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000287281 1001_ $$aGödicke, Swenja$$b0
000287281 245__ $$aClinically relevant molecular hallmarks of PFA ependymomas display intratumoral heterogeneity and correlate with tumor morphology.
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000287281 520__ $$aPosterior fossa type A (PF-EPN-A, PFA) ependymoma are aggressive tumors that mainly affect children and have a poor prognosis. Histopathology shows significant intratumoral heterogeneity, ranging from loose tissue to often sharply demarcated, extremely cell-dense tumor areas. To determine molecular differences in morphologically different areas and to understand their clinical significance, we analyzed 113 PF-EPN-A samples, including 40 corresponding relapse samples. Cell-dense areas ranged from 0 to 100% of the tumor area and displayed a higher proportion of proliferating tumor cells (p < 0.01). Clinically, cell density was associated with poor progression-free and overall survival (pPFS = 0.0026, pOS < 0.01). Molecularly, tumor areas with low and high cell density showed diverging DNA methylation profiles regarding their similarity to distinct previously discovered PF-EPN-A subtypes in 9/21 cases. Prognostically relevant chromosomal changes at 1q and 6q showed spatial heterogeneity within single tumors and were significantly enriched in cell-dense tumor areas as shown by single-cell RNA (scRNA)-sequencing as well as copy number profiling and fluorescence in situ hybridization (FISH) analyses of different tumor areas. Finally, spatial transcriptomics revealed cell-dense areas of different tumors to be more similar than various different areas of the same tumor. High-density areas distinctly overexpressed genes encoding histone proteins, WNT5A, TGFB1, or IGF2. Relapsing tumors displayed a higher proportion of cell-dense areas (p = 0.036), a change in PF-EPN-A methylation subtypes (13/32 patients), and novel chromosome 1q gains and 6q losses (12/32 cases) compared to corresponding primary tumors. Our data suggest that PF-EPN-A ependymomas habor a previously unrecognized intratumoral heterogeneity with clinical implications, which has to be accounted for when selecting diagnostic material, inter alia, by histological evaluation of the proportion of cell-dense areas.
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000287281 650_7 $$2Other$$a1q gain
000287281 650_7 $$2Other$$a6q loss
000287281 650_7 $$2Other$$aDNA methylation
000287281 650_7 $$2Other$$aEpendymoma
000287281 650_7 $$2Other$$aIntratumoral heterogeneity
000287281 650_7 $$2Other$$aMorphology
000287281 650_7 $$2NLM Chemicals$$aHistones
000287281 650_2 $$2MeSH$$aChild
000287281 650_2 $$2MeSH$$aHumans
000287281 650_2 $$2MeSH$$aIn Situ Hybridization, Fluorescence
000287281 650_2 $$2MeSH$$aNeoplasm Recurrence, Local
000287281 650_2 $$2MeSH$$aEpendymoma
000287281 650_2 $$2MeSH$$aHistones
000287281 650_2 $$2MeSH$$aGene Expression Profiling
000287281 7001_ $$aKresbach, Catena$$b1
000287281 7001_ $$aEhlert, Max$$b2
000287281 7001_ $$aObrecht, Denise$$b3
000287281 7001_ $$aAltendorf, Lea$$b4
000287281 7001_ $$aHack, Karoline$$b5
000287281 7001_ $$avon Hoff, Katja$$b6
000287281 7001_ $$aCarén, Helena$$b7
000287281 7001_ $$aMelcher, Viktoria$$b8
000287281 7001_ $$aKerl, Kornelius$$b9
000287281 7001_ $$aEnglinger, Bernhard$$b10
000287281 7001_ $$aFilbin, Mariella$$b11
000287281 7001_ $$0P:(DE-He78)a7c1bbac024fa232d9c6b78443328d9d$$aPajtler, Kristian W$$b12$$udkfz
000287281 7001_ $$aGojo, Johannes$$b13
000287281 7001_ $$aPietsch, Torsten$$b14
000287281 7001_ $$aRutkowski, Stefan$$b15
000287281 7001_ $$00000-0002-8731-1121$$aSchüller, Ulrich$$b16
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