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首页> 外文期刊>Nature >Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma
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Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma

机译：复发性非编码性U1 snRNA突变驱动SHH髓母细胞瘤的隐秘剪接

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摘要

In cancer, recurrent somatic single-nucleotide variants-which are rare in most paediatric cancers-are confined largely to protein-coding genes(1-3). 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 SHH delta) and 25% of adolescents (subtype SHH alpha) 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.
机译：在癌症中，复发性的体细胞单核苷酸变异体（在大多数儿科癌症中很少见）主要局限于蛋白质编码基因（1-3）。在这里，我们报道了大约50％的声波刺猬（SHH）髓母细胞瘤中U1剪接小核RNA（snRNA）的高度复发性热点突变（r.3A> G）。这些突变在髓母细胞瘤的其他亚组中不存在，我们在其他36种肿瘤类型中，仅在<442％的癌症中，只有<0.1％的U1 snRNA中发现了这些热点突变。该突变发生在97％的成年人（SHH三角型亚型）和25％的青少年（SHHα型亚型）患有SHH髓母细胞瘤的突变中，但婴儿SHH髓母细胞瘤却很少出现这种突变。 U1 snRNA突变发生在5'剪接位点结合区域，并且snRNA突变的肿瘤已显着破坏RNA剪接和过多的5'隐式剪接事件。由突变U1 snRNA介导的选择性剪接使肿瘤抑制基因（PTCH1）失活并激活癌基因（GLI2和CCND2），是治疗的靶点。这些U1 snRNA突变为癌症中非蛋白质编码基因的高度复发性和组织特异性突变提供了一个例子。

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  • 来源
    《Nature》 |2019年第7780期|707-711|共5页
  • 作者

    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; Fevre-Montange Michelle; Garre Maria Luisa; Rao Amulya A. Nageswara; 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; Lopez-Aguilar Enrique; Lach Boleslaw; Massimino Maura; Van Meir Erwin G.; Rubin Joshua B.; Vibhakar Rajeev; Chambless Lola B.; Kijima Noriyuki; Klekner Almos; Bognar Laszlo; 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.;

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    Hosp Sick Children Arthur & Sonia Labatt Brain Tumour Res Ctr Toronto ON Canada|Hosp Sick Children Dev & Stem Cell Biol Program Toronto ON Canada;

    Hosp Sick Children Arthur & Sonia Labatt Brain Tumour Res Ctr Toronto ON Canada|Hosp Sick Children Dev & Stem Cell Biol Program Toronto ON Canada|Univ Toronto Dept Lab Med & Pathobiol Toronto ON Canada;

    Ontario Inst Canc Res Informat & Biocomp Toronto ON Canada|Univ Toronto Dept Mol Genet Toronto ON Canada;

    Univ Oviedo Inst Univ Oncol Dept Bioquim & Biol Mol Oviedo Spain|Ctr Invest Biomed Red Canc Madrid Spain;

    Hosp Sick Children Dev & Stem Cell Biol Program Toronto ON Canada;

    PSL Res Univ Inst Curie INSERM CNRS UMR Orsay France|Univ Paris Saclay Univ Paris Sud INSERM CNRS UMR 3347 U1021 Orsay France;

    Hosp Sick Children Arthur & Sonia Labatt Brain Tumour Res Ctr Toronto ON Canada|Hosp Sick Children Dev & Stem Cell Biol Program Toronto ON Canada|Univ Toronto Dept Mol Genet Toronto ON Canada;

    Sanford Burnham Prebys Med Discovery Inst NCI Designated Canc Ctr Tumor Initiat & Maintenance Program La Jolla CA USA;

    Seoul Natl Univ Childrens Hosp Div Pediat Neurosurg Dept Neurosurg Seoul South Korea;

    Childrens Mem Hlth Inst Dept Pathol Warsaw Poland;

    Univ Lyon Grp Hosp EST Ctr Pathol EST Bron France;

    Univ Lyon Ctr Rech Neurosci INSERM CNRS UMR5292 U1028 Lyon France;

    Ist Giannina Gaslini Neurooncol Unit Genoa Italy;

    Mayo Clin Div Pediat Hematol Oncol Rochester MN USA;

    Mayo Clin Dept Lab Med & Pathol Rochester MN USA;

    Erasmus MC Dept Pathol Rotterdam Netherlands;

    Erasmus MC Dept Neurol Rotterdam Netherlands;

    McGill Univ Div Expt Med Montreal PQ Canada;

    Chinese Univ Hong Kong Dept Anat & Cellular Pathol Hong Kong Peoples R China;

    Chinese Univ Hong Kong Dept Surg Hong Kong Peoples R China;

    Johns Hopkins Univ Sch Med Dept Pathol Baltimore MD 21205 USA|Johns Hopkins Univ Sch Med Dept Ophthalmol Baltimore MD 21205 USA|Johns Hopkins Univ Sch Med Dept Oncol Baltimore MD 21205 USA;

    Univ Pittsburgh Sch Med Dept Neurol Surg Pittsburgh PA 15261 USA;

    Fred Hutchinson Canc Res Ctr Div Clin Res 1124 Columbia St Seattle WA 98104 USA;

    Univ Calif San Francisco Dept Neurol Surg San Francisco CA USA|Univ Calif San Francisco Dept Pediat San Francisco CA USA|Univ Calif San Francisco Dept Neurol San Francisco CA USA;

    Kitasato Univ Dept Neurosurg Sch Med Sagamihara Kanagawa Japan;

    Hosp Pediat Ctr Med Nacl Century XXI Div Pediat Hematol Oncol Mexico City DF Mexico;

    McMaster Univ Div Anat Pathol Dept Pathol & Mol Med Hamilton ON Canada|Hamilton Gen Hosp Dept Pathol & Lab Med Hamilton ON Canada;

    Fdn IRCCS Ist Nazl Tumori Milan Italy;

    Emory Univ Winship Canc Inst Atlanta GA 30322 USA|Emory Univ Sch Med Dept Neurosurg Lab Mol Neurooncol Atlanta GA USA|Emory Univ Sch Med Dept Hematol & Med Oncol Atlanta GA USA;

    Washington Univ Sch Med Dept Neurosci St Louis MO USA|Washington Univ Sch Med Dept Pediat St Louis MO 63110 USA;

    Univ Colorado Dept Pediat Anschutz Med Campus Aurora CO USA;

    Vanderbilt Univ Sch Med Dept Neurol Surg Nashville TN USA;

    Osaka Natl Hosp Dept Neurosurg Osaka Japan;

    Univ Debrecen Med & Hlth Sci Ctr Dept Neurosurg Debrecen Hungary;

    Univ Calgary Charbonneau Canc Inst Calgary AB Canada;

    Hosp Santa Maria Ctr Hosp Lisboa Norte Div Neurosurg Lisbon Portugal|Univ Lisbon Fac Med Inst Med Mol Joao Lobo Antunes Lisbon Portugal;

    McGill Univ Montreal PQ Canada|McGill Univ Genome Quebec Innovat Ctr Dept Human Genet Montreal PQ Canada|McGill Univ Dept Bioengn Montreal PQ Canada;

    Hopp Childrens Canc Ctr Heidelberg KiTZ Heidelberg Germany|German Canc Res Ctr Div Pediat Neurooncol Heidelberg Germany|German Canc Consortium DKTK Heidelberg Germany|Heidelberg Univ Hosp Dept Pediat Hematol & Oncol Heidelberg Germany;

    Univ Toronto Dept Comp Sci Toronto ON Canada|Hosp Sick Children Program Genet & Genome Biol Toronto ON Canada;

    Sanford Burnham Prebys Med Discovery Inst NCI Designated Canc Ctr Tumor Initiat & Maintenance Program La Jolla CA USA|Univ Calif San Diego Dept Pediat San Diego CA 92103 USA;

    McGill Univ Fac Med Div Thorac & Upper Gastrointestinal Surg Dept Surg Montreal PQ Canada|McGill Univ Res Inst Canc Res Program Ctr Hlth Montreal PQ Canada;

    McGill Univ Res Inst Canc Res Program Ctr Hlth Montreal PQ Canada|McGill Univ Div Orthoped Surg Dept Surg Fac Med Montreal PQ Canada;

    Univ Calgary Charbonneau Canc Inst Calgary AB Canada|Univ Calgary Cumming Sch Med Dept Biochem & Mol Biol Calgary AB Canada;

    BC Canc Agcy Canadas Michael Smith Genome Sci Ctr Vancouver BC Canada|Univ British Columbia Dept Med Genet Vancouver BC Canada;

    Hosp Sick Children Dept Pediat Dept Haematol Oncol Toronto ON Canada;

    Hosp Sick Children Dev & Stem Cell Biol Program Toronto ON Canada|Hosp Sick Children Dept Pediat Dept Haematol Oncol Toronto ON Canada;

    Univ Toronto Dept Cell & Syst Biol Toronto ON Canada;

    Ontario Inst Canc Res Informat & Biocomp Toronto ON Canada;

    Hosp Sick Children Arthur & Sonia Labatt Brain Tumour Res Ctr Toronto ON Canada|Hosp Sick Children Dev & Stem Cell Biol Program Toronto ON Canada|Univ Toronto Dept Lab Med & Pathobiol Toronto ON Canada|Hosp Sick Children Div Neurosurg Toronto ON Canada;

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