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000303359 1001_ $$0P:(DE-He78)9f1196ab1abb80483e1f69e8c0c4172d$$aKeck, Michaela-Kristina$$b0$$eFirst author$$udkfz
000303359 245__ $$aPLAG1 fusions define a third subtype of CNS embryonal tumor with PLAG family gene alteration.
000303359 260__ $$aHeidelberg$$bSpringer$$c2025
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000303359 520__ $$aCNS 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.
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000303359 650_7 $$2Other$$aPLAG1
000303359 650_7 $$2Other$$aPLAG1 fusion
000303359 650_7 $$2Other$$aPLAGL1
000303359 650_7 $$2Other$$aPLAGL2
000303359 650_7 $$2Other$$aEmbryonal CNS tumor
000303359 650_7 $$2NLM Chemicals$$aPLAG1 protein, human
000303359 650_7 $$2NLM Chemicals$$aDNA-Binding Proteins
000303359 650_7 $$2NLM Chemicals$$aTranscription Factors
000303359 650_2 $$2MeSH$$aHumans
000303359 650_2 $$2MeSH$$aDNA-Binding Proteins: genetics
000303359 650_2 $$2MeSH$$aMale
000303359 650_2 $$2MeSH$$aFemale
000303359 650_2 $$2MeSH$$aCentral Nervous System Neoplasms: genetics
000303359 650_2 $$2MeSH$$aCentral Nervous System Neoplasms: pathology
000303359 650_2 $$2MeSH$$aNeoplasms, Germ Cell and Embryonal: genetics
000303359 650_2 $$2MeSH$$aNeoplasms, Germ Cell and Embryonal: pathology
000303359 650_2 $$2MeSH$$aChild
000303359 650_2 $$2MeSH$$aChild, Preschool
000303359 650_2 $$2MeSH$$aTranscription Factors: genetics
000303359 650_2 $$2MeSH$$aAdolescent
000303359 650_2 $$2MeSH$$aGene Fusion
000303359 7001_ $$aAl-Hussaini, Maysa$$b1
000303359 7001_ $$aAmayiri, Nisreen$$b2
000303359 7001_ $$0P:(DE-HGF)0$$aYiadom, Akosua Adoma Boakye$$b3
000303359 7001_ $$aChamyan, Gabriel$$b4
000303359 7001_ $$aCheesman, Edmund$$b5
000303359 7001_ $$aFaure-Conter, Cécile$$b6
000303359 7001_ $$aGarcia-Ariza, Miguel$$b7
000303359 7001_ $$aGauchotte, Guillaume$$b8
000303359 7001_ $$aHasselblatt, Martin$$b9
000303359 7001_ $$aJorgensen, Mette$$b10
000303359 7001_ $$aKilday, John-Paul$$b11
000303359 7001_ $$aLamas, Gabriela$$b12
000303359 7001_ $$aLavarino, Cinzia$$b13
000303359 7001_ $$aLi, Marilyn M$$b14
000303359 7001_ $$aLubieniecki, Fabiana$$b15
000303359 7001_ $$aMaher, Ossama M$$b16
000303359 7001_ $$aMeyronet, David$$b17
000303359 7001_ $$0P:(DE-HGF)0$$aMueller, Jan$$b18
000303359 7001_ $$aSanti, Mariarita$$b19
000303359 7001_ $$aSchüller, Ulrich$$b20
000303359 7001_ $$aSeidinger, Ana Luiza$$b21
000303359 7001_ $$0P:(DE-He78)45440b44791309bd4b7dbb4f73333f9b$$aSill, Martin$$b22$$udkfz
000303359 7001_ $$aSudhakar, Sniya$$b23
000303359 7001_ $$aGarcía, María Tallón$$b24
000303359 7001_ $$aTauziede-Espariat, Arnault$$b25
000303359 7001_ $$aVarlet, Pascale$$b26
000303359 7001_ $$aVasiljevic, Alexandre$$b27
000303359 7001_ $$0P:(DE-He78)adf0bc22f6c87d09ddb939645a7870ed$$aWittmann, Andrea$$b28$$udkfz
000303359 7001_ $$0P:(DE-He78)a8a10626a848d31e70cfd96a133cc144$$avon Deimling, Andreas$$b29$$udkfz
000303359 7001_ $$aSolomon, David A$$b30
000303359 7001_ $$0P:(DE-He78)a1f4b408b9155beb2a8f7cba4d04fe88$$aSahm, Felix$$b31$$udkfz
000303359 7001_ $$aTietze, Anna$$b32
000303359 7001_ $$avon Hoff, Katja$$b33
000303359 7001_ $$0P:(DE-He78)8aad075b17d93a5636a34942bdbd7ee6$$aSievers, Philipp$$b34$$eLast author$$udkfz
000303359 7001_ $$0P:(DE-He78)551bb92841f634070997aa168d818492$$aJones, David$$b35$$eLast author$$udkfz
000303359 773__ $$0PERI:(DE-600)1458410-4$$a10.1007/s00401-025-02917-z$$gVol. 150, no. 1, p. 12$$n1$$p12$$tActa neuropathologica$$v150$$x0001-6322$$y2025
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