Rodriguez-Fos Elias, Planas-Fèlix Mercè, Burkert Martin, Puiggròs Montserrat, Toedling Joern, Thiessen Nina, Blanc Eric, Szymansky Annabell, Hertwig Falk, Ishaque Naveed, Beule Dieter, Torrents David, Eggert Angelika, Koche Richard P, Schwarz Roland F, Haase Kerstin, Schulte Johannes H, Henssen Anton G
Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin, Berlin, Germany.
Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
Cell Genom. 2023 Sep 7;3(10):100402. doi: 10.1016/j.xgen.2023.100402. eCollection 2023 Oct 11.
Neuroblastoma is a pediatric solid tumor characterized by strong clinical heterogeneity. Although clinical risk-defining genomic alterations exist in neuroblastomas, the mutational processes involved in their generation remain largely unclear. By examining the topography and mutational signatures derived from all variant classes, we identified co-occurring mutational footprints, which we termed mutational scenarios. We demonstrate that clinical neuroblastoma heterogeneity is associated with differences in the mutational processes driving these scenarios, linking risk-defining pathognomonic variants to distinct molecular processes. Whereas high-risk -amplified neuroblastomas were characterized by signs of replication slippage and stress, homologous recombination-associated signatures defined high-risk non--amplified patients. Non-high-risk neuroblastomas were marked by footprints of chromosome mis-segregation and TOP1 mutational activity. Furthermore, analysis of subclonal mutations uncovered differential activity of these processes through neuroblastoma evolution. Thus, clinical heterogeneity of neuroblastoma patients can be linked to differences in the mutational processes that are active in their tumors.
神经母细胞瘤是一种具有强烈临床异质性的儿科实体瘤。尽管神经母细胞瘤中存在定义临床风险的基因组改变，但其产生所涉及的突变过程在很大程度上仍不清楚。通过检查源自所有变异类别的拓扑结构和突变特征，我们识别出了共同出现的突变足迹，我们将其称为突变情况。我们证明，临床神经母细胞瘤的异质性与驱动这些情况的突变过程差异有关，将定义风险的特征性变异与不同的分子过程联系起来。高风险扩增型神经母细胞瘤的特征是复制滑移和应激迹象，而同源重组相关特征则定义了高风险非扩增型患者。非高风险神经母细胞瘤的特征是染色体错分离和TOP1突变活性的足迹。此外，对亚克隆突变的分析揭示了这些过程在神经母细胞瘤进化过程中的差异活性。因此，神经母细胞瘤患者的临床异质性可与肿瘤中活跃的突变过程差异联系起来。
