Department of Neurosurgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa- ku, Nagoya, 466-8550, Japan.
Department of Pathology and Laboratory Medicine, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
Acta Neuropathol Commun. 2024 Oct 26;12(1):169. doi: 10.1186/s40478-024-01879-9.
Mutations in the isocitrate dehydrogenase (IDH) gene are recognized as the key drivers in the oncogenesis of astrocytoma and oligodendroglioma. However, the significance of IDH mutation in tumor maintenance and malignant transformation has not been elucidated. We encountered a unique case of IDH-mutant astrocytoma that, upon malignant transformation, presented two distinct intratumoral components: one IDH-wildtype and one IDH-mutant. The IDH-wild-type component exhibited histological findings similar to those of small cell-type glioblastoma with a higher Ki-67 index than the IDH-mutant component. Despite their genetic divergence, both components exhibited similar comprehensive methylation profiles within the CpG island and were classified into methylation class of "Astrocytoma, IDH-mutant; High Grade" by the German Cancer Center (DKFZ) classifier v11.4. Phylogenetic analysis demonstrated that the IDH-wildtype component emerged as a subclonal component of the primary tumor. Detailed molecular analyses revealed that the loss of the IDH mutation was induced by the hemizygous loss of the entire arm of chromosome 2, on which IDH1 gene is located. Notably, the IDH-wild-type subclones uniquely acquired CDKN2A/B homozygous deletion and PDGFRA amplification, which is a marker of the aggressive phenotype of astrocytoma, IDH-mutant. Because these genetic abnormalities can drive oncogenic pathways, such as the PI3K/AKT/mTOR and RB signaling pathway, IDH-mutant gliomas that acquired these mutations were no longer dependent on the initial driver mutation, the IDH mutation. Molecular analysis of this unique case provides insight that in a subset of astrocytoma, IDH-mutant that acquired these genetic abnormalities, IDH mutation may not play a pivotal role in tumor growth and acquisition of these genetic abnormalities may contribute to the acquisition of resistance to IDH inhibitors.
异柠檬酸脱氢酶（IDH）基因突变被认为是星形细胞瘤和少突胶质细胞瘤发生的关键驱动因素。然而，IDH 突变在肿瘤维持和恶性转化中的意义尚未阐明。我们遇到了一个独特的 IDH 突变型星形细胞瘤病例，该肿瘤在恶性转化后呈现出两个截然不同的肿瘤内成分：一个 IDH 野生型和一个 IDH 突变型。IDH 野生型成分表现出类似于小细胞型胶质母细胞瘤的组织学特征，Ki-67 指数高于 IDH 突变型成分。尽管它们在遗传上存在差异，但两个成分在 CpG 岛内表现出相似的综合甲基化谱，并通过德国癌症中心（DKFZ）分类器 v11.4 被分类为“IDH 突变型星形细胞瘤，高级别”。系统发生分析表明，IDH 野生型成分是原发性肿瘤的亚克隆成分。详细的分子分析显示，IDH 突变的丧失是由整条 2 号染色体臂的杂合性缺失引起的，IDH1 基因位于该染色体臂上。值得注意的是，IDH 野生型亚克隆独特地获得了 CDKN2A/B 纯合缺失和 PDGFRA 扩增，这是 IDH 突变型星形细胞瘤侵袭性表型的标志物。由于这些遗传异常可以驱动致癌途径，如 PI3K/AKT/mTOR 和 RB 信号通路，因此获得这些突变的 IDH 突变型神经胶质瘤不再依赖于最初的驱动突变，即 IDH 突变。对这个独特病例的分子分析提供了一个见解，即在一部分 IDH 突变型星形细胞瘤中，获得这些遗传异常的 IDH 突变可能不再在肿瘤生长中发挥关键作用，并且获得这些遗传异常可能有助于对 IDH 抑制剂产生耐药性。
