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000182802 1001_ $$0P:(DE-He78)9f1196ab1abb80483e1f69e8c0c4172d$$aKeck, Michaela-Kristina$$b0$$eFirst author$$udkfz
000182802 245__ $$aAmplification of the PLAG-family genes-PLAGL1 and PLAGL2-is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification.
000182802 260__ $$aHeidelberg$$bSpringer$$c2023
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000182802 500__ $$a#EA:B360#LA:B360# / 2023 Jan;145(1):49-69
000182802 520__ $$aPediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0-14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type. In addition, we report histology, patient characteristics, and survival data in this tumor type. We describe a biologically distinct pediatric CNS tumor type (n = 31 cases) that is characterized by focal high-level amplification and resultant overexpression of either PLAGL1 or PLAGL2, and an absence of recurrent genetic alterations characteristic of other pediatric CNS tumor types. Both genes act as transcription factors for a regulatory subset of imprinted genes (IGs), components of the Wnt/β-Catenin pathway, and the potential drug targets RET and CYP2W1, which are also specifically overexpressed in this tumor type. A derived PLAGL-specific gene expression signature indicates dysregulation of imprinting control and differentiation/development. These tumors occurred throughout the neuroaxis including the cerebral hemispheres, cerebellum, and brainstem, and were predominantly composed of primitive embryonal-like cells lacking robust expression of markers of glial or neuronal differentiation (e.g., GFAP, OLIG2, and synaptophysin). Tumors with PLAGL1 amplification were typically diagnosed during adolescence (median age 10.5 years), whereas those with PLAGL2 amplification were diagnosed during early childhood (median age 2 years). The 10-year overall survival was 66% for PLAGL1-amplified tumors, 25% for PLAGL2-amplified tumors, 18% for male patients, and 82% for female patients. In summary, we describe a new type of biologically distinct CNS tumor characterized by PLAGL1/2 amplification that occurs predominantly in infants and toddlers (PLAGL2) or adolescents (PLAGL1) which we consider best classified as a CNS embryonal tumor and which is associated with intermediate survival. The cell of origin and optimal treatment strategies remain to be defined.
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000182802 650_7 $$2Other$$aMolecular neuro-oncology
000182802 650_7 $$2Other$$aPLAGL1
000182802 650_7 $$2Other$$aPLAGL2
000182802 650_7 $$2Other$$aPediatric cancer
000182802 7001_ $$0P:(DE-He78)45440b44791309bd4b7dbb4f73333f9b$$aSill, Martin$$b1$$udkfz
000182802 7001_ $$0P:(DE-He78)adf0bc22f6c87d09ddb939645a7870ed$$aWittmann, Andrea$$b2$$udkfz
000182802 7001_ $$0P:(DE-He78)ee036c22158d4b18f5228616af640355$$aJoshi, Piyush$$b3$$udkfz
000182802 7001_ $$0P:(DE-He78)d20d08adc992abdb6ccffa1686f1ba17$$aStichel, Damian$$b4
000182802 7001_ $$0P:(DE-He78)b8f2b74d0482aed61472c7065dc1ed56$$aBeck, Pengbo$$b5$$udkfz
000182802 7001_ $$0P:(DE-HGF)0$$aOkonechnikow, Konstantin$$b6
000182802 7001_ $$0P:(DE-He78)8aad075b17d93a5636a34942bdbd7ee6$$aSievers, Philipp$$b7$$udkfz
000182802 7001_ $$aWefers, Annika K$$b8
000182802 7001_ $$aRoncaroli, Federico$$b9
000182802 7001_ $$aAvula, Shivaram$$b10
000182802 7001_ $$aMcCabe, Martin G$$b11
000182802 7001_ $$aHayden, James T$$b12
000182802 7001_ $$aWesseling, Pieter$$b13
000182802 7001_ $$aØra, Ingrid$$b14
000182802 7001_ $$aNistér, Monica$$b15
000182802 7001_ $$aKranendonk, Mariëtte E G$$b16
000182802 7001_ $$aTops, Bastiaan B J$$b17
000182802 7001_ $$aZapotocky, Michal$$b18
000182802 7001_ $$aZamecnik, Josef$$b19
000182802 7001_ $$aVasiljevic, Alexandre$$b20
000182802 7001_ $$aFenouil, Tanguy$$b21
000182802 7001_ $$aMeyronet, David$$b22
000182802 7001_ $$avon Hoff, Katja$$b23
000182802 7001_ $$aSchüller, Ulrich$$b24
000182802 7001_ $$aLoiseau, Hugues$$b25
000182802 7001_ $$aFigarella-Branger, Dominique$$b26
000182802 7001_ $$aKramm, Christof M$$b27
000182802 7001_ $$0P:(DE-He78)a46a5b2a871859c8e2d63d2f8c666807$$aSturm, Dominik$$b28$$udkfz
000182802 7001_ $$aScheie, David$$b29
000182802 7001_ $$aRauramaa, Tuomas$$b30
000182802 7001_ $$aPesola, Jouni$$b31
000182802 7001_ $$aGojo, Johannes$$b32
000182802 7001_ $$aHaberler, Christine$$b33
000182802 7001_ $$aBrandner, Sebastian$$b34
000182802 7001_ $$aJacques, Tom$$b35
000182802 7001_ $$aSexton Oates, Alexandra$$b36
000182802 7001_ $$aSaffery, Richard$$b37
000182802 7001_ $$aKoscielniak, Ewa$$b38
000182802 7001_ $$aBaker, Suzanne J$$b39
000182802 7001_ $$aYip, Stephen$$b40
000182802 7001_ $$aSnuderl, Matija$$b41
000182802 7001_ $$aUd Din, Nasir$$b42
000182802 7001_ $$aSamuel, David$$b43
000182802 7001_ $$0P:(DE-He78)2f592d9d8339bee07cca3956b7472b61$$aSchramm, Kathrin$$b44$$udkfz
000182802 7001_ $$0P:(DE-He78)261d2b84aded878003e6e35d18113831$$aBlattner-Johnson, Mirjam$$b45$$udkfz
000182802 7001_ $$0P:(DE-He78)a23e88cc676489fe05be8c178ceaf58e$$aSelt, Florian$$b46$$udkfz
000182802 7001_ $$0P:(DE-He78)3de637452ba900e2bdd359b8f41953bf$$aEcker, Jonas$$b47$$udkfz
000182802 7001_ $$0P:(DE-He78)0be2f86573954f87e97f8a4dbb05cb0f$$aMilde, Till$$b48$$udkfz
000182802 7001_ $$0P:(DE-He78)a8a10626a848d31e70cfd96a133cc144$$avon Deimling, Andreas$$b49$$udkfz
000182802 7001_ $$0P:(DE-He78)8d9c904a6cea14d4c99c78ba46e41f93$$aKorshunov, Andrey$$b50$$udkfz
000182802 7001_ $$aPerry, Arie$$b51
000182802 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan M$$b52$$udkfz
000182802 7001_ $$0P:(DE-He78)a1f4b408b9155beb2a8f7cba4d04fe88$$aSahm, Felix$$b53$$udkfz
000182802 7001_ $$aSolomon, David A$$b54
000182802 7001_ $$0P:(DE-He78)551bb92841f634070997aa168d818492$$aJones, David$$b55$$eLast author$$udkfz
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