About this item:

265 Views | 65 Downloads

Author Notes:

Correspondence: Michael D. Taylor

Author contributions: M.D.T. led the study. H.S., S.S. and S.D.B. performed whole genome sequencing analysis (Figure 1,​,2,2, Extended Data Fig. 1–3). F.M.G.C., N.G., J.R. and A.S.M. contributed to the pre-processing of RNA-seq data. H.S. and H.F. contributed to SNP6 copy number analyses (Extended Data Fig. 1,​,4c4c,​,d).d).

H.S., S.S., F.M.G.C., I.S. and J.Z. contributed to RNA expression analyses (Extended Data Fig. 7a). H.S., S.S., I.S., A.F., S.D.B. and O.A. contributed to alternative splicing analyses (Figure 4a–d, Extended Data Fig. 5–10). H.S. and V.R. performed clinical analysis (Figure 3, Extended Data Fig. 4e–i).

A.G. and M.A.M. helped with bioinformatics analyses and provided expert advice. S.A.K., P.D.A., K.J. and M.C.V. performed RT-PCR and qPCR analyses (Figure 4e,​,f,f, Extended Data Fig. 9d, 10e,​,l).l). S.A.K., A.D.-N., A.G.-F., P.D.A., K.J., I.S., N.A., D.P., A.M., J.W., W.D., R.J.W.-R. and X.S.P. contributed to exogenous expression experiments (Extended Data Fig. 7b–d).

S.A.K., K.J. and I. S. performed rhAMP SNP experiments (Figure 1, ​,3a3a–c, Extended Data Fig. 1, ​,4a4a,​,b).b). P.S. and B.Luu contributed to the collection and processing of human tissue samples. C.D., X.W., R.J.W.-R., L.G., X.H., X.S.P., J.A.Chan and L.S. provided expert advice for experiments.

S-K.K., W.A.G., A.J., M.F-M., M.L.G., A.A.N.R., C.G., J.M.K., P.J.F., N.J., H.-K. N., W.S.P., C.G.E., I.F.P., J.M.O., W.A.W., T.K., E.L.-A., B.Lach, M.M., E.G.V.M., J.B.R., R.V., L.B.C., N.K., A.K., L.B., J.A.Calarco, C.C.F., S.M.P., L.G. and D.M. provided patient material and helped design the study. H.S., S.A.K., S.S., J.A.Calarco, L.S., and M.D.T. prepared manuscript and figures.

Competing interests: The authors declare no competing interests.

Subjects:

Research Funding:

M.D.T. is supported by the NIH (R01CA148699 and R01CA159859), The Pediatric Brain Tumour Foundation, The Terry Fox Research Institute, The Canadian Institutes of Health Research, The Cure Search Foundation, b.r.a.i.n.child, Meagan’s Walk, Genome Canada, Genome BC, Genome Quebec, the Ontario Research Fund, Worldwide Cancer Research, V-Foundation for Cancer Research, and the Ontario Institute for Cancer Research through funding provided by the Government of Ontario.

M.D.T. is also supported by a Canadian Cancer Society Research Institute Impact grant and by a Stand Up To Cancer (SU2C) St. Baldrick’s Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113) and SU2C Canada Cancer Stem Cell Dream Team Research Funding (SU2C-AACR-DT-19–15) provided by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, with supplementary support from the Ontario Institute for Cancer Research through funding provided by the Government of Ontario.

Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. M.D.T. is also supported by the Garron Family Chair in Childhood Cancer Research at the Hospital for Sick Children and the University of Toronto. E.G.V.M. is supported by the NIH (R01-NS096236 and R01CA235162) and the CURE Childhood Cancer Foundation.

X. S. P. is supported by Ministerio de Economía y Competitividad (MINECO) (SAF2013–45836-R). A.K. was supported by 2017–1.2.1-NKP-2017–00002 National Brain Research Program NAP 2.0. M. L. G. is supported by AIRC (Italian Association for Cancer Research) and by Fondazione Berlucchi.

H.S. is a recipient of a Research Fellowship (Astellas Foundation for Research on Metabolic Disorders). S.A.K. is a recipient of funding from the Restracomp Research Fellowship (SickKids Research Institute) and the MD/PhD Studentship Award (Canadian Institute of Health Research).

A. D-N is a recipient of the Department of Education of the Basque Government (PRE_2017_1_0100). J.R. is supported by Genome Canada Genome Technology Platform Grant 12505, Canada Foundation for Innovation Project 33408.

Computations were partially performed on the NIG supercomputer at ROIS National Institute of Genetics and on the Niagara supercomputer at the SciNet HPC Consortium.

SciNet is funded by the Canada Foundation for Innovation under the auspices of Compute Canada; the Government of Ontario; Ontario Research Fund - Research Excellence; and the University of Toronto.

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • Somatic point mutations
  • Copt number
  • RNA
  • Identification
  • Cancer

Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma

Tools:

Journal Title:

Nature

Volume:

Volume 574, Number 7780

Publisher:

, Pages 707-+

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© The Author(s), under exclusive licence to Springer Nature Limited 2019.

Export to EndNote