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Science. 2014 Jan 10;343(6167):189-193. doi: 10.1126/science.1239947. Epub 2013 Dec 12.

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

Author information

1
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
2
Department ofPathology, University of California San Francisco, San Francisco, CA, USA.
3
Genome Science Laboratory, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan.
4
Department of Neurosurgery, University of Tokyo, Tokyo, Japan.
5
Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
6
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
7
Department ofBioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
8
Department ofRadiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA.
9
Department ofPediatrics, University of California San Francisco, San Francisco, CA, USA.
10
Department ofNeurology, University of California San Francisco, San Francisco, CA, USA.
11
Department ofEpidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.
12
Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
13
Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada.
#
Contributed equally

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.

PMID:
24336570
PMCID:
PMC3998672
DOI:
10.1126/science.1239947
[Indexed for MEDLINE]
Free PMC Article

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