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Clinically relevant...
Clinically relevant molecular hallmarks of PFA ependymomas display intratumoral heterogeneity and correlate with tumor morphology
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Goedicke, Swenja (author)
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Kresbach, Catena (author)
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Ehlert, Max (author)
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Obrecht, Denise (author)
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Altendorf, Lea (author)
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Hack, Karoline (author)
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von Hoff, Katja (author)
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- Carén, Helena, 1979 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för laboratoriemedicin,Department of Laboratory Medicine
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Melcher, Viktoria (author)
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Kerl, Kornelius (author)
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Englinger, Bernhard (author)
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Filbin, Mariella (author)
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Pajtler, Kristian W. (author)
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Gojo, Johannes (author)
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Pietsch, Torsten (author)
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Rutkowski, Stefan (author)
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Schueller, Ulrich (author)
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(creator_code:org_t)
- 2024
- 2024
- English.
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In: ACTA NEUROPATHOLOGICA. - 0001-6322 .- 1432-0533. ; 147:1
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https://gup.ub.gu.se...
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https://doi.org/10.1...
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Abstract
Subject headings
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- Posterior 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Keyword
- Ependymoma
- Intratumoral heterogeneity
- 1q gain
- 6q loss
- Morphology
- DNA methylation
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Goedicke, Swenja
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Kresbach, Catena
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Ehlert, Max
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Obrecht, Denise
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Altendorf, Lea
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Hack, Karoline
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show more...
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von Hoff, Katja
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Carén, Helena, 1 ...
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Melcher, Viktori ...
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Kerl, Kornelius
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Englinger, Bernh ...
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Filbin, Mariella
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Pajtler, Kristia ...
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Gojo, Johannes
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Pietsch, Torsten
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Rutkowski, Stefa ...
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Schueller, Ulric ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Neurosciences
- Articles in the publication
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ACTA NEUROPATHOL ...
- By the university
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University of Gothenburg