Department of Pathology, Xuanwu Hospital, Capital Medical University, Beijing, China.
Department of Neuropathology, University Hospital Erlangen, Erlangen, Germany.
Brain Pathol. 2022 Jan;32(1):e13011. doi: 10.1111/bpa.13011. Epub 2021 Aug 5.
The BRAF p.V600E mutation is the most common genetic alteration in ganglioglioma (GG). Herein, we collected a consecutive series of 30 GG specimens from Xuanwu Hospital in order to corroborate the genetic landscape and genotype-phenotype correlation of this enigmatic and often difficult-to-classify epilepsy-associated brain tumor entity. All specimens with histopathologically confirmed lesions were submitted to targeted next-generation sequencing using a panel of 131 genes. Genetic alterations in three cases with histologically distinct tumor components, that is, GG plus pleomorphic xanthoastrocytoma (PXA), dysembryoplastic neuroepithelial tumor (DNT), or an oligodendroglioma (ODG)-like tumor component, were separately studied. A mean post-surgical follow-up time-period of 23 months was available in 24 patients. Seventy seven percent of GG in our series can be explained by genetic alterations, with BRAF p.V600E mutations being most prevalent (n = 20). Three additional cases showed KRAS p.Q22R and KRAS p.G13R, IRS2 copy number gain (CNG) and a KIAA1549-BRAF fusion. When genetically studying different histopathology patterns from the same tumor we identified composite features with BRAF p.V600E plus CDKN2A/B homozygous deletion in a GG with PXA features, IRS2 CNG in a GG with DNT features, and a BRAF p.V600E plus CNG of chromosome 7 in a GG with ODG-like features. Follow-up revealed no malignant tumor progression but nine patients had seizure recurrence. Eight of these nine GG were immunoreactive for CD34, six patients were male, five were BRAF wildtype, and atypical histopathology features were encountered in four patients, that is, ki-67 proliferation index above 5% or with PXA component. Our results strongly point to activation of the MAP kinase pathway in the vast majority of GG and their molecular-genetic differentiation from the cohort of low-grade pediatric type diffuse glioma remains, however, to be further clarified. In addition, histopathologically distinct tumor components accumulated different genetic alterations suggesting collision or composite glio-neuronal GG variants.
BRAF p.V600E 突变是神经节胶质瘤（GG）中最常见的遗传改变。在此，我们收集了宣武医院的 30 例连续 GG 标本，以证实这种神秘且常难以分类的癫痫相关脑肿瘤实体的遗传特征和基因型-表型相关性。所有具有组织病理学证实病变的标本均采用 131 个基因的靶向下一代测序进行检测。对三种具有组织学上明显肿瘤成分的病例（即 GG 加多形性黄色星形细胞瘤（PXA）、发育不良性神经上皮肿瘤（DNT）或少突胶质细胞瘤样肿瘤成分）的遗传改变分别进行了研究。在 24 例患者中，平均术后随访时间为 23 个月。在我们的系列中，77%的 GG 可以用遗传改变来解释，其中 BRAF p.V600E 突变最为常见（n=20）。另外三个病例显示 KRAS p.Q22R 和 KRAS p.G13R、IRS2 拷贝数增益（CNG）和 KIAA1549-BRAF 融合。当对来自同一肿瘤的不同组织病理学模式进行基因研究时，我们发现了具有 BRAF p.V600E 加 CDKN2A/B 纯合缺失的 GG 与 PXA 特征、具有 DNT 特征的 GG 中的 IRS2 CNG 以及具有 ODG 样特征的 GG 中的 BRAF p.V600E 加 7 号染色体 CNG 的复合特征。随访没有发现恶性肿瘤进展，但 9 例患者出现癫痫复发。这 9 例 GG 中有 8 例对 CD34 免疫反应阳性，6 例为男性，5 例为 BRAF 野生型，4 例患者出现非典型组织病理学特征，即 ki-67 增殖指数>5%或有 PXA 成分。我们的结果强烈表明 MAP 激酶通路在绝大多数 GG 中被激活，它们与低级别儿科弥漫性神经胶质瘤队列的分子遗传学分化仍有待进一步阐明。此外，组织学上不同的肿瘤成分积累了不同的遗传改变，提示碰撞或复合神经胶质 GG 变体。
