Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
Department of Pediatrics - Research, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Nat Commun. 2022 Jan 31;13(1):588. doi: 10.1038/s41467-022-28253-4.
High-grade diffuse glioma (HGG) is the leading cause of brain tumour death. While the genetic drivers of HGG have been well described, targeting these has thus far had little impact on survival suggesting other mechanisms are at play. Here we interrogate the alternative splicing landscape of pediatric and adult HGG through multi-omic analyses, uncovering an increased splicing burden compared with normal brain. The rate of recurrent alternative splicing in cancer drivers exceeds their mutation rate, a pattern that is recapitulated in pan-cancer analyses, and is associated with worse prognosis in HGG. We investigate potential oncogenicity by interrogating cancer pathways affected by alternative splicing in HGG; spliced cancer drivers include members of the RAS/MAPK pathway. RAS suppressor neurofibromin 1 is differentially spliced to a less active isoform in >80% of HGG downstream from REST upregulation, activating the RAS/MAPK pathway and reducing glioblastoma patient survival. Overall, our results identify non-mutagenic mechanisms by which cancers activate oncogenic pathways which need to accounted for in personalized medicine approaches.
高级别弥漫性神经胶质瘤（HGG）是导致脑肿瘤死亡的主要原因。尽管 HGG 的遗传驱动因素已经得到很好的描述，但针对这些因素的治疗迄今对生存几乎没有影响，这表明还有其他机制在起作用。在这里，我们通过多组学分析研究了儿童和成人 HGG 的选择性剪接图谱，发现与正常大脑相比，其剪接负担增加。在癌症驱动基因中，反复发生的选择性剪接的频率超过了其突变率，这种模式在泛癌症分析中得到了重现，并且与 HGG 的预后较差相关。我们通过研究 HGG 中受选择性剪接影响的癌症途径来探究潜在的致癌性；剪接的癌症驱动基因包括 RAS/MAPK 途径的成员。RAS 抑制因子神经纤维瘤 1 在 >80%的 HGG 中从 REST 上调后发生差异剪接，形成一种活性较低的异构体，激活 RAS/MAPK 途径并降低胶质母细胞瘤患者的生存率。总的来说，我们的研究结果确定了癌症激活致癌途径的非突变机制，这在个性化医疗方法中需要加以考虑。
