霍普儿童癌症中心Stefan M. Pfister研究团队的一项最新研究揭示了癌基因畸变驱动成神经管细胞瘤的进展，而不是起始。2025年5月7日出版的《自然》发表了这项成果。

为了分析这种相互作用，该课题组人员将单细胞技术（单核RNA测序（snRNA-seq）、单核转座酶可及染色质高通量测序（snATAC-seq）和空间转录组学）应用于一组已知致癌基因MYC、MYCN和PRDM6改变的3/4组髓母细胞瘤。该研究团队发现，大规模染色体畸变是早期肿瘤启动事件，而单基因致癌事件出现较晚，通常是亚克隆的，但MYC可以在疾病进展时变成克隆，从而进一步推动肿瘤的发展和治疗耐药性。空间转录组学显示亚克隆大多分布在肿瘤组织中，但也存在明显的分离。使用群体遗传学模型，研究组估计髓母细胞瘤起源于小脑单极brthemh细胞谱系从妊娠早期开始。他们的发现证明了单细胞技术可以应用于这种致命疾病的早期检测和诊断。

研究人员表示，尽管最近在了解疾病生物学方面取得了进展，但治疗3/4组髓母细胞瘤仍然是儿科神经肿瘤学的治疗挑战。大量组学方法已经在3/4组髓母细胞瘤中发现了相当大的肿瘤间异质性，包括仅在一小部分病例中存在明确的单基因致癌驱动因素，而在大多数病例中，大规模拷贝数畸变普遍存在。然而，瘤内异质性、癌基因畸变的作用以及拷贝数在肿瘤进化和治疗耐药性中的广泛变化仍然知之甚少。

附：英文原文

Title: Oncogene aberrations drive medulloblastoma progression, not initiation

Author: Okonechnikov, Konstantin, Joshi, Piyush, Krber, Verena, Rademacher, Anne, Bortolomeazzi, Michele, Mallm, Jan-Philipp, Vaillant, Jan, da Silva, Patricia Benites Goncalves, Statz, Britta, Sepp, Mari, Sarropoulos, Ioannis, Yamada, Tetsuya, Wittmann, Andrea, Schramm, Kathrin, Blattner-Johnson, Mirjam, Fiesel, Petra, Jones, Barbara, Jger, Natalie, Milde, Till, Pajtler, Kristian W., van Tilburg, Cornelis M., Witt, Olaf, Bochennek, Konrad, Weber, Katharina Johanna, Nonnenmacher, Lisa, Reimann, Christian, Ghasemi, David R., Schller, Ulrich, Mynarek, Martin, Rutkowski, Stefan, Jones, David T. W., Korshunov, Andrey, Rippe, Karsten, Westermann, Frank, Thongjuea, Supat, Hfer, Thomas, Kaessmann, Henrik, Kutscher, Lena M., Pfister, Stefan M.

Issue&Volume: 2025-05-07

Abstract: Despite recent advances in understanding disease biology, treatment of group 3/4 medulloblastoma remains a therapeutic challenge in paediatric neuro-oncology1. Bulk-omics approaches have identified considerable intertumoural heterogeneity in group 3/4 medulloblastoma, including the presence of clear single-gene oncogenic drivers in only a subset of cases, whereas in most cases, large-scale copy number aberrations prevail2,3. However, intratumoural heterogeneity, the role of oncogene aberrations, and broad copy number variation in tumour evolution and treatment resistance remain poorly understood. To dissect this interplay, we used single-cell technologies (single-nucleus RNA sequencing (snRNA-seq), single-nucleus assay for transposase-accessible chromatin with high-throughput sequencing (snATAC-seq) and spatial transcriptomics) on a cohort of group 3/4 medulloblastoma with known alterations in the oncogenes MYC, MYCN and PRDM6. We show that large-scale chromosomal aberrations are early tumour-initiating events, whereas the single-gene oncogenic events arise late and are typically subclonal, but MYC can become clonal upon disease progression to drive further tumour development and therapy resistance. Spatial transcriptomics shows that the subclones are mostly interspersed across tumour tissue, but clear segregation is also present. Using a population genetics model, we estimate medulloblastoma initiation in the cerebellar unipolar brush cell lineage starting from the first gestational trimester. Our findings demonstrate how single-cell technologies can be applied for early detection and diagnosis of this fatal disease.

DOI: 10.1038/s41586-025-08973-5

Source: https://www.nature.com/articles/s41586-025-08973-5