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

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2019
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Abstract
Recurrent somatic single nucleotide variants (SNVs) in cancer are largely confined to protein-coding genes, and are rare in most paediatric cancers. 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.
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suzuki2019recurrentnature Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors 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
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Journal Nature
Year 2019
DOI
10.1038/s41586-019-1650-0
URL
Keywords
immune response fungal infections fungi-mirna interactions mirna regulation mirna-immune response interactions

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