Gliomas arising in the setting of neurofibromatosis type 1 (NF1) are heterogeneous, occurring from childhood through adulthood, can be histologically low-grade or high-grade, and follow an indolent or aggressive clinical course. Comprehensive profiling of genetic alterations beyond NF1 inactivation and epigenetic classification of these tumors remain limited. Through next-generation sequencing, copy number analysis, and DNA methylation profiling of gliomas from 47 NF1 patients, we identified 2 molecular subgroups of NF1-associated gliomas. The first harbored biallelic NF1 inactivation only, occurred primarily during childhood, followed a more indolent clinical course, and had a unique epigenetic signature for which we propose the terminology “pilocytic astrocytoma, arising in the setting of NF1”. The second subgroup harbored additional oncogenic alterations including CDKN2A homozygous deletion and ATRX mutation, occurred primarily during adulthood, followed a more aggressive clinical course, and was epigenetically diverse, with most tumors aligning with either high-grade astrocytoma with piloid features or various subclasses of IDH-wildtype glioblastoma. Several patients were treated with small molecule MEK inhibitors that resulted in stable disease or tumor regression when used as a single agent, but only in the context of those tumors with NF1 inactivation lacking additional oncogenic alterations. Together, these findings highlight recurrently altered pathways in NF1-associated gliomas and help inform targeted therapeutic strategies for this patient population.

1 型神经纤维瘤病 (NF1) 中产生的胶质瘤具有异质性，从儿童期到成年期均可发生，组织学上可以是低级别或高级别，并遵循惰性或侵袭性临床过程。除了NF1失活和这些肿瘤的表观遗传分类之外，对遗传改变的全面分析仍然有限。通过对 47 名 NF1 患者的神经胶质瘤进行新一代测序、拷贝数分析和 DNA 甲基化分析，我们确定了 NF1 相关神经胶质瘤的 2 个分子亚组。第一个仅存在双等位基因NF1失活，主要发生在儿童时期，遵循更惰性的临床过程，并具有独特的表观遗传特征，我们提出术语“毛细胞星形细胞瘤，在 NF1 背景下出现”。第二个亚组具有额外的致癌改变，包括CDKN2A纯合性缺失和ATRX突变，主要发生在成年期，遵循更具侵袭性的临床过程，并且具有表观遗传多样性，大多数肿瘤与具有毛状特征的高级星形细胞瘤或 IDH 的各种亚类一致-野生型胶质母细胞瘤。几名患者接受了小分子 MEK 抑制剂治疗，当作为单一药物使用时，这些抑制剂导致疾病稳定或肿瘤消退，但仅限于NF1失活且缺乏额外致癌改变的肿瘤。总之，这些发现强调了 NF1 相关神经胶质瘤中反复改变的通路，并有助于为该患者群体制定针对性的治疗策略。