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         headline:Clinically relevant molecular hallmarks of PFA ependymomas display intratumoral heterogeneity and correlate with tumor morphology
         description: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.
         datePublished:2024-01-24T00:00:00Z
         dateModified:2024-01-24T00:00:00Z
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         keywords:
            Ependymoma
            Intratumoral heterogeneity
            1q gain
            6q loss
            Morphology
            DNA methylation
            Pathology
            Neurosciences
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      headline:Clinically relevant molecular hallmarks of PFA ependymomas display intratumoral heterogeneity and correlate with tumor morphology
      description: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.
      datePublished:2024-01-24T00:00:00Z
      dateModified:2024-01-24T00:00:00Z
      pageStart:1
      pageEnd:16
      license:http://creativecommons.org/licenses/by/4.0/
      sameAs:https://doi.org/10.1007/s00401-023-02682-x
      keywords:
         Ependymoma
         Intratumoral heterogeneity
         1q gain
         6q loss
         Morphology
         DNA methylation
         Pathology
         Neurosciences
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      name:Department of Pediatric Hematolgoy and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
      name:Research Institute Children’s Cancer Center, Hamburg-Eppendorf, Hamburg, Germany
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      name:Department of Pediatric Hematolgoy and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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      name:Research Institute Children’s Cancer Center, Hamburg-Eppendorf, Hamburg, Germany
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      name:Research Institute Children’s Cancer Center, Hamburg-Eppendorf, Hamburg, Germany
      name:Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, Berlin Institute of Health, Berlin, Germany
      name:Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark
      name:Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
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      name:Research Institute Children’s Cancer Center, Hamburg-Eppendorf, Hamburg, Germany
      name:Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

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