Article, 2024
Clinically relevant molecular hallmarks of PFA ependymomas display intratumoral heterogeneity and correlate with tumor morphology
Acta Neuropathologica,
ISSN
0001-6322,
1432-0533,
Volume 147,
1,
Page 23,
10.1007/s00401-023-02682-x
Contributors
Gödicke, Swenja
[1]
[2]
Kresbach, Catena
0000-0002-6004-7332
[1]
[2]
Ehlert, Max
[1]
[2]
Obrecht, Denise
0000-0002-3216-8452
[1]
Altendorf, Lea
[1]
[2]
Hack, Karoline
[1]
[2]
Von Hoff, Katja
0000-0002-5669-8546
[3]
[4]
Carén, Helena Margareta
0000-0002-8584-555X
[5]
Melcher, Viktoria
[6]
Kerl, Kornelius
[6]
Englinger, Bernhard
0000-0002-9701-2600
[7]
[8]
[9]
[10]
Filbin, Mariella Gruber
0000-0002-2613-8126
[8]
[9]
Pajtler, Kristian W
0000-0002-3562-6121
[11]
[12]
[13]
Gojo, Johannes Salomon
0000-0002-8113-3416
[10]
Pietsch, Torsten
0000-0003-0763-6506
[14]
Rutkowski, Stefan
0000-0002-5446-9571
[1]
Schüller, Ulrich
0000-0002-8731-1121
(Corresponding author)
[1]
[2]
Affiliations
- [1]
University Medical Center Hamburg-Eppendorf
[NORA names:
Germany; Europe, EU; OECD];
- [2]
Kinderkrebs-Zentrum Hamburg
[NORA names:
Germany; Europe, EU; OECD];
- [3]
Aarhus University Hospital
[NORA names:
Central Denmark Region; Hospital; Denmark; Europe, EU; Nordic; OECD];
- [4]
Humboldt-Universität zu Berlin
[NORA names:
Germany; Europe, EU; OECD];
- [5]
University of Gothenburg
[NORA names:
Sweden; Europe, EU; Nordic; OECD];
(... more)
- [6]
University Hospital Münster
[NORA names:
Germany; Europe, EU; OECD];
- [7]
Comprehensive Cancer Center Vienna
[NORA names:
Austria; Europe, EU; OECD];
- [8]
Broad Institute
[NORA names:
United States; America, North; OECD];
- [9]
Dana-Farber/Boston Children's Cancer and Blood Disorders Center
[NORA names:
United States; America, North; OECD];
- [10]
Medical University of Vienna
[NORA names:
Austria; Europe, EU; OECD];
- [11]
German Cancer Research Center
[NORA names:
Germany; Europe, EU; OECD];
- [12]
Hopp Children's Cancer Center Heidelberg
[NORA names:
Germany; Europe, EU; OECD];
- [13]
University Hospital Heidelberg
[NORA names:
Germany; Europe, EU; OECD];
- [14]
University Hospital Bonn
[NORA names:
Germany; Europe, EU; OECD]
(less)
Abstract
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.
Keywords
DNA,
DNA methylation profiles,
IGF2,
PF-EPN-A,
PFA ependymomas,
TGFB1,
Wnt5a,
aggressive tumors,
alia,
analysis,
area,
associated with poor progression-free,
cases,
cell density,
cell-dense areas,
cells,
changes,
children,
chromosomal changes,
chromosome 1q gain,
clinic,
clinical implications,
clinical significance,
copy,
copy number profiles,
data,
density,
diagnostic material,
differences,
different areas,
ependymoma,
evaluation,
fluorescence,
fluorescence in situ hybridization,
gain,
genes,
habor,
heterogeneity,
high cell density,
high-density areas,
histological evaluation,
histone,
histone proteins,
histopathology,
hybrid,
implications,
inter alia,
intratumoral heterogeneity,
loose tissue,
loss,
materials,
methylation profiles,
methylation subtypes,
molecular differences,
morphologically different areas,
morphology,
overall survival,
overexpressed genes,
patients,
poor prognosis,
primary tumor,
profile,
prognosis,
prognostication,
progression-free,
proportion,
proportion of proliferating tumor cells,
protein,
relapse,
relapse samples,
relapsed tumors,
samples,
significance,
similarity,
single tumors,
spatial heterogeneity,
spatial transcriptomics,
subtypes,
survival,
tissue,
transcriptome,
tumor,
tumor area,
tumor cells,
tumor morphology,
type A
Funders
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