Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Nat Commun. 2021 Mar 19;12(1):1749. doi: 10.1038/s41467-021-21883-0.
Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.
Sonic hedgehog 型髓母细胞瘤包含一组临床上和分子上多样化的发育性中枢神经系统癌症。在这里，我们使用转录组的无偏测序对 250 个肿瘤的大样本进行分析，揭示了该疾病分子亚型之间的差异，并证明了非编码 RNA 转录本以前未被重视的重要性。我们鉴定了 cAMP 依赖途径（GNAS、PRKAR1A）内的改变，这些改变集中在 GLI2 活性上，并表明 18%的肿瘤具有直接靶向 MYCN 丰度和/或稳定性的遗传事件。此外，我们在包含 GLI2 的局灶性扩增区域中发现了广泛的融合网络，以及肿瘤抑制基因 PTCH1、SUFU 和 NCOR1 中的几个失活融合。核苷酸变异、拷贝数异常和基因融合使一组基因在分子上趋同，突出了特定通路在 Sonic hedgehog 型髓母细胞瘤发病机制中的关键作用，并为治疗干预提供了机会。
