Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH1

Mazor Tali; Chesnelong Charles; Pankov AleksandrJalbert Llewellyn E.Hong ChiboHayes JosieSmirnov Ivan V.Marshall RoxanneSouza Camila F.Shen YaoqingViswanath PavithraNoushmehr HoutanRonen Sabrina M.Jones Steven J. M.Marra Marco A.Cairncross J. GregoryPerry ArieNelson Sarah J.Chang Susan M.Bollen Andrew W.Molinaro Annette M.Bengtsson HenrikOlshen Adam B.Weiss SamuelPhillips Joanna J.Luchman H. ArteeCostello Joseph F.

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Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH1

机译：Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH1

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IDH1 mutation is the earliest genetic alteration in low-grade gliomas (LGGs), but its role in tumor recurrence is unclear. Mutant IDH1 drives overproduction of the oncometabolite D-2-hydroxyglutarate (2HG) and a CpG island (CGI) hypermethylation phenotype (G-CIMP). To investigate the role of mutant IDH1 at recurrence, we performed a longitudinal analysis of 50 IDH1 mutant LGGs. We discovered six cases with copy number alterations (CNAs) at the IDH1 locus at recurrence. Deletion or amplification of IDH1 was followed by clonal expansion and recurrence at a higher grade. Successful cultures derived from IDH1 mutant, but not IDH1 wild type, gliomas systematically deleted IDH1 in vitro and in vivo, further suggestive of selection against the heterozygous mutant state as tumors progress. Tumors and cultures with IDH1 CNA had decreased 2HG, maintenance of G-CIMP, and DNA methylation reprogramming outside CGI. Thus, while IDH1 mutation initiates gliomagenesis, in some patients mutant IDH1 and 2HG are not required for later clonal expansions.

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《Proceedings of the National Academy of Sciences of the United States of America.》 |2017年第40期|10743-10748|共6页
作者
Mazor Tali; Chesnelong Charles; Pankov AleksandrJalbert Llewellyn E.Hong ChiboHayes JosieSmirnov Ivan V.Marshall RoxanneSouza Camila F.Shen YaoqingViswanath PavithraNoushmehr HoutanRonen Sabrina M.Jones Steven J. M.Marra Marco A.Cairncross J. GregoryPerry ArieNelson Sarah J.Chang Susan M.Bollen Andrew W.Molinaro Annette M.Bengtsson HenrikOlshen Adam B.Weiss SamuelPhillips Joanna J.Luchman H. ArteeCostello Joseph F.;
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作者单位

Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94158 USA;

Univ Calgary, Cumming Sch Med, Dept Cell Biol & Anat, Hotchkiss Brain Inst, Calgary, AB T2N 4N1, Canada;

Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94158 USAUniv Calif San Francisco, Dept Pathol, San Francisco, CA 94158 USAHenry Ford Hlth Syst, Dept Neurosurg, Detroit, MI 48202 USABritish Columbia Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 4S6, CanadaUniv Calgary, Cumming Sch Med, Dept Clin Neurosci, Clark H Smith Brain Tumor Ctr,Arnie Charbonneau C, Calgary, AB T2N 4N1, CanadaUniv Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94158 USA;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
IDH1; DNA methylation; 2HG; glioma; copy number;

Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH1

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