Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Republic of Korea.
Department of Neurosurgery, Seoul National University College of Medicine, 101 Daehak-ro Jongno-gu, Seoul, 110-744, Republic of Korea.
BMC Cancer. 2019 Aug 28;19(1):848. doi: 10.1186/s12885-019-6044-z.
Atypical teratoid/rhabdoid tumors (AT/RTs) are highly malignant brain tumors with inactivation of the SMARCB1 gene, which play a critical role in genomic transcriptional control. In this study, we analyzed the genomic and transcriptomic profiles of human AT/RTs to discover new druggable targets.
Multiplanar sequencing analyses, including whole exome sequencing (WES), single nucleotide polymorphism (SNP) arrays, array comparative genomic hybridization (aCGH), and whole transcriptome sequencing (RNA-Seq), were performed on 4 AT/RT tissues. Validation of a druggable target was conducted using AT/RT cell lines.
WES revealed that the AT/RT genome is extremely stable except for the inactivation of SMARCB1. However, we identified 897 significantly upregulated genes and 523 significantly downregulated genes identified using RNA-Seq, indicating that the transcriptional profiles of the AT/RT tissues changed substantially. Gene set enrichment assays revealed genes related to the canonical pathways of cancers, and nucleophosmin (NPM1) was the most significantly upregulated gene in the AT/RT samples. An NPM1 inhibitor (NSC348884) effectively suppressed the viability of 7 AT/RT cell lines. Network analyses showed that genes associated with NPM1 are mainly involved in cell cycle regulation. Upon treatment with an NPM1 inhibitor, cell cycle arrest at G1 phase was observed in AT/RT cells.
We propose that NPM1 is a novel therapeutic target for AT/RTs.
非典型畸胎样/横纹肌样肿瘤（AT/RTs）是一种高度恶性的脑瘤，其特征是 SMARCB1 基因失活，该基因在基因组转录控制中起着关键作用。在这项研究中，我们分析了人类 AT/RTs 的基因组和转录组谱，以发现新的可药物治疗靶点。
对 4 例 AT/RT 组织进行了多平面测序分析，包括全外显子测序（WES）、单核苷酸多态性（SNP）芯片、阵列比较基因组杂交（aCGH）和全转录组测序（RNA-Seq）。使用 AT/RT 细胞系验证了一个可药物治疗的靶点。
WES 显示，除了 SMARCB1 的失活外，AT/RT 基因组非常稳定。然而，我们使用 RNA-Seq 鉴定了 897 个显著上调的基因和 523 个显著下调的基因，这表明 AT/RT 组织的转录谱发生了显著变化。基因集富集分析显示了与癌症经典途径相关的基因，核磷蛋白（NPM1）是 AT/RT 样本中上调最显著的基因。NPM1 抑制剂（NSC348884）有效地抑制了 7 种 AT/RT 细胞系的活力。网络分析表明，与 NPM1 相关的基因主要参与细胞周期调控。用 NPM1 抑制剂处理后，AT/RT 细胞出现 G1 期细胞周期停滞。
我们提出 NPM1 是 AT/RTs 的一个新的治疗靶点。
