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Article: Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma

TitleRecurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma
Authors
Issue Date2019
Citation
Nature, 2019, v. 574, n. 7780, p. 707-711 How to Cite?
AbstractIn 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.
Persistent Identifierhttp://hdl.handle.net/10722/325452
ISSN
2023 Impact Factor: 50.5
2023 SCImago Journal Rankings: 18.509
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorSuzuki, Hiromichi-
dc.contributor.authorKumar, Sachin A.-
dc.contributor.authorShuai, Shimin-
dc.contributor.authorDiaz-Navarro, Ander-
dc.contributor.authorGutierrez-Fernandez, Ana-
dc.contributor.authorDe Antonellis, Pasqualino-
dc.contributor.authorCavalli, Florence M.G.-
dc.contributor.authorJuraschka, Kyle-
dc.contributor.authorFarooq, Hamza-
dc.contributor.authorShibahara, Ichiyo-
dc.contributor.authorVladoiu, Maria C.-
dc.contributor.authorZhang, Jiao-
dc.contributor.authorAbeysundara, Namal-
dc.contributor.authorPrzelicki, David-
dc.contributor.authorSkowron, Patryk-
dc.contributor.authorGauer, Nicole-
dc.contributor.authorLuu, Betty-
dc.contributor.authorDaniels, Craig-
dc.contributor.authorWu, Xiaochong-
dc.contributor.authorForget, Antoine-
dc.contributor.authorMomin, Ali-
dc.contributor.authorWang, Jun-
dc.contributor.authorDong, Weifan-
dc.contributor.authorKim, Seung Ki-
dc.contributor.authorGrajkowska, Wieslawa A.-
dc.contributor.authorJouvet, Anne-
dc.contributor.authorFèvre-Montange, Michelle-
dc.contributor.authorGarrè, Maria Luisa-
dc.contributor.authorNageswara Rao, Amulya A.-
dc.contributor.authorGiannini, Caterina-
dc.contributor.authorKros, Johan M.-
dc.contributor.authorFrench, Pim J.-
dc.contributor.authorJabado, Nada-
dc.contributor.authorNg, Ho Keung-
dc.contributor.authorPoon, Wai Sang-
dc.contributor.authorEberhart, Charles G.-
dc.contributor.authorPollack, Ian F.-
dc.contributor.authorOlson, James M.-
dc.contributor.authorWeiss, William A.-
dc.contributor.authorKumabe, Toshihiro-
dc.contributor.authorLópez-Aguilar, Enrique-
dc.contributor.authorLach, Boleslaw-
dc.contributor.authorMassimino, Maura-
dc.contributor.authorVan Meir, Erwin G.-
dc.contributor.authorRubin, Joshua B.-
dc.contributor.authorVibhakar, Rajeev-
dc.contributor.authorChambless, Lola B.-
dc.contributor.authorKijima, Noriyuki-
dc.contributor.authorKlekner, Almos-
dc.contributor.authorBognár, László-
dc.contributor.authorChan, Jennifer A.-
dc.contributor.authorFaria, Claudia C.-
dc.contributor.authorRagoussis, Jiannis-
dc.contributor.authorPfister, Stefan M.-
dc.contributor.authorGoldenberg, Anna-
dc.contributor.authorWechsler-Reya, Robert J.-
dc.contributor.authorBailey, Swneke D.-
dc.contributor.authorGarzia, Livia-
dc.contributor.authorMorrissy, A. Sorana-
dc.contributor.authorMarra, Marco A.-
dc.contributor.authorHuang, Xi-
dc.contributor.authorMalkin, David-
dc.contributor.authorAyrault, Olivier-
dc.contributor.authorRamaswamy, Vijay-
dc.contributor.authorPuente, Xose S.-
dc.contributor.authorCalarco, John A.-
dc.contributor.authorStein, Lincoln-
dc.contributor.authorTaylor, Michael D.-
dc.date.accessioned2023-02-27T07:33:26Z-
dc.date.available2023-02-27T07:33:26Z-
dc.date.issued2019-
dc.identifier.citationNature, 2019, v. 574, n. 7780, p. 707-711-
dc.identifier.issn0028-0836-
dc.identifier.urihttp://hdl.handle.net/10722/325452-
dc.description.abstractIn 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.-
dc.languageeng-
dc.relation.ispartofNature-
dc.titleRecurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1038/s41586-019-1650-0-
dc.identifier.pmid31664194-
dc.identifier.scopuseid_2-s2.0-85074231650-
dc.identifier.volume574-
dc.identifier.issue7780-
dc.identifier.spage707-
dc.identifier.epage711-
dc.identifier.eissn1476-4687-
dc.identifier.isiWOS:000493807800049-

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