Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma.

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.

Citation

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. Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma. Nature. 2019 Oct;574(7780):707-711

Mesh Tags

Substances

PMID: 31664194

search → result