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.
Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma / Suzuki, H.; Kumar, S. A.; Shuai, S.; Diaz-Navarro, A.; Gutierrez-Fernandez, A.; De Antonellis, P.; Cavalli, F. M. G.; Juraschka, K.; Farooq, H.; Shibahara, I.; Vladoiu, M. C.; Zhang, J.; Abeysundara, N.; Przelicki, D.; Skowron, P.; Gauer, N.; Luu, B.; Daniels, C.; Wu, X.; Forget, A.; Momin, A.; Wang, J.; Dong, W.; Kim, S. -K.; Grajkowska, W. A.; Jouvet, A.; Fevre-Montange, M.; Garre, M. L.; Nageswara Rao, A. A.; Giannini, C.; Kros, J. M.; French, P. J.; Jabado, N.; Ng, H. -K.; Poon, W. S.; Eberhart, C. G.; Pollack, I. F.; Olson, J. M.; Weiss, W. A.; Kumabe, T.; Lopez-Aguilar, E.; Lach, B.; Massimino, M.; Van Meir, E. G.; Rubin, J. B.; Vibhakar, R.; Chambless, L. B.; Kijima, N.; Klekner, A.; Bognar, L.; Chan, J. A.; Faria, C. C.; Ragoussis, J.; Pfister, S. M.; Goldenberg, A.; Wechsler-Reya, R. J.; Bailey, S. D.; Garzia, L.; Morrissy, A. S.; Marra, M. A.; Huang, X.; Malkin, D.; Ayrault, O.; Ramaswamy, V.; Puente, X. S.; Calarco, J. A.; Stein, L.; Taylor, M. D.. - In: NATURE. - ISSN 0028-0836. - 574:7780(2019), pp. 707-711. [10.1038/s41586-019-1650-0]
Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma
De Antonellis P.;
2019
Abstract
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
