Sievers Philipp, Sill Martin, Schrimpf Daniel, Abdullaev Zied, Donson Andrew M, Lake Jessica A, Friedel Dennis, Scheie David, Tynninen Olli, Rauramaa Tuomas, Vepsäläinen Kaisa L, Samuel David, Chapman Rebecca, Grundy Richard G, Pajtler Kristian W, Tauziède-Espariat Arnault, Métais Alice, Varlet Pascale, Snuderl Matija, Jacques Thomas S, Aldape Kenneth, Reuss David E, Korshunov Andrey, Wick Wolfgang, Pfister Stefan M, von Deimling Andreas, Sahm Felix, Jones David T W
Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
NPJ Precis Oncol. 2023 Mar 24;7(1):30. doi: 10.1038/s41698-023-00372-1.
Pediatric neoplasms in the central nervous system (CNS) show extensive clinical and molecular heterogeneity and are fundamentally different from those occurring in adults. Molecular genetic testing contributes to accurate diagnosis and enables an optimal clinical management of affected children. Here, we investigated a rare, molecularly distinct type of pediatric high-grade neuroepithelial tumor (n = 18), that was identified through unsupervised visualization of genome-wide DNA methylation array data, together with copy number profiling, targeted next-generation DNA sequencing, and RNA transcriptome sequencing. DNA and/or RNA sequencing revealed recurrent fusions involving the capicua transcriptional repressor (CIC) gene in 10/10 tumor samples analyzed, with the most common fusion being CIC::LEUTX (n = 9). In addition, a CIC::NUTM1 fusion was detected in one of the tumors. Apart from the detected fusion events, no additional oncogenic alteration was identified in these tumors. The histopathological review demonstrated a morphologically heterogeneous group of high-grade neuroepithelial tumors with positive immunostaining for markers of glial differentiation in combination with weak and focal expression of synaptophysin, CD56 and CD99. All tumors were located in the supratentorial compartment, occurred during childhood (median age 8.5 years) and typically showed early relapses. In summary, we expand the spectrum of pediatric-type tumors of the CNS by reporting a previously uncharacterized group of rare high-grade neuroepithelial tumors that share a common DNA methylation signature and recurrent gene fusions involving the transcriptional repressor CIC. Downstream functional consequences of the fusion protein CIC::LEUTX and potential therapeutic implications need to be further investigated.
中枢神经系统（CNS）中的小儿肿瘤表现出广泛的临床和分子异质性，与成人发生的肿瘤有根本区别。分子基因检测有助于准确诊断，并能对患病儿童进行最佳临床管理。在此，我们研究了一种罕见的、分子特征独特的小儿高级别神经上皮肿瘤（n = 18），该肿瘤是通过对全基因组DNA甲基化阵列数据进行无监督可视化分析，同时结合拷贝数分析、靶向二代DNA测序和RNA转录组测序确定的。DNA和/或RNA测序显示，在分析的10/10个肿瘤样本中存在涉及capicua转录抑制因子（CIC）基因的复发性融合，最常见的融合是CIC::LEUTX（n = 9）。此外，在其中一个肿瘤中检测到CIC::NUTM1融合。除了检测到的融合事件外，在这些肿瘤中未发现其他致癌改变。组织病理学检查显示，这是一组形态学上异质性的高级别神经上皮肿瘤，胶质分化标志物免疫染色呈阳性，同时突触素、CD56和CD99呈弱阳性和局灶性表达。所有肿瘤均位于幕上腔，发生于儿童期（中位年龄8.5岁），通常表现为早期复发。总之，我们通过报告一组以前未被描述的罕见高级别神经上皮肿瘤，扩大了中枢神经系统小儿型肿瘤的范围，这些肿瘤具有共同的DNA甲基化特征和涉及转录抑制因子CIC的复发性基因融合。融合蛋白CIC::LEUTX的下游功能后果和潜在治疗意义需要进一步研究。
