Honma Hirokuni, Tateishi Kensuke, Iwashita Hiromichi, Miyake Yohei, Tsujimoto Shinichi, Hayashi Hiroaki, Ohgaki Fukutaro, Nakano Yoshiko, Ichimura Koichi, Yamanaka Shoji, Kato Motohiro, Fujii Satoshi, Ito Shuichi, Yokoo Hideaki, Yamamoto Tetsuya
Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa, Yokohama, 2360004, Japan.
Neurosurgical-Oncology Laboratory, Yokohama City University, Yokohama, Japan.
Brain Tumor Pathol. 2025 Jan;42(1):12-20. doi: 10.1007/s10014-024-00495-8. Epub 2024 Nov 10.
Primary intracranial sarcoma (PIS) is a rare and aggressive pediatric brain tumor, which is partially associated with DICER1 mutant. Although the molecular genetic characteristics of this tumor have previously been investigated, novel therapeutic targets remain unclear. Further, the lack of faithful preclinical models has hampered the development of novel therapeutic strategies. Herein, we describe a pediatric case of PIS with DICER1 mutant and describe the development of the first novel patient-derived xenograft (PDX) model of this rare tumor. Somatic genomic profiling of the tumor revealed mutations in DICER1, TP53, and ATRX. Germline analysis further revealed a pathogenic variant of DICER1, significant for the diagnosis and management of hereditary tumor predisposition syndrome. Overall, we demonstrated that the PDX model faithfully retained the phenotype and genotype of the patient's tumor, as well as the DNA methylation profile. Through high-throughput drug screening using PDX tumor cells, we found that activation of the retinoic acid receptor (RAR) signaling pathway reduced tumor cell viability. These findings indicate that the RAR signaling pathway is a potential therapeutic target for PIS in DICER1 mutant.
原发性颅内肉瘤（PIS）是一种罕见且侵袭性强的儿童脑肿瘤，部分与DICER1突变有关。尽管此前已对该肿瘤的分子遗传学特征进行了研究，但新的治疗靶点仍不明确。此外，缺乏可靠的临床前模型阻碍了新治疗策略的开发。在此，我们描述了一例患有DICER1突变的儿童PIS病例，并介绍了这种罕见肿瘤首个新的患者来源异种移植（PDX）模型的建立。对肿瘤进行的体细胞基因组分析揭示了DICER1、TP53和ATRX的突变。种系分析进一步揭示了DICER1的一个致病变体，这对遗传性肿瘤易感性综合征的诊断和管理具有重要意义。总体而言，我们证明PDX模型忠实地保留了患者肿瘤的表型、基因型以及DNA甲基化谱。通过使用PDX肿瘤细胞进行高通量药物筛选，我们发现视黄酸受体（RAR）信号通路的激活降低了肿瘤细胞活力。这些发现表明，RAR信号通路是DICER1突变型PIS的一个潜在治疗靶点。
