PMID- 38265527 OWN - NLM STAT- MEDLINE DCOM- 20240125 LR - 20240204 IS - 1432-0533 (Electronic) IS - 0001-6322 (Print) IS - 0001-6322 (Linking) VI - 147 IP - 1 DP - 2024 Jan 24 TI - Clinically relevant molecular hallmarks of PFA ependymomas display intratumoral heterogeneity and correlate with tumor morphology. PG - 23 LID - 10.1007/s00401-023-02682-x [doi] LID - 23 AB - 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 (p(PFS) = 0.0026, p(OS) < 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. CI - (c) 2024. The Author(s). FAU - Godicke, Swenja AU - Godicke S AD - Department of Pediatric Hematolgoy and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. AD - Research Institute Children's Cancer Center, Hamburg-Eppendorf, Hamburg, Germany. FAU - Kresbach, Catena AU - Kresbach C AD - Department of Pediatric Hematolgoy and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. AD - Research Institute Children's Cancer Center, Hamburg-Eppendorf, Hamburg, Germany. AD - Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany. FAU - Ehlert, Max AU - Ehlert M AD - Department of Pediatric Hematolgoy and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. AD - Research Institute Children's Cancer Center, Hamburg-Eppendorf, Hamburg, Germany. FAU - Obrecht, Denise AU - Obrecht D AD - Department of Pediatric Hematolgoy and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. FAU - Altendorf, Lea AU - Altendorf L AD - Department of Pediatric Hematolgoy and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. AD - Research Institute Children's Cancer Center, Hamburg-Eppendorf, Hamburg, Germany. FAU - Hack, Karoline AU - Hack K AD - Department of Pediatric Hematolgoy and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. AD - Research Institute Children's Cancer Center, Hamburg-Eppendorf, Hamburg, Germany. FAU - von Hoff, Katja AU - von Hoff K AD - Department of Pediatric Oncology and Hematology, Charite-Universitatsmedizin Berlin, corporate member of Freie Universitat Berlin, Humboldt-Universitat Zu Berlin, Berlin Institute of Health, Berlin, Germany. AD - Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark. FAU - Caren, Helena AU - Caren H AD - Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Goteborg, Sweden. FAU - Melcher, Viktoria AU - Melcher V AD - Department of Pediatric Hematology and Oncology, University Children's Hospital Munster, 48149, Munster, Germany. FAU - Kerl, Kornelius AU - Kerl K AD - Department of Pediatric Hematology and Oncology, University Children's Hospital Munster, 48149, Munster, Germany. FAU - Englinger, Bernhard AU - Englinger B AD - Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02115, USA. AD - Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA. AD - Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, 1090, Vienna, Austria. AD - Center for Cancer Research and Comprehensive Cancer Center, Medical University Vienna, 1090, Vienna, Austria. FAU - Filbin, Mariella AU - Filbin M AD - Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02115, USA. AD - Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA. FAU - Pajtler, Kristian W AU - Pajtler KW AD - Hopp Children's Cancer Center Heidelberg (KiTZ), 69120, Heidelberg, Germany. AD - Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), 69120, Heidelberg, Germany. AD - Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, 69120, Heidelberg, Germany. FAU - Gojo, Johannes AU - Gojo J AD - Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090, Vienna, Austria. FAU - Pietsch, Torsten AU - Pietsch T AD - Institute of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn Medical Center, Bonn, Germany. FAU - Rutkowski, Stefan AU - Rutkowski S AD - Department of Pediatric Hematolgoy and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. FAU - Schuller, Ulrich AU - Schuller U AUID- ORCID: 0000-0002-8731-1121 AD - Department of Pediatric Hematolgoy and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. u.schueller@uke.de. AD - Research Institute Children's Cancer Center, Hamburg-Eppendorf, Hamburg, Germany. u.schueller@uke.de. AD - Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany. u.schueller@uke.de. LA - eng PT - Journal Article DEP - 20240124 PL - Germany TA - Acta Neuropathol JT - Acta neuropathologica JID - 0412041 RN - 0 (Histones) SB - IM MH - Child MH - Humans MH - In Situ Hybridization, Fluorescence MH - *Neoplasm Recurrence, Local MH - *Ependymoma MH - Histones MH - Gene Expression Profiling PMC - PMC10808473 OTO - NOTNLM OT - 1q gain OT - 6q loss OT - DNA methylation OT - Ependymoma OT - Intratumoral heterogeneity OT - Morphology EDAT- 2024/01/24 12:44 MHDA- 2024/01/25 06:44 PMCR- 2024/01/24 CRDT- 2024/01/24 11:08 PHST- 2023/09/13 00:00 [received] PHST- 2023/12/30 00:00 [accepted] PHST- 2023/12/05 00:00 [revised] PHST- 2024/01/25 06:44 [medline] PHST- 2024/01/24 12:44 [pubmed] PHST- 2024/01/24 11:08 [entrez] PHST- 2024/01/24 00:00 [pmc-release] AID - 10.1007/s00401-023-02682-x [pii] AID - 2682 [pii] AID - 10.1007/s00401-023-02682-x [doi] PST - epublish SO - Acta Neuropathol. 2024 Jan 24;147(1):23. doi: 10.1007/s00401-023-02682-x.