Spontaneous loss of heterozygosity leading to homozygous R132H in a patient-derived IDH1 mutant cell line

Abstract

Dear Editor, We report a novel follow-up observation pertaining to “An in vivo patient-derived model of endogenous IDH1-mutant glioma,” which was recently published in Neuro-Oncology.1 Since publication, we have observed the gradual and repeated loss of the wild-type IDH1 allele in vitro with retention of the mutant allele. Sequencing of IDH1 exon 4 from 3 independent late passage cultures showed homozygosity for the R132H allele (mut/-), whereas both mutant and wild-type alleles were present in the original line (mut/wt) and tumor (Fig. 1A). In addition, a decreased copy number was seen at the IDH locus, consistent with loss of the IDH1 wild-type allele (Fig. 1B). The American Type Culture Collection (ATCC) has independently observed this phenomenon in BT142. The ATCC is preparing to distribute the BT142 mut/-,2 while we test conditions that best preserve the heterozygous phenotype. Fig. 1. Loss of heterozygosity in favor of the mutant allele of IDH1 correlates with a decreased copy number of the IDH1 locus. (a) IDH sequencing on the IDH1-mutant anaplastic oligoastrocytoma and derived IDHmt brain tumor stem cell line (BT142). (b) Copy number ... The loss of the wild-type allele has been reported in vivo in patients and has been shown to be similar to phenotypically wild-type IDH, resulting in decreased 2-hydroxyglutarate production,3,4 also observed in the BT142 mut/- line. This unforeseen change leading to a second cell line will be valuable for comparisons of the implications of mutant and wild-type IDH phenotypes on proliferation, tumorigenicity, and therapeutic resistance in a syngeneic setting.