Lucas Calixto-Hope G, Al-Adli Nadeem N, Young Jacob S, Gupta Rohit, Morshed Ramin A, Wu Jasper, Ravindranathan Ajay, Shai Anny, Oberheim Bush Nancy Ann, Taylor Jennie W, de Groot John, Villanueva-Meyer Javier E, Pekmezci Melike, Perry Arie, Bollen Andrew W, Theodosopoulos Philip V, Aghi Manish K, Chang Edward F, Hervey-Jumper Shawn L, Raleigh David R, Molinaro Annette M, Costello Joseph F, Diaz Aaron A, Clarke Jennifer L, Butowski Nicholas A, Phillips Joanna J, Chang Susan M, Berger Mitchel S, Solomon David A
UCSF Brain Tumor Center, University of California, San Francisco, California, USA.
Department of Pathology, University of California, San Francisco, California, USA.
Neuro Oncol. 2025 Jan 12;27(1):89-105. doi: 10.1093/neuonc/noae214.
Despite recent advances in the biology of IDH-wildtype glioblastoma, it remains a devastating disease with median survival of less than 2 years. However, the molecular underpinnings of the heterogeneous response to the current standard-of-care treatment regimen consisting of maximal safe resection, adjuvant radiation, and chemotherapy with temozolomide remain unknown.
Comprehensive histopathologic, genomic, and epigenomic evaluation of paired initial and recurrent glioblastoma specimens from 106 patients was performed to investigate the molecular evolution and cellular phenotypes underlying differential treatment responses.
While TERT promoter mutation and CDKN2A homozygous deletion were early events during gliomagenesis shared by initial and recurrent tumors, most other recurrent genetic alterations (eg, EGFR, PTEN, and NF1) were commonly private to initial or recurrent tumors indicating acquisition later during clonal evolution. Furthermore, glioblastomas exhibited heterogeneous epigenomic evolution with subsets becoming more globally hypermethylated, hypomethylated, or remaining stable. Glioblastoma that underwent sarcomatous transformation had shorter interval to recurrence and were significantly enriched in NF1, TP53, and RB1 alterations and the mesenchymal epigenetic class. Patients who developed somatic hypermutation following temozolomide treatment had significantly longer interval to disease recurrence and prolonged overall survival, and increased methylation at 4 specific CpG sites in the promoter region of MGMT was significantly associated with this development of hypermutation. Finally, an epigenomic evolution signature incorporating change in DNA methylation levels across 347 critical CpG sites was developed that significantly correlated with clinical outcomes.
Glioblastoma undergoes heterogeneous genetic, epigenetic, and cellular evolution that underlies prognostically different treatment responses.
尽管异柠檬酸脱氢酶（IDH）野生型胶质母细胞瘤的生物学研究最近取得了进展，但它仍然是一种毁灭性疾病，中位生存期不到2年。然而，对于由最大安全切除、辅助放疗和替莫唑胺化疗组成的当前标准治疗方案的异质性反应的分子基础仍然未知。
对106例患者的配对初始和复发性胶质母细胞瘤标本进行了全面的组织病理学、基因组和表观基因组评估，以研究差异治疗反应背后的分子进化和细胞表型。
虽然端粒酶逆转录酶（TERT）启动子突变和细胞周期蛋白依赖性激酶抑制剂2A（CDKN2A）纯合缺失是初始和复发性肿瘤在胶质瘤发生过程中的早期事件，但大多数其他复发性基因改变（如表皮生长因子受体（EGFR）、磷酸酶和张力蛋白同源物（PTEN）和神经纤维瘤病1型（NF1））通常是初始或复发性肿瘤特有的，表明是在克隆进化后期获得的。此外，胶质母细胞瘤表现出异质性的表观基因组进化，亚组变得更普遍地高甲基化、低甲基化或保持稳定。发生肉瘤样转化的胶质母细胞瘤复发间隔较短，并且在NF1、TP53和视网膜母细胞瘤1（RB1）改变以及间充质表观遗传类别中显著富集。替莫唑胺治疗后发生体细胞超突变的患者疾病复发间隔显著更长，总生存期延长，并且在O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）启动子区域的4个特定CpG位点的甲基化增加与这种超突变的发生显著相关。最后，开发了一种表观基因组进化特征，其纳入了347个关键CpG位点的DNA甲基化水平变化，该特征与临床结果显著相关。
胶质母细胞瘤经历异质性的遗传、表观遗传和细胞进化，这是预后不同的治疗反应的基础。
