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

Proc Natl Acad Sci U S A. 2017 Oct 3;114(40):10743-10748. doi: 10.1073/pnas.1708914114. Epub 2017 Sep 15.

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.

Keywords: 2HG; DNA methylation; IDH1; copy number; glioma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • DNA Copy Number Variations
  • DNA Methylation
  • Epigenomics*
  • Gene Amplification*
  • Gene Expression Profiling
  • Glioma / genetics*
  • Glioma / pathology
  • Glutarates / metabolism
  • Humans
  • Isocitrate Dehydrogenase / genetics*
  • Isocitrate Dehydrogenase / metabolism
  • Mutation*
  • Neoplasm Recurrence, Local / genetics*
  • Neoplasm Recurrence, Local / metabolism
  • Neoplasm Recurrence, Local / pathology
  • Sequence Deletion*
  • Tumor Cells, Cultured

Substances

  • Glutarates
  • alpha-hydroxyglutarate
  • Isocitrate Dehydrogenase
  • IDH1 protein, human