| Literature DB >> 28916733 |
Tali Mazor1, Charles Chesnelong2,3, Aleksandr Pankov1, Llewellyn E Jalbert4, Chibo Hong1, Josie Hayes1, Ivan V Smirnov1, Roxanne Marshall5, Camila F Souza6,7, Yaoqing Shen8, Pavithra Viswanath4, Houtan Noushmehr6,7, Sabrina M Ronen4, Steven J M Jones8,9, Marco A Marra8,9, J Gregory Cairncross3, Arie Perry1,5, Sarah J Nelson4,10, Susan M Chang1, Andrew W Bollen5, Annette M Molinaro1,11, Henrik Bengtsson11,12, Adam B Olshen11,12, Samuel Weiss2,3, Joanna J Phillips1,5, H Artee Luchman13,3, Joseph F Costello14.
Abstract
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.Entities:
Keywords: 2HG; DNA methylation; IDH1; copy number; glioma
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Year: 2017 PMID： 28916733 PMCID： PMC5635900 DOI： 10.1073/pnas.1708914114
Source DB: PubMed Journal: Proc Natl Acad Sci U S A ISSN： 0027-8424 Impact factor: 11.205