Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK.
Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK; Department of Applied Sciences, Northumbria University, Newcastle upon Tyne, UK.
Cell Rep. 2022 Aug 2;40(5):111162. doi: 10.1016/j.celrep.2022.111162.
Medulloblastoma is currently subclassified into distinct DNA methylation subgroups/subtypes with particular clinico-molecular features. Using RNA sequencing (RNA-seq) in large, well-annotated cohorts of medulloblastoma, we show that transcriptionally group 3 and group 4 medulloblastomas exist as intermediates on a bipolar continuum between archetypal group 3 and group 4 entities. Continuum position is prognostic, reflecting a propensity for specific DNA copy-number changes, and specific switches in isoform/enhancer usage and RNA editing. Examining single-cell RNA-seq (scRNA-seq) profiles, we show that intratumoral transcriptional heterogeneity along the continuum is limited in a subtype-dependent manner. By integrating with a human scRNA-seq reference atlas, we show that this continuum is mirrored by an equivalent continuum of transcriptional cell types in early fetal cerebellar development. We identify distinct developmental niches for all four major subgroups and link each to a common developmental antecedent. Our findings show a transcriptional continuum arising from oncogenic disruption of highly specific fetal cerebellar cell types, linked to almost every aspect of group 3/group 4 molecular biology and clinico-pathology.
髓母细胞瘤目前根据特定的临床-分子特征分为不同的 DNA 甲基化亚组/亚型。通过对大型、注释良好的髓母细胞瘤队列进行 RNA 测序 (RNA-seq)，我们表明转录组 3 组和 4 组髓母细胞瘤在典型的 3 组和 4 组实体之间存在两极连续统的中间状态。连续统位置具有预后意义，反映了特定 DNA 拷贝数变化的倾向，以及异构体/增强子使用和 RNA 编辑的特定开关。通过检查单细胞 RNA-seq(scRNA-seq)图谱，我们表明，沿连续统的肿瘤内转录异质性以亚型依赖性的方式受到限制。通过与人类 scRNA-seq 参考图谱整合，我们表明，这种连续统在早期胎儿小脑发育中以转录细胞类型的等效连续统为镜像。我们为所有四个主要亚组确定了不同的发育小生境，并将每个亚组与一个共同的发育前体联系起来。我们的研究结果表明，转录连续统是由高度特异性胎儿小脑细胞类型的致癌破坏引起的，与 3 组/4 组分子生物学和临床病理学的几乎每个方面都有关联。
