Keck Michaela-Kristina, Al-Hussaini Maysa, Amayiri Nisreen, Yiadom Akosua Adoma Boakye, Chamyan Gabriel, Cheesman Edmund, Faure-Conter Cécile, Garcia-Ariza Miguel, Gauchotte Guillaume, Hasselblatt Martin, Jorgensen Mette, Kilday John-Paul, Lamas Gabriela, Lavarino Cinzia, Li Marilyn M, Lubieniecki Fabiana, Maher Ossama M, Meyronet David, Mueller Jan, Santi Mariarita, Schüller Ulrich, Seidinger Ana Luiza, Sill Martin, Sudhakar Sniya, García María Tallón, Tauziede-Espariat Arnault, Varlet Pascale, Vasiljevic Alexandre, Wittmann Andrea, von Deimling Andreas, Solomon David A, Sahm Felix, Tietze Anna, von Hoff Katja, Sievers Philipp, Jones David T W
Division of Pediatric Glioma Research, Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany.
Acta Neuropathol. 2025 Aug 2;150(1):12. doi: 10.1007/s00401-025-02917-z.
CNS embryonal tumors with PLAGL amplification (ET, PLAGL) are a recently described tumor type marked by amplification of one of the PLAG family genes, PLAGL1 or PLAGL2. Separately, a supratentorial, ependymoma-like CNS tumor type with PLAG family alteration, namely PLAGL1 fusion, was also reported (NET_PLAGL1). Here, we use DNA methylation profiling in combination with copy number, RNA-seq, and histological analysis to characterize and classify a novel group of CNS embryonal tumors harboring PLAG1 gene fusions (n=12). Through our screening, we identified a subset of CNS tumors (n=12) epigenetically distinct from other known CNS tumor types, but clustering close to the PLAGL1- and PLAGL2-amplified ET, PLAGL subtypes in our t-SNE analysis. Copy number profiles indicated putative PLAG1 fusions, which were confirmed in 9/12 tumors (not determined in 3/12). Different 5' fusion partners (ASAP1, ADGRG1, TMEM68, TCF4, CHD7, NCALD, HNRNPK, LOC105378102) were identified that upregulate wild-type PLAG1 through promoter hijacking. Expression analysis shows upregulation of PLAG1 as well as IGF2, DLK1, Desmin, CYP2W1, and RET, which are also robustly expressed in PLAGL1/2-amplified tumors. Patient characteristics, survival data, and clinical/imaging analysis show additional similarities to PLAGL1/2-amplified tumors. Median age at diagnosis was 5 years, tumors were located throughout the neuroaxis, and original histological diagnoses were heterogeneous. The tumors demonstrated morphologic heterogeneity, with most composed of densely cellular areas of primitive small blue cells, alongside focal regions showing clear cell morphology, microcystic changes, and ependymoma-like perivascular pseudorosettes. Applied treatment regimens were also heterogeneous, but some favorable responses to therapy were observed. In summary, we describe a third subtype of PLAG family-altered pediatric CNS embryonal tumor characterized by PLAG1 gene fusion, which leads to upregulation of PLAG1 and downstream genes. We therefore propose to rename ET, PLAGL to ET, PLAG (CNS embryonal tumor with PLAG family gene alteration) together with a specification of the respective subtype.
伴有PLAGL扩增的中枢神经系统胚胎性肿瘤（ET，PLAGL）是一种最近描述的肿瘤类型，其特征是PLAG家族基因之一PLAGL1或PLAGL2的扩增。另外，还报道了一种伴有PLAG家族改变（即PLAGL1融合）的幕上室管膜瘤样中枢神经系统肿瘤类型（NET_PLAGL1）。在此，我们结合DNA甲基化分析、拷贝数分析、RNA测序和组织学分析，对一组新的携带PLAG1基因融合的中枢神经系统胚胎性肿瘤（n = 12）进行特征描述和分类。通过筛查，我们鉴定出一组中枢神经系统肿瘤（n = 12），其表观遗传学特征与其他已知的中枢神经系统肿瘤类型不同，但在我们的t-SNE分析中，它们与PLAGL1和PLAGL2扩增的ET、PLAGL亚型聚类较近。拷贝数分析显示存在假定的PLAG1融合，在12例肿瘤中有9例得到证实（12例中有3例未确定）。鉴定出不同的5'融合伴侣（ASAP1、ADGRG1、TMEM68、TCF4、CHD7、NCALD、HNRNPK、LOC105378102），它们通过启动子劫持上调野生型PLAG1。表达分析显示PLAG1以及IGF2、DLK1、结蛋白、CYP2W1和RET上调，这些基因在PLAGL1/2扩增的肿瘤中也大量表达。患者特征、生存数据以及临床/影像学分析显示与PLAGL1/2扩增的肿瘤还有其他相似之处。诊断时的中位年龄为5岁，肿瘤遍布神经轴，最初的组织学诊断各不相同。这些肿瘤表现出形态学异质性，大多数由原始小蓝细胞的密集细胞区组成，同时局部区域显示透明细胞形态、微囊性改变和室管膜瘤样血管周围假菊形团。应用的治疗方案也各不相同，但观察到一些对治疗的良好反应。总之，我们描述了一种伴有PLAG家族改变的儿童中枢神经系统胚胎性肿瘤的第三种亚型，其特征为PLAG1基因融合，导致PLAG1及其下游基因上调。因此，我们建议将ET，PLAGL重新命名为ET，PLAG（伴有PLAG家族基因改变的中枢神经系统胚胎性肿瘤），并对各自的亚型进行具体说明。
