Publication Date:
2013-12-18
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3998672/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3998672/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 J M -- Hirst, Martin -- Marra, Marco A -- Saito, Nobuhito -- Aburatani, Hiroyuki -- Mukasa, Akitake -- Berger, Mitchel S -- Chang, Susan M -- Taylor, Barry S -- Costello, Joseph F -- 1T32CA15102201/CA/NCI NIH HHS/ -- K08 NS079485/NS/NINDS NIH HHS/ -- K08NS079485/NS/NINDS NIH HHS/ -- P01CA81403/CA/NCI NIH HHS/ -- P30 CA082103/CA/NCI NIH HHS/ -- P30CA82103/CA/NCI NIH HHS/ -- P50 CA097257/CA/NCI NIH HHS/ -- P50CA097257/CA/NCI NIH HHS/ -- R01 CA163336/CA/NCI NIH HHS/ -- R01 CA169316/CA/NCI NIH HHS/ -- R01CA163336/CA/NCI NIH HHS/ -- R01CA169316-01/CA/NCI NIH HHS/ -- R25NS070680/NS/NINDS NIH HHS/ -- T32 CA128583/CA/NCI NIH HHS/ -- T32GM008568/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2014 Jan 10;343(6167):189-93. doi: 10.1126/science.1239947. Epub 2013 Dec 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurological Surgery, University of California, San Francisco, CA 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24336570" target="_blank"〉PubMed〈/a〉
Keywords:
Antineoplastic Agents, Alkylating/*adverse effects/therapeutic use
;
Brain/drug effects/pathology
;
Brain Neoplasms/*drug therapy/genetics/*pathology
;
DNA Helicases/genetics
;
DNA Mutational Analysis
;
Dacarbazine/adverse effects/*analogs & derivatives/therapeutic use
;
Glioma/*drug therapy/genetics/*pathology
;
Humans
;
Mutagenesis/drug effects
;
Neoplasm Grading
;
Neoplasm Recurrence, Local/*chemically induced/drug therapy/*genetics
;
Nuclear Proteins/genetics
;
Proto-Oncogene Proteins B-raf/genetics
;
Proto-Oncogene Proteins c-akt/genetics
;
TOR Serine-Threonine Kinases/genetics
;
Transcription Factors/genetics
;
Tumor Suppressor Protein p53/genetics
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
Permalink
