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

Abstract

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.

Comprehensive genomic profiling of glioblastoma tumors, BTICs, and xenografts reveals stability and adaptation to growth environments

“…BT-142 from patient PT-EV3071 and BT-92 from patient PT-AR5365 each had an IDH1 R132H mutation in the tumor, but the BT-142 cell line lost the wild-type allele while the BT-92 cell line lost the mutated allele, suggesting that this allele has to be homozygous in order to establish cell lines. This finding was confirmed with more samples and these results have been previously published (13).…”

Isocitrate dehydrogenase 1–mutated human gliomas depend on lactate and glutamate to alleviate metabolic stress

“…Generation of cell lines under in vitro culture conditions therefore has a risk of outgrowth of artificially selected subclones that have undergone epigenetic reprogramming because of IDH locus loss or amplification (24). To bypass these events, we concentrated in the current study on metabolism in a cohort of surgically obtained glioma tissues, using metabolic gene expression levels as surrogate markers of metabolic pathways.…”

Detection of glioma and prognostic subtypes by non-invasive circulating cell-free DNA methylation markers

“…In addition, a possible advantage of detecting and characterizing the IDH status of aggressive gliomas rekindles the concept of neoadjuvant therapy prior to surgical resection, a frontier that has yet to be fully explored in this type of pathology. Recently, IDH mutation status of a solid tumor has been shown to change during tumor progression possibly due to drug response 40 , which is only confirmed during recurrence by biopsy or resection. However, as suggested by Mazor et al 40 , longitudinal monitoring of IDH status during treatment offers significant opportunities to understand the role of IDH1 inhibitors.…”

“…Recently, IDH mutation status of a solid tumor has been shown to change during tumor progression possibly due to drug response 40 , which is only confirmed during recurrence by biopsy or resection. However, as suggested by Mazor et al 40 , longitudinal monitoring of IDH status during treatment offers significant opportunities to understand the role of IDH1 inhibitors. Last, but not least, although the cost of profiling whole-epigenome arrays may currently limit its potential application, the discovery of an alternative, sensitive and more cost-effective method to profile the epigenome of cfDNA has shown promise in several tumors 34 .…”