Department of Pediatric Hematolgoy and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Research Institute Children's Cancer Center, Hamburg-Eppendorf, Hamburg, Germany.
Acta Neuropathol. 2024 Jan 24;147(1):23. doi: 10.1007/s00401-023-02682-x.
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 = 0.0026, p < 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.
后颅窝型 A 型（PF-EPN-A，PFA）室管膜瘤是一种侵袭性肿瘤，主要影响儿童，预后不良。组织病理学显示明显的肿瘤内异质性，从疏松组织到通常界限分明的极度细胞密集肿瘤区域不等。为了确定形态学上不同区域的分子差异，并了解其临床意义，我们分析了 113 例 PF-EPN-A 样本，包括 40 例相应的复发样本。细胞密集区域占肿瘤区域的 0%至 100%，显示出更高比例的增殖肿瘤细胞（p<0.01）。临床上，细胞密度与无进展生存期和总生存期不良相关（p=0.0026，p<0.01）。分子上，低细胞密度和高细胞密度的肿瘤区域在与 9/21 例中不同的先前发现的 PF-EPN-A 亚型的相似性方面显示出不同的 DNA 甲基化谱。1q 和 6q 号染色体的预后相关染色体变化在单个肿瘤内具有空间异质性，并且在单细胞 RNA（scRNA）测序以及不同肿瘤区域的拷贝数分析和荧光原位杂交（FISH）分析中，在细胞密集的肿瘤区域中显著富集。最后，空间转录组学揭示了不同肿瘤的高密度区域比同一肿瘤的不同区域更为相似。高密度区域明显过表达编码组蛋白、WNT5A、TGFB1 或 IGF2 的基因。与相应的原发性肿瘤相比，复发肿瘤显示出更高比例的细胞密集区域（p=0.036）、PF-EPN-A 甲基化亚型的变化（13/32 例患者）以及新的 1q 号染色体增益和 6q 号染色体缺失（12/32 例患者）。我们的数据表明，PF-EPN-A 室管膜瘤具有以前未被认识到的肿瘤内异质性，具有临床意义，在选择诊断材料时必须考虑到这一点，例如通过对细胞密集区域比例的组织学评估。
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