Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma

Nature. 2019 Oct;574(7780):707-711. doi: 10.1038/s41586-019-1650-0. Epub 2019 Oct 9.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Alternative Splicing
  • Cerebellar Neoplasms / genetics*
  • Hedgehog Proteins / genetics*
  • Hedgehog Proteins / metabolism
  • Humans
  • Medulloblastoma / genetics*
  • Mutation
  • RNA Splice Sites
  • RNA Splicing
  • RNA, Small Nuclear / genetics*

Substances

  • Hedgehog Proteins
  • RNA Splice Sites
  • RNA, Small Nuclear
  • U1 small nuclear RNA