Shi Zhi-Feng, Li Kay Ka-Wai, Kwan Johnny Sheung-Him, Chung Nellie Yuk-Fei, Wong Sze-Ching, Chu Abby Wai-Yan, Chen Hong, Chan Danny Tat-Ming, Mao Ying, Ng Ho-Keung
Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
Hong Kong and Shanghai Brain Consortium (HSBC), Hong Kong, China.
Brain Pathol. 2025 Mar;35(2):e13300. doi: 10.1111/bpa.13300. Epub 2024 Oct 30.
Hypermutation and malignant transformation are potential complications arising from temozolomide treatment of IDH-mutant gliomas. However, the natural history of IDH-mutant low-grade gliomas without temozolomide treatment is actually under-studied. We retrieved retrospectively from our hospitals paired tumors from 19 patients with IDH-mutant, 1p19q non-codeleted Grade 2 astrocytomas where no interim adjuvant treatment with either temozolomide or radiotherapy was given between primary resections and first recurrences. Tissues from multiple recurrences were available from two patients and radiotherapy but not temozolomide was given before the last specimens were resected. We studied the natural molecular history of these low-grade IDH-mutant astrocytomas without pressure of temozolomide with DNA methylation profiling and copy number variation (CNV) analyses, targeted DNA sequencing, TERTp sequencing, FISH for ALT and selected biomarkers. Recurrences were mostly higher grades (15/19 patients) and characterized by new CNVs not present in the primary tumors (17/19 cases). Few novel mutations were identified in recurrences. Tumors from 17/19 (89.5%) patients showed either CDKN2A homozygous deletion, MYC or PDGFRA focal and non-focal gains at recurrences. There was no case of hypermutation. Phylogenetic trees constructed for tumors for the two patients with multiple recurrences suggested a lack of subclone development in their evolution when under no pressure from temozolomide. In summary, our studies demonstrated, in contrast to the phenomenon of temozolomide-induced hypermutation, IDH-mutant, 1p19q non-codeleted Grade 2 astrocytomas which had not been treated by temozolomide, acquired new CNVs at tumor recurrences. These findings improve our understanding of the molecular life history of IDH-mutant astrocytomas.
高突变率和恶性转化是替莫唑胺治疗异柠檬酸脱氢酶（IDH）突变型胶质瘤的潜在并发症。然而，未接受替莫唑胺治疗的IDH突变型低级别胶质瘤的自然病史实际上研究不足。我们从我院回顾性检索了19例IDH突变、1p19q未缺失的2级星形细胞瘤患者的配对肿瘤，这些患者在初次切除和首次复发之间未接受替莫唑胺或放疗的中期辅助治疗。两名患者有多次复发的组织样本，在切除最后样本之前给予了放疗但未给予替莫唑胺。我们通过DNA甲基化谱分析和拷贝数变异（CNV）分析、靶向DNA测序、TERTp测序、端粒酶替代（ALT）荧光原位杂交（FISH）以及选定的生物标志物研究了这些未受替莫唑胺影响的低级别IDH突变型星形细胞瘤的自然分子病史。复发大多为高级别（15/19例患者），其特征是原发性肿瘤中不存在的新CNV（17/19例）。复发时几乎未发现新的突变。17/19（89.5%）例患者的肿瘤在复发时显示CDKN2A纯合缺失、MYC或血小板衍生生长因子受体α（PDGFRA）局灶性和非局灶性扩增。没有高突变率的病例。为两名有多次复发的患者的肿瘤构建的系统发育树表明，在没有替莫唑胺压力的情况下，它们在进化过程中缺乏亚克隆发展。总之，我们的研究表明，与替莫唑胺诱导的高突变现象相反，未接受替莫唑胺治疗的IDH突变、1p19q未缺失的2级星形细胞瘤在肿瘤复发时获得了新的CNV。这些发现提高了我们对IDH突变型星形细胞瘤分子生命史的理解。
