小柯机器人

近日，加拿大病童医院Michael D. Taylor研究组发现复发性非编码的U1-snRNA突变驱动Shh型母细胞瘤的隐性剪接。2019年10月9日，国际知名学术期刊《自然》在线发表了这一成果。

研究人员报道了约50％的Sonic hedgehog型髓母细胞瘤（Shh-MB）中U1剪接体小核RNA（snRNA）的高度复发性热点突变，该突变在其他髓母细胞瘤亚型中均不存在。在其他36种其他肿瘤类型的2442例癌症中，发现此U1-snRNA热点突变（r.3a> g）小于0.1％。婴儿Shh-MB基本上不存在这种突变，这种突变发生在97％的成年人（Shhδ）和25％的青少年（Shhα）中。U1-snRNA突变发生在5'剪接位点结合区域，并且snRNA突变型肿瘤显著破坏RNA剪接，并带有过量的5'隐性剪接事件。突变的U1-snRNA介导的可变剪接使肿瘤抑制基因（PTCH1）失活，并激活癌基因（GLI2、CCND2），这是治疗的新靶点，并造成了癌症中非蛋白质编码基因的高度复发性和组织特异性突变。

据介绍，癌症中的复发性体细胞单核苷酸变异（SNV）很大程度上局限于蛋白质编码基因，在大多数儿童癌症中很少见。

附：英文原文

Title: Recurrent non-coding U1-snRNA mutations drive cryptic splicing in Shh medulloblastoma

Author: Hiromichi Suzuki, Sachin A. Kumar, Shimin Shuai, Ander Diaz-Navarro, Ana Gutierrez-Fernandez, Pasqualino De Antonellis, Florence M. G. Cavalli, Kyle Juraschka, Hamza Farooq, Ichiyo Shibahara, Maria C. Vladoiu, Jiao Zhang, Namal Abeysundara, David Przelicki, Patryk Skowron, Nicole Gauer, Betty Luu, Craig Daniels, Xiaochong Wu, Antoine Forget, Ali Momin, Jun Wang, Weifan Dong, Seung-Ki Kim, Wieslawa A. Grajkowska, Anne Jouvet, Michelle Fèvre-Montange, Maria Luisa Garrè, Amulya A. Nageswara Rao, Caterina Giannini, Johan M. Kros, Pim J. French, Nada Jabado, Ho-Keung Ng, Wai Sang Poon, Charles G. Eberhart, Ian F. Pollack, James M. Olson, William A. Weiss, Toshihiro Kumabe, Enrique López-Aguilar, Boleslaw Lach, Maura Massimino, Erwin G. Van Meir, Joshua B. Rubin, Rajeev Vibhakar, Lola B. Chambless, Noriyuki Kijima, Almos Klekner, László Bognár, Jennifer A. Chan, Claudia C. Faria, Jiannis Ragoussis, Stefan M. Pfister, Anna Goldenberg, Robert J. Wechsler-Reya, Swneke D. Bailey, Livia Garzia, A. Sorana Morrissy, Marco A. Marra, Xi Huang, David Malkin, Olivier Ayrault, Vijay Ramaswamy, Xose S. Puente, John A. Calarco, Lincoln Stein & Michael D. Taylor 

Issue&Volume: 2019-10-09

Abstract: 

Recurrent somatic single nucleotide variants (SNVs) in cancer are largely confined to protein-coding genes, and are rare in most paediatric cancers1–3. Here we report highly recurrent hotspot mutations of U1 spliceosomal small nuclear RNAs (snRNAs) in ~50% of Sonic hedgehog medulloblastomas (Shh-MB), which were not present across other medulloblastoma subgroups. This U1-snRNA hotspot mutation (r.3a>g), was identified in <0.1% of 2,442 cancers across 36 other tumour types. Largely absent from infant Shh-MB, the mutation occurs in 97% of adults (Shhδ), and 25% of adolescents (Shhα). The U1-snRNA mutation occurs in the 5′ splice site binding region, and snRNA mutant tumours have significantly disrupted RNA splicing with an excess of 5′ cryptic splicing events. Mutant U1-snRNA-mediated alternative splicing inactivates tumour suppressor genes (PTCH1), and activates oncogenes (GLI2, CCND2), represents a novel target for therapy, and constitutes a highly recurrent and tissue-specific mutation of a non-protein coding gene in cancer.

DOI: 10.1038/s41586-019-1650-0

Source:https://www.nature.com/articles/s41586-019-1650-0

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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