| Literature DB >> 31597162 |
Hiromichi Suzuki1,2, Sachin A Kumar1,2,3, Shimin Shuai4,5, Ander Diaz-Navarro6,7, Ana Gutierrez-Fernandez6,7, Pasqualino De Antonellis1,2, Florence M G Cavalli1,2, Kyle Juraschka1,2,3, Hamza Farooq1,2,3, Ichiyo Shibahara1,2, Maria C Vladoiu1,2,3, Jiao Zhang1,2, Namal Abeysundara1,2, David Przelicki1,2,3, Patryk Skowron1,2,3, Nicole Gauer1,2, Betty Luu1,2, Craig Daniels1,2, Xiaochong Wu1,2, Antoine Forget8,9, Ali Momin1,2,5, Jun Wang10, Weifan Dong1,2,5, Seung-Ki Kim11, Wieslawa A Grajkowska12, Anne Jouvet13, Michelle Fèvre-Montange14, Maria Luisa Garrè15, Amulya A Nageswara Rao16, Caterina Giannini17, Johan M Kros18, Pim J French19, Nada Jabado20, Ho-Keung Ng21, Wai Sang Poon22, Charles G Eberhart23, Ian F Pollack24, James M Olson25, William A Weiss26, Toshihiro Kumabe27, Enrique López-Aguilar28, Boleslaw Lach29,30, Maura Massimino31, Erwin G Van Meir32, Joshua B Rubin33, Rajeev Vibhakar34, Lola B Chambless35, Noriyuki Kijima36, Almos Klekner37, László Bognár37, Jennifer A Chan38, Claudia C Faria39,40, Jiannis Ragoussis41,42, Stefan M Pfister43,44,45, Anna Goldenberg46,47, Robert J Wechsler-Reya10,48, Swneke D Bailey49,50, Livia Garzia50,51, A Sorana Morrissy38,52, Marco A Marra53, Xi Huang1,2, David Malkin54, Olivier Ayrault8,9, Vijay Ramaswamy2,54, Xose S Puente6,7, John A Calarco55, Lincoln Stein4, Michael D Taylor56,57,58,59.
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.Year: 2019 PMID： 31597162 PMCID： PMC7141958 DOI： 10.1038/s41586-019-1650-0
Source DB: PubMed Journal: Nature ISSN： 0028-0836 Impact factor: 49.962