Vij Meenakshi, Yokoda Raquel T, Rashidipour Omid, Tran Ivy, Vasudevaraja Varshini, Snuderl Matija, Yong Raymund L, Cobb William S, Umphlett Melissa, Walker Jamie M, Tsankova Nadejda M, Richardson Timothy E
Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Department of Pathology, NYU Langone Health, New York, New York, USA.
Neurooncol Adv. 2023 May 29;5(1):vdad069. doi: 10.1093/noajnl/vdad069. eCollection 2023 Jan-Dec.
Isocitrate dehydrogenase (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).
We present 2 institutional cases with subclonal R132H mutation. In addition, 2 large publicly available cohorts of IDH-mutant astrocytomas were mined for cases harboring subclonal IDH mutations (defined as tumor cell fraction with IDH mutation ≤0.67) and the clinical and molecular features of these subclonal cases were compared to clonal IDH-mutant astrocytomas.
Immunohistochemistry (IHC) performed on 2 institutional World Health Organization 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 variant allele frequencies compared to other pathogenic mutations, including and/or . DNA methylation classified the first tumor as high-grade IDH-mutant astrocytoma with high confidence (0.98 scores). 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 = 156), subclonal cases demonstrated worse overall survival in grades 3 ( = .0106) and 4 ( = .0184).
While rare, subclonal 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 mutation evaluation by IHC and NGS.
异柠檬酸脱氢酶（IDH）突变被认为是胶质瘤发生发展过程中的早期致癌事件，在肿瘤细胞中具有高发生率；然而，在罕见情况下，IDH突变可能仅存在于全部肿瘤细胞的一小部分中（亚克隆IDH突变）。
我们展示了2例伴有亚克隆R132H突变的病例。此外，我们在2个公开的IDH突变型星形细胞瘤大型队列中筛选出携带亚克隆IDH突变的病例（定义为IDH突变的肿瘤细胞比例≤0.67），并将这些亚克隆病例的临床和分子特征与克隆性IDH突变型星形细胞瘤进行比较。
对2例机构性世界卫生组织4级IDH突变型星形细胞瘤进行免疫组织化学（IHC）检测，结果显示每例中仅有少数肿瘤细胞表达IDH1 R132H突变蛋白，与其他致病突变（包括 和/或 ）相比，二代测序（NGS）显示变异等位基因频率极低。DNA甲基化将第一个肿瘤高度可靠地分类为高级别IDH突变型星形细胞瘤（评分0.98）。在公开数据集中，3.9%的IDH突变型星形细胞瘤（18/466例肿瘤）存在亚克隆IDH突变。与克隆性IDH突变型星形细胞瘤（ = 156）相比，亚克隆病例在3级（ = 0.0106）和4级（ = 0.0184）的总生存期更差。
虽然罕见，但亚克隆 突变存在于所有级别的IDH突变型星形细胞瘤的一个亚组中，这可能导致IHC结果与基因/表观遗传分类之间的不匹配。这些发现提示IDH突变亚克隆性可能具有预后作用，并突出了通过IHC和NGS进行IDH突变定量评估的潜在临床应用价值。
