Journal
SCIENCE
Volume 343, Issue 6167, Pages 189-193Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1239947
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Funding
- Accelerate Brain Cancer Cure
- Grove Foundation
- TDC Foundation
- Anne and Jason Farber Foundation
- Samuel Waxman Cancer Research Foundation
- Alex Lemonade Stand Foundation
- Entertainment Industry Foundation
- Anne Feeley
- National Institute of General Medical Sciences [T32GM008568]
- NIH [1T32CA15102201, R25NS070680, P50CA097257]
- National Cancer Institute [R01CA169316-01, P01CA81403, P30CA82103, R01CA163336]
- National Institute of Neurological Disorders and Stroke [K08NS079485]
- UCSF Academic Senate
- Sontag Foundation
- BC Cancer Foundation
- Genome BC
- Genome Canada
- Goldhirsh Foundation
- Ministry of Education, Culture, Sports, Science and Technology of Japan [23134501, 24221011]
- Grants-in-Aid for Scientific Research [23134501, 23390343] Funding Source: KAKEN
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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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