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

Giannini C.;
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.
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.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/722196
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