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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 (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.01). Clinically, cell density was associated with poor progression-free and overall survival (\n                    <jats:italic>p<\/jats:italic>\n                    <jats:sub>PFS<\/jats:sub>\n                    \u2009=\u20090.0026,\n                    <jats:italic>p<\/jats:italic>\n                    <jats:sub>OS<\/jats:sub>\n                    \u2009&lt;\u20090.01). 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 (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.036), 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.\n                  <\/jats:p>","DOI":"10.1007\/s00401-023-02682-x","type":"journal-article","created":{"date-parts":[[2024,1,24]],"date-time":"2024-01-24T11:02:34Z","timestamp":1706094154000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Clinically relevant molecular hallmarks of PFA ependymomas display intratumoral heterogeneity and correlate with tumor morphology"],"prefix":"10.1007","volume":"147","author":[{"given":"Swenja","family":"G\u00f6dicke","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catena","family":"Kresbach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max","family":"Ehlert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"Obrecht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lea","family":"Altendorf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karoline","family":"Hack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"von Hoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Car\u00e9n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viktoria","family":"Melcher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kornelius","family":"Kerl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard","family":"Englinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariella","family":"Filbin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristian W.","family":"Pajtler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Gojo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torsten","family":"Pietsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Rutkowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8731-1121","authenticated-orcid":false,"given":"Ulrich","family":"Sch\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,1,24]]},"reference":[{"issue":"11","key":"2682_CR1","doi-asserted-by":"publisher","first-page":"e31323","DOI":"10.7759\/cureus.31323","volume":"14","author":"KM Aguilar-Hidalgo","year":"2022","unstructured":"Aguilar-Hidalgo KM, Alvarez-Castro JA, Santell\u00e1n-Hern\u00e1ndez JO, Calder\u00f3n-Garcidue\u00f1as AL, Romero-Luna G, Monjar\u00e1s-Romo G et al (2022) A patient with epilepsy, ganglioglioma, and oligodendroglioma with anaplastic foci in the same left frontoparietal lesion: a case report. 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