The prognostic impact of subclonal IDH1 mutation in grade 2–4 astrocytomas

Abstract

Background IDH mutations are thought to represent an early oncogenic event in glioma evolution, found with high penetrance across tumor cells, however in rare cases IDH mutation may exist only in a small subset of the total tumor cells (subclonal IDH-mutation). Methods We present two institutional cases with subclonal IDH1 R132H mutation. In addition, two large publicly-available cohorts of IDH-mutant astrocytomas were mined for cases harboring subclonal IDH mutations (defined as tumor cell fraction (TCF) with IDH mutation ≤0.67) and the clinical and molecular features of these subclonal cases were compared to clonal IDH-mutant astrocytomas. Results Immunohistochemistry (IHC) performed on two institutional WHO grade 4 IDH-mutant astrocytomas revealed only a minority of tumor cells in each case with IDH1 R132H mutant protein, and next-generation sequencing (NGS) revealed remarkably low IDH1 variant allele frequencies compared to other pathogenic mutations, including TP53 and/or ATRX. DNA methylation classified the first tumor as high-grade IDH-mutant astrocytoma with high confidence (0.98 score). In the publicly-available datasets, subclonal IDH mutation was present in 3.9% of IDH-mutant astrocytomas (18/466 tumors). Compared to clonal IDH-mutant astrocytomas (n=156), subclonal cases demonstrated worse overall survival in grades 3 (p=0.0106) and 4 (p=0.0184). Conclusions While rare, subclonal IDH1 mutations are present in a subset of IDH-mutant astrocytomas of all grades, which may lead to a mismatch between IHC results and genetic/epigenetic classification. These findings suggest a possible prognostic role of IDH mutation subclonality, and highlight the potential clinical utility of quantitative IDH1 mutation evaluation by IHC and NGS.

Mismatch repair protein mutations in isocitrate dehydrogenase (IDH)-mutant astrocytoma and IDH-wild-type glioblastoma

“… 10 , 36–39 The variant allele frequency (VAF) for each mutation was defined as the ratio of mutant alleles divided by total alleles. 40 , 41 The fraction of the genome with copy number alterations was calculated from the above data as the fraction of the genome with log2 of copy number > 0.3 following the procedure used in cBioPortal. 28 Differential analysis and visualization of mutations were done using Maftools.…”

Genetic and epigenetic instability as an underlying driver of progression and aggressive behavior in IDH-mutant astrocytoma

“…As a general rule, diffuse gliomas are composed of numerous subclones comprised of cells with different epigenetically regulated transcriptional states, different mutational or copy number states, and different microenvironmental states and interactions [ 156 , 201 ]. This principle becomes more complex with tumor recurrence and treatment, and even genetic alterations thought to be foundational to tumorigenesis, such as IDH mutation, may become subclonal and relegated to “passenger mutation” status with tumor evolution, while other newly acquired mutations may emerge in dominant clones and drive tumor biology [ 17 , 65 , 100 , 132 , 138 , 142 , 215 ]. This heterogeneity makes diffusely infiltrating gliomas incredibly diverse and adaptable and is believed to contribute significantly to resistance to immune regulation and therapeutics.…”