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Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma

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Resumo: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.
Autores principais:Suzuki, Hiromichi
Outros Autores:Kumar, Sachin A.; Shuai, Shimin; Diaz-Navarro, Ander; Gutierrez-Fernandez, Ana; De Antonellis, Pasqualino; Cavalli, Florence M. G.; Juraschka, Kyle; Farooq, Hamza; Shibahara, Ichiyo; Vladoiu, Maria C.; Zhang, Jiao; Abeysundara, Namal; Przelicki, David; Skowron, Patryk; Gauer, Nicole; Luu, Betty; Daniels, Craig; Wu, Xiaochong; Forget, Antoine; Momin, Ali; Wang, Jun; Dong, Weifan; Kim, Seung-Ki; Grajkowska, Wieslawa A.; Jouvet, Anne; Fèvre-Montange, Michelle; Garrè, Maria Luisa; Nageswara Rao, Amulya A.; Giannini, Caterina; Kros, Johan M; French, Pim J.; Jabado, Nada; Ng, Ho-Keung; Poon, Wai Sang; Eberhart, Charles G.; Pollack, Ian F.; Olson, James M.; Weiss, William A.; Kumabe, Toshihiro; López-Aguilar, Enrique; Lach, Boleslaw; Massimino, Maura; Van Meir, Erwin G.; Rubin, Joshua B.; Vibhakar, Rajeev; Chambless, Lola B.; Kijima, Noriyuki; Klekner, Almos; Bognár, László; Chan, Jennifer A.; Faria, Claudia; Ragoussis, Jiannis; Pfister, Stefan M.; Goldenberg, Anna; Wechsler-Reya, Robert J.; Bailey, Swneke D.; Garzia, Livia; Morrissy, A Sorana; Marra, Marco A.; Huang, Xi; Malkin, David; Ayrault, Olivier; Ramaswamy, Vijay; Puente, Xose S.; Calarco, John A.; Stein, Lincoln; Taylor, Michael D.
Ano:2019
País:Portugal
Tipo de documento:artigo
Tipo de acesso:acesso restrito
Instituição associada:Universidade de Lisboa
Idioma:inglês
Origem:Repositório da Universidade de Lisboa

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