Department of Neurological Surgery, University of California, San Francisco, CA 94158.
Hotchkiss Brain Institute, Department of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
Proc Natl Acad Sci U S A. 2017 Oct 3;114(40):10743-10748. doi: 10.1073/pnas.1708914114. Epub 2017 Sep 15.
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 mutant LGGs. We discovered six cases with copy number alterations (CNAs) at the locus at recurrence. Deletion or amplification of was followed by clonal expansion and recurrence at a higher grade. Successful cultures derived from mutant, but not wild type, gliomas systematically deleted in vitro and in vivo, further suggestive of selection against the heterozygous mutant state as tumors progress. Tumors and cultures with CNA had decreased 2HG, maintenance of G-CIMP, and DNA methylation reprogramming outside CGI. Thus, while mutation initiates gliomagenesis, in some patients mutant IDH1 and 2HG are not required for later clonal expansions.
突变是低级别胶质瘤 (LGG) 中最早的遗传改变，但它在肿瘤复发中的作用尚不清楚。突变 IDH1 驱动致癌代谢物 d-2-羟戊酸 (2HG) 和 CpG 岛 (CGI) 超甲基化表型 (G-CIMP) 的过度产生。为了研究突变 IDH1 在复发中的作用，我们对 50 例突变 LGG 进行了纵向分析。我们在复发时发现了 6 例在 基因座存在拷贝数改变 (CNA) 的病例。 的缺失或扩增后会出现克隆性扩张，并向更高级别复发。从突变 IDH1 但不是野生型胶质瘤成功培养的细胞在体外和体内系统地缺失了 ，这进一步表明随着肿瘤的进展，对杂合突变状态的选择是不利的。具有 CNA 的肿瘤和培养物 2HG 减少，G-CIMP 得以维持，并且 CGI 之外的 DNA 甲基化重新编程。因此，虽然 突变启动了胶质瘤发生，但在某些患者中，突变 IDH1 和 2HG 并不需要用于随后的克隆扩张。
