A novel isocitrate dehydrogenase 1 G131D mutation in glioblastoma

To the Editor: A 68-year-old man presented with a 2-month aphasia. Magnetic resonance imaging scan revealed an abnormal signal in the left temporal lobe with heterogenous enhancement [Figure 1A]. Glioma was considered, and the patient underwent total tumor resection. Microscopic examination of the resected tumor showed a high-grade glial tumor with pleomorphic cells, elevated mitotic activity, microvascular proliferation, and pseudopalisading necrosis [Figure 1B and 1C]. Part of the lesion contained round cells with perinuclear halos. Tumor cells also grew around neurons, forming secondary structures [Figure 1D]. On immunohistochemical investigation, the tumor cells expressed glial fibrillary acidic protein and oligodendrocyte transcription factor 2 [Figure 1E]. There was only focal positivity for p53 protein (about 5% of tumor cells), while alpha-thalassemia/mental retardation syndrome X-linked protein expression was positive. The tumor cells were negative for isocitrate dehydrogenase 1 (IDH1) R132H, NeuN, and H3 K27M. The Ki-67 index was approximately 20%. Next-generation sequencing analysis (Simcere Diagnostics, Nanjing, China) was performed on the formalin-fixed paraffin-embedded tumor tissues. The results showed a heterozygous IDH1 CGT>AGT G131D mutation, epidermal growth factor receptor (EGFR) amplification, cyclin-dependent kinase inhibitors 2A/B (CDKN2A/B) deletion, loss of chromosome 10 as well as 1p loss of heterozygosity [Figure 1F and 1G], while chromosome 19q was intact. Mutations of IDH2, H3F3A, HIST1H3B, BRAF, and TERT promoters were absent. IDH1 G131D mutation was confirmed by sanger sequencing [Figure 1H]. The presence of 1p /19q [Figure 1I and 1J] and EGFR amplification [Figure 1K] was confirmed via fluorescence in situ hybridization (Guangzhou LBP Pharmaceutical Technology Co. Ltd, China). The tumor was finally diagnosed as glioblastoma, IDH-mutant (IDH1 G131D mutation), World Health Organization grade IV. Post-operatively, the patient received combination of radiotherapy and chemotherapy (temozolomide, 140 mg, qd). No recurrence or progression was observed from a follow-up of 2 months. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (No. [2019]004) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The authors have obtained the appropriate patient's consent form.

Figure 1.

Radiologic and pathologic features of isocitrate dehydrogenase 1 (IDH1) G131D mutant-glioblastoma. (A) T1-weighted, post-contrast imaging shows a heterogenous-enhancing mass in the left temporal lobe (arrow). (B–D) Histologic features showed a high-grade glial tumor including round cells with perinuclear halos microvascular proliferation (arrow) (B, original magnification ×200), necrosis (arrow) (C, original magnification ×200), and some tumor cells growing around neurons (D, original magnification ×400). (E) Immunohistochemical stain showed the tumor cells were positive for oligodendrocyte transcription factor 2 (Olig-2) (original magnification, ×400). (F and G) Next-generation sequencing revealed cyclin-dependent kinase inhibitors 2A/B (CDKN2A/B) deletion (F) and epidermal growth factor receptor (EGFR) amplification (G). (H) Sanger sequencing of IDH1 exon 4 demonstrated IDH1 (c.392G-A, p.G131D) mutation (arrow). (I–K) 1p loss of heterozygosity (LOH) (I), 19q intact (J), and EGFR amplification (K) were confirmed with fluorescence in situ hybridization (FISH, original magnification, ×1000).

IDH mutations are known to be a favorable prognostic factor in patients with diffuse gliomas.^[1] Mutations in the IDH1 gene are heterozygous and virtually always affect only a single residue (arginine 132) which is replaced by histidine in approximately 90% of tumors (c.395G>A resulting in IDH1 R132H).^[2] Although some new IDH1 mutations have been reported, they mostly also change the R132 residue.^[3] Here, we present a case of IDH1 G131D mutant glioblastoma diagnosed based on histopathological and molecular genetic findings. To the best of our knowledge, the IDH1 G131D mutation has not been reported in gliomas to date. Although there were some oligodendroglioma-like cells in the present case, chromosome 19q was intact and there was no mutation of the TERT promoter. Moreover, the tumor had an EGFR amplification, CDKN2A/B deletion, and loss of chromosome 10. Therefore, these results support the integrated diagnosis of glioblastoma or “Astrocytoma, IDH-mutant, grade 4.”^[4,5] Our findings suggest that the IDH1 G131D mutation may also be a pathogenic event in the gliomas mutagenesis cascade leading to glioma, which expands the spectrum of known pathogenic IDH mutations. Given that IDH1 mutations are often associated with less aggressive behavior and favorable outcomes in brain tumors in adults, the effect of this novel IDH1 G131D mutation on prognosis in the present case requires longer follow-up.

Funding

This work was supported by the Beijing Excellent Talents Training Project, China (No. 201600026833ZK07) and the Beijing Higher Education Young Elite Teacher Project, China (No. CIT&TCD201904091).

Conflicts of interest

None.