Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma

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

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)707-711
Number of pages5
JournalNature
Volume574
Issue number7780
DOIs
StatePublished - Oct 31 2019

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Medulloblastoma
Mutation
Neoplasms
RNA Splicing
Small Nuclear RNA
RNA Splice Sites
Neoplasm Genes
Alternative Splicing
Tumor Suppressor Genes
Oncogenes
Nucleotides
U1 small nuclear RNA
Pediatrics

ASJC Scopus subject areas

  • General

Cite this

Suzuki, H., Kumar, S. A., Shuai, S., Diaz-Navarro, A., Gutierrez-Fernandez, A., De Antonellis, P., ... Taylor, M. D. (2019). Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma. Nature, 574(7780), 707-711. https://doi.org/10.1038/s41586-019-1650-0

Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma. / 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 C.; 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.

In: Nature, Vol. 574, No. 7780, 31.10.2019, p. 707-711.

Research output: Contribution to journalArticle

Suzuki, H, Kumar, SA, Shuai, S, Diaz-Navarro, A, Gutierrez-Fernandez, A, De Antonellis, P, Cavalli, FMG, Juraschka, K, Farooq, H, Shibahara, I, Vladoiu, MC, 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, SK, Grajkowska, WA, Jouvet, A, Fèvre-Montange, M, Garrè, ML, Nageswara Rao, AA, Giannini, C, Kros, JM, French, PJ, Jabado, N, Ng, HK, Poon, WS, Eberhart, CG, Pollack, IF, Olson, JM, Weiss, WA, Kumabe, T, López-Aguilar, E, Lach, B, Massimino, M, Van Meir, EG, Rubin, JB, Vibhakar, R, Chambless, LB, Kijima, N, Klekner, A, Bognár, L, Chan, JA, Faria, CC, Ragoussis, J, Pfister, SM, Goldenberg, A, Wechsler-Reya, RJ, Bailey, SD, Garzia, L, Morrissy, AS, Marra, MA, Huang, X, Malkin, D, Ayrault, O, Ramaswamy, V, Puente, XS, Calarco, JA, Stein, L & Taylor, MD 2019, 'Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma', Nature, vol. 574, no. 7780, pp. 707-711. https://doi.org/10.1038/s41586-019-1650-0
Suzuki H, Kumar SA, Shuai S, Diaz-Navarro A, Gutierrez-Fernandez A, De Antonellis P et al. Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma. Nature. 2019 Oct 31;574(7780):707-711. https://doi.org/10.1038/s41586-019-1650-0
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 C. ; 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. / Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma. In: Nature. 2019 ; Vol. 574, No. 7780. pp. 707-711.
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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.",
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T1 - Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma

AU - Suzuki, Hiromichi

AU - Kumar, Sachin A.

AU - Shuai, Shimin

AU - Diaz-Navarro, Ander

AU - Gutierrez-Fernandez, Ana

AU - De Antonellis, Pasqualino

AU - Cavalli, Florence M.G.

AU - Juraschka, Kyle

AU - Farooq, Hamza

AU - Shibahara, Ichiyo

AU - Vladoiu, Maria C.

AU - Zhang, Jiao

AU - Abeysundara, Namal

AU - Przelicki, David

AU - Skowron, Patryk

AU - Gauer, Nicole

AU - Luu, Betty

AU - Daniels, Craig

AU - Wu, Xiaochong

AU - Forget, Antoine

AU - Momin, Ali

AU - Wang, Jun

AU - Dong, Weifan

AU - Kim, Seung Ki

AU - Grajkowska, Wieslawa A.

AU - Jouvet, Anne

AU - Fèvre-Montange, Michelle

AU - Garrè, Maria Luisa

AU - Nageswara Rao, Amulya A.

AU - Giannini, Caterina

AU - Kros, Johan M.

AU - French, Pim J.

AU - Jabado, Nada

AU - Ng, Ho Keung

AU - Poon, Wai Sang

AU - Eberhart, Charles G.

AU - Pollack, Ian F.

AU - Olson, James M.

AU - Weiss, William A.

AU - Kumabe, Toshihiro

AU - López-Aguilar, Enrique

AU - Lach, Boleslaw

AU - Massimino, Maura

AU - Van Meir, Erwin G.

AU - Rubin, Joshua B.

AU - Vibhakar, Rajeev

AU - Chambless, Lola B.

AU - Kijima, Noriyuki

AU - Klekner, Almos

AU - Bognár, László

AU - Chan, Jennifer A.

AU - Faria, Claudia C.

AU - Ragoussis, Jiannis

AU - Pfister, Stefan M.

AU - Goldenberg, Anna

AU - Wechsler-Reya, Robert J.

AU - Bailey, Swneke D.

AU - Garzia, Livia

AU - Morrissy, A. Sorana

AU - Marra, Marco A.

AU - Huang, Xi

AU - Malkin, David

AU - Ayrault, Olivier

AU - Ramaswamy, Vijay

AU - Puente, Xose S.

AU - Calarco, John A.

AU - Stein, Lincoln

AU - Taylor, Michael D.

PY - 2019/10/31

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N2 - 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.

AB - 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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