Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma

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 ForgetAli 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

Research output: Contribution to journalArticlepeer-review

115 Scopus citations


In cancer, recurrent somatic single-nucleotide variants—which are rare in most paediatric cancers—are confined largely to protein-coding genes1–3. Here we report highly recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs) in about 50% of Sonic hedgehog (SHH) medulloblastomas. These mutations were not present across other subgroups of medulloblastoma, and we identified these hotspot mutations in U1 snRNA in only <0.1% of 2,442 cancers, across 36 other tumour types. The mutations occur in 97% of adults (subtype SHHδ) and 25% of adolescents (subtype SHHα) with SHH medulloblastoma, but are largely absent from SHH medulloblastoma in infants. The U1 snRNA mutations occur in the 5′ splice-site binding region, and snRNA-mutant tumours have significantly disrupted RNA splicing and an excess of 5′ cryptic splicing events. Alternative splicing mediated by mutant U1 snRNA inactivates tumour-suppressor genes (PTCH1) and activates oncogenes (GLI2 and CCND2), and represents a target for therapy. These U1 snRNA mutations provide an example of highly recurrent and tissue-specific mutations of a non-protein-coding gene in cancer.

Original languageEnglish
Pages (from-to)707-711
Number of pages5
Issue number7780
StatePublished - Oct 31 2019


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