan Smirnov(University of California, San Francisco), Jun S. Song(University of California, San Francisco), Adam B. Olshen(University of California, San Francisco), Soonmee Cha(University of California, San Francisco), Yongjun Zhao(Canada's Michael Smith Genome Sciences Centre), Richard A. Moore(Canada's Michael Smith Genome Sciences Centre), Andrew J. Mungall(Canada's Michael Smith Genome Sciences Centre), Steven J.M. Jones(Canada's Michael Smith Genome Sciences Centre), Martin Hirst(Canada's Michael Smith Genome Sciences Centre), Marco A. Marra(Canada's Michael Smith Genome Sciences Centre), Nobuhito Saito(Bunkyo University), Hiroyuki Aburatani(Tokyo University of Science), Akitake Mukasa(Bunkyo University), Mitchel S. Berger(University of California, San Francisco), Susan M. Chang(University of California, San Francisco), Barry S. Taylor(University of California, San Francisco), J Costello(University of California, San Francisco)
Science
December 12, 2013
10.1126/science.1239947
Cited by 1,384

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.

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