1. Mutational Analysis Reveals the Origin and Therapy-Driven Evolution of Recurrent Glioma
- Author
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Johnson, Brett E, Mazor, Tali, Hong, Chibo, Barnes, Michael, Aihara, Koki, McLean, Cory Y, Fouse, Shaun D, Yamamoto, Shogo, Ueda, Hiroki, Tatsuno, Kenji, Asthana, Saurabh, Jalbert, Llewellyn E, Nelson, Sarah J, Bollen, Andrew W, Gustafson, W Clay, Charron, Elise, Weiss, William A, Smirnov, Ivan V, Song, Jun S, Olshen, Adam B, Cha, Soonmee, Zhao, Yongjun, Moore, Richard A, Mungall, Andrew J, Jones, Steven JM, Hirst, Martin, Marra, Marco A, Saito, Nobuhito, Aburatani, Hiroyuki, Mukasa, Akitake, Berger, Mitchel S, Chang, Susan M, Taylor, Barry S, and Costello, Joseph F
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Human Genome ,Brain Cancer ,Neurosciences ,Brain Disorders ,Orphan Drug ,Genetics ,Cancer ,Rare Diseases ,Cancer Genomics ,Good Health and Well Being ,Antineoplastic Agents ,Alkylating ,Brain ,Brain Neoplasms ,DNA Helicases ,DNA Mutational Analysis ,Dacarbazine ,Glioma ,Humans ,Mutagenesis ,Neoplasm Grading ,Neoplasm Recurrence ,Local ,Nuclear Proteins ,Proto-Oncogene Proteins B-raf ,Proto-Oncogene Proteins c-akt ,TOR Serine-Threonine Kinases ,Temozolomide ,Transcription Factors ,Tumor Suppressor Protein p53 ,X-linked Nuclear Protein ,General Science & Technology - 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.
- Published
- 2014