Dual phenotypes in recurrent astrocytoma, IDH-mutant; coexistence of IDH-mutant and IDH-wildtype components: a case report with genetic and epigenetic analysis.

IF 6.2 2区 医学 Q1 NEUROSCIENCES Acta Neuropathologica Communications Pub Date : 2024-10-26 DOI:10.1186/s40478-024-01879-9
Junya Yamaguchi, Fumiharu Ohka, Masafumi Seki, Kazuya Motomura, Shoichi Deguchi, Yoshiki Shiba, Yuka Okumura, Yuji Kibe, Hiroki Shimizu, Sachi Maeda, Yuhei Takido, Ryo Yamamoto, Akihiro Nakamura, Kennosuke Karube, Ryuta Saito
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Abstract

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.

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IDH突变型复发性星形细胞瘤的双重表型;IDH突变型和IDH野生型成分共存:一份病例报告及遗传学和表观遗传学分析。
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肿瘤发生的关键驱动因素。然而,IDH 基因突变在肿瘤维持和恶性转化中的意义尚未得到阐明。我们遇到了一例独特的IDH突变星形细胞瘤,该瘤在恶性转化后出现了两种不同的瘤内成分:一种是IDH野生型,一种是IDH突变型。IDH野生型成分的组织学表现与小细胞型胶质母细胞瘤相似,Ki-67指数高于IDH突变型成分。尽管在基因上存在差异,但这两种成分在 CpG 岛内都表现出类似的全面甲基化特征,并被德国癌症中心(DKFZ)分类器 v11.4 归入 "星形细胞瘤,IDH 突变;高级别 "甲基化类别。系统发育分析表明,IDH-野生型成分是原发肿瘤的亚克隆成分。详细的分子分析表明,IDH突变的缺失是由IDH1基因所在的2号染色体整个臂的半等位缺失引起的。值得注意的是,IDH-wild 型亚克隆独特地获得了 CDKN2A/B 同源缺失和 PDGFRA 扩增,这是 IDH 突变型星形细胞瘤侵袭性表型的标志。由于这些基因异常可以驱动致癌通路,如PI3K/AKT/mTOR和RB信号通路,因此获得这些突变的IDH突变胶质瘤不再依赖于最初的驱动突变,即IDH突变。对这一独特病例的分子分析表明,在获得这些基因异常的IDH突变型星形细胞瘤亚群中,IDH突变可能在肿瘤生长中不再起关键作用,而获得这些基因异常可能有助于获得对IDH抑制剂的耐药性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Acta Neuropathologica Communications
Acta Neuropathologica Communications Medicine-Pathology and Forensic Medicine
CiteScore
11.20
自引率
2.80%
发文量
162
审稿时长
8 weeks
期刊介绍: "Acta Neuropathologica Communications (ANC)" is a peer-reviewed journal that specializes in the rapid publication of research articles focused on the mechanisms underlying neurological diseases. The journal emphasizes the use of molecular, cellular, and morphological techniques applied to experimental or human tissues to investigate the pathogenesis of neurological disorders. ANC is committed to a fast-track publication process, aiming to publish accepted manuscripts within two months of submission. This expedited timeline is designed to ensure that the latest findings in neuroscience and pathology are disseminated quickly to the scientific community, fostering rapid advancements in the field of neurology and neuroscience. The journal's focus on cutting-edge research and its swift publication schedule make it a valuable resource for researchers, clinicians, and other professionals interested in the study and treatment of neurological conditions.
期刊最新文献
Correction: Revisiting gliomatosis cerebri in adult-type diffuse gliomas: a comprehensive imaging, genomic and clinical analysis. Host genetics and gut microbiota influence lipid metabolism and inflammation: potential implications for ALS pathophysiology in SOD1G93A mice. NF1 expression profiling in IDH-wildtype glioblastoma: genomic associations and survival outcomes. Genotype‒phenotype correlation in recessive DNAJB4 myopathy. Glioma immune microenvironment composition calculator (GIMiCC): a method of estimating the proportions of eighteen cell types from DNA methylation microarray data.
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