Publicação
Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma
| 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 |
| _version_ | 1866810674907185152 |
|---|---|
| author | Suzuki, Hiromichi |
| author2 | 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. |
| author2_role | author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
| author_facet | Suzuki, Hiromichi 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. |
| author_role | author |
| contributor_name_str_mv | Repositório Científico de Acesso Aberto da ULisboa |
| country_str | PT |
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| datacite.contributors.contributor.contributorName.fl_str_mv | Repositório Científico de Acesso Aberto da ULisboa |
| datacite.creators.creator.creatorName.fl_str_mv | Suzuki, Hiromichi 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. |
| datacite.date.Accepted.fl_str_mv | 2019-01-01T00:00:00Z |
| datacite.date.available.fl_str_mv | 2021-02-17T17:10:37Z |
| datacite.date.embargoed.fl_str_mv | 2021-02-17T17:10:37Z |
| datacite.rights.fl_str_mv | http://purl.org/coar/access_right/c_16ec |
| datacite.titles.title.fl_str_mv | Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma |
| dc.contributor.none.fl_str_mv | Repositório Científico de Acesso Aberto da ULisboa |
| dc.creator.none.fl_str_mv | Suzuki, Hiromichi 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. |
| dc.date.Accepted.fl_str_mv | 2019-01-01T00:00:00Z |
| dc.date.available.fl_str_mv | 2021-02-17T17:10:37Z |
| dc.date.embargoed.fl_str_mv | 2021-02-17T17:10:37Z |
| dc.format.none.fl_str_mv | application/pdf |
| dc.identifier.none.fl_str_mv | http://hdl.handle.net/10451/46407 |
| dc.language.none.fl_str_mv | eng |
| dc.publisher.none.fl_str_mv | Springer Nature |
| dc.rights.none.fl_str_mv | http://purl.org/coar/access_right/c_16ec |
| dc.title.fl_str_mv | Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma |
| dc.type.none.fl_str_mv | http://purl.org/coar/resource_type/c_6501 |
| description | 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. |
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| format | article |
| fulltext.url.fl_str_mv | https://repositorio.ulisboa.pt/bitstreams/4883936f-7ede-400b-9909-2acfd56ddef6/download |
| id | ul_d2094cebefb49e920c4c3ebacecffbbc |
| identifier.url.fl_str_mv | http://hdl.handle.net/10451/46407 |
| instacron_str | ul |
| institution | Universidade de Lisboa |
| instname_str | Universidade de Lisboa |
| language | eng |
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| network_name_str | Repositório da Universidade de Lisboa |
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| organization_str_mv | urn:organizationAcronym:ul |
| person_str_mv | Suzuki, Hiromichi 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 Faria, Claudia https://www.ciencia-id.pt/AD1B-C408-B6A8 AD1B-C408-B6A8 http://orcid.org/0000-0003-1259-9922 0000-0003-1259-9922 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. |
| publishDate | 2019 |
| publisher.none.fl_str_mv | Springer Nature |
| reponame_str | Repositório da Universidade de Lisboa |
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| spelling | engSpringer Naturept_PTIn 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.application/pdfpt_PTRecurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastomaSuzuki, HiromichiKumar, Sachin A.Shuai, ShiminDiaz-Navarro, AnderGutierrez-Fernandez, AnaDe Antonellis, PasqualinoCavalli, Florence M. G.Juraschka, KyleFarooq, HamzaShibahara, IchiyoVladoiu, Maria C.Zhang, JiaoAbeysundara, NamalPrzelicki, DavidSkowron, PatrykGauer, NicoleLuu, BettyDaniels, CraigWu, XiaochongForget, AntoineMomin, AliWang, JunDong, WeifanKim, Seung-KiGrajkowska, Wieslawa A.Jouvet, AnneFèvre-Montange, MichelleGarrè, Maria LuisaNageswara Rao, Amulya A.Giannini, CaterinaKros, Johan MFrench, Pim J.Jabado, NadaNg, Ho-KeungPoon, Wai SangEberhart, Charles G.Pollack, Ian F.Olson, James M.Weiss, William A.Kumabe, ToshihiroLópez-Aguilar, EnriqueLach, BoleslawMassimino, MauraVan Meir, Erwin G.Rubin, Joshua B.Vibhakar, RajeevChambless, Lola B.Kijima, NoriyukiKlekner, AlmosBognár, LászlóChan, Jennifer A.PersonalFaria, ClaudiaDSpacehttp://dspace.org/items/94ff2476-7001-4e97-9396-4a8716a7cbbaDSpacehttp://dspace.org/items/94ff2476-7001-4e97-9396-4a8716a7cbbaFariaClaudiaCiência IDhttps://www.ciencia-id.ptAD1B-C408-B6A8ORCIDhttp://orcid.org0000-0003-1259-9922Ragoussis, JiannisPfister, Stefan M.Goldenberg, AnnaWechsler-Reya, Robert J.Bailey, Swneke D.Garzia, LiviaMorrissy, A SoranaMarra, Marco A.Huang, XiMalkin, DavidAyrault, OlivierRamaswamy, VijayPuente, Xose S.Calarco, John A.Stein, LincolnTaylor, Michael D.HostingInstitutionOrganizationalRepositório Científico de Acesso Aberto da ULisboae-mailmailto:repositorio@reitoria.ulisboa.ptrepositorio@reitoria.ulisboa.ptISSNIsPartOf0028-0836DOIIsPartOf10.1038/s41586-019-1650-02021-02-17T17:10:37Z20192019-01-01T00:00:00ZHandlehttp://hdl.handle.net/10451/46407http://purl.org/coar/access_right/c_16ecrestricted access12977499 bytesliteraturehttp://purl.org/coar/resource_type/c_6501journal articlehttp://purl.org/coar/access_right/c_16ecapplication/pdffulltexthttps://repositorio.ulisboa.pt/bitstreams/4883936f-7ede-400b-9909-2acfd56ddef6/downloadNature5747780707711 |
| spellingShingle | Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma Suzuki, Hiromichi |
| status | SINGLETON |
| title | Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma |
| title_full | Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma |
| title_fullStr | Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma |
| title_full_unstemmed | Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma |
| title_short | Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma |
| title_sort | Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma |
| url | http://hdl.handle.net/10451/46407 |
| visible | 1 |