title: Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma.
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.
authors: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
authors: Brett E
authors: BE
authors: Johnson
authors: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
authors: Tali
authors: T
authors: Mazor
authors: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
authors: Chibo
authors: C
authors: Hong
authors: Department ofPathology, University of California San Francisco, San Francisco, CA, USA.
authors: Michael
authors: M
authors: Barnes
authors: Genome Science Laboratory, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan.|Department of Neurosurgery, University of Tokyo, Tokyo, Japan.
authors: Koki
authors: K
authors: Aihara
authors: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
authors: Cory Y
authors: CY
authors: McLean
authors: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
authors: Shaun D
authors: SD
authors: Fouse
authors: Genome Science Laboratory, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan.
authors: Shogo
authors: S
authors: Yamamoto
authors: Genome Science Laboratory, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan.
authors: Hiroki
authors: H
authors: Ueda
authors: Genome Science Laboratory, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan.
authors: Kenji
authors: K
authors: Tatsuno
authors: Department of Medicine, University of California San Francisco, San Francisco, CA, USA.|Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
authors: Saurabh
authors: S
authors: Asthana
authors: Department ofBioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
authors: Llewellyn E
authors: LE
authors: Jalbert
authors: Department ofBioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.|Department ofRadiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA.
authors: Sarah J
authors: SJ
authors: Nelson
authors: Department ofPathology, University of California San Francisco, San Francisco, CA, USA.
authors: Andrew W
authors: AW
authors: Bollen
authors: Department ofPediatrics, University of California San Francisco, San Francisco, CA, USA.
authors: W Clay
authors: WC
authors: Gustafson
authors: Department ofNeurology, University of California San Francisco, San Francisco, CA, USA.
authors: Elise
authors: E
authors: Charron
authors: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.|Department ofPediatrics, University of California San Francisco, San Francisco, CA, USA.|Department ofNeurology, University of California San Francisco, San Francisco, CA, USA.
authors: William A
authors: WA
authors: Weiss
authors: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
authors: Ivan V
authors: IV
authors: Smirnov
authors: Department ofEpidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.|Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
authors: Jun S
authors: JS
authors: Song
authors: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.|Department ofEpidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.
authors: Adam B
authors: AB
authors: Olshen
authors: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
authors: Soonmee
authors: S
authors: Cha
authors: Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors: Yongjun
authors: Y
authors: Zhao
authors: Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors: Richard A
authors: RA
authors: Moore
authors: Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors: Andrew J
authors: AJ
authors: Mungall
authors: Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors: Steven J M
authors: SJM
authors: Jones
authors: Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors: Martin
authors: M
authors: Hirst
authors: Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors: Marco A
authors: MA
authors: Marra
authors: Department of Neurosurgery, University of Tokyo, Tokyo, Japan.
authors: Nobuhito
authors: N
authors: Saito
authors: Genome Science Laboratory, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan.
authors: Hiroyuki
authors: H
authors: Aburatani
authors: Department of Neurosurgery, University of Tokyo, Tokyo, Japan.
authors: Akitake
authors: A
authors: Mukasa
authors: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
authors: Mitchel S
authors: MS
authors: Berger
authors: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
authors: Susan M
authors: SM
authors: Chang
authors: Department of Medicine, University of California San Francisco, San Francisco, CA, USA.|Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.|Department ofEpidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.
authors: Barry S
authors: BS
authors: Taylor
authors: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
authors: Joseph F
authors: JF
authors: Costello
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D004265:DNA Helicases / Q000235:genetics; D004252:DNA Mutational Analysis; D003606:Dacarbazine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D006801:Humans; D016296:Mutagenesis / Q000187:drug effects; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000139:chemically induced* / Q000188:drug therapy / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D000077204:Temozolomide; D014157:Transcription Factors / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D000075924:X-linked Nuclear Protein
chemical_list: D018906:Antineoplastic Agents, Alkylating; D009687:Nuclear Proteins; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D003606:Dacarbazine; C546842:MTOR protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C084108:SMARCA4 protein, human; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein; D000077204:Temozolomide