The U1 spliceosomal RNA is recurrently mutated in multiple cancers

Nature. 2019 Oct;574(7780):712-716. doi: 10.1038/s41586-019-1651-z. Epub 2019 Oct 9.

Abstract

Cancers are caused by genomic alterations known as drivers. Hundreds of drivers in coding genes are known but, to date, only a handful of noncoding drivers have been discovered-despite intensive searching1,2. Attention has recently shifted to the role of altered RNA splicing in cancer; driver mutations that lead to transcriptome-wide aberrant splicing have been identified in multiple types of cancer, although these mutations have only been found in protein-coding splicing factors such as splicing factor 3b subunit 1 (SF3B1)3-6. By contrast, cancer-related alterations in the noncoding component of the spliceosome-a series of small nuclear RNAs (snRNAs)-have barely been studied, owing to the combined challenges of characterizing noncoding cancer drivers and the repetitive nature of snRNA genes1,7,8. Here we report a highly recurrent A>C somatic mutation at the third base of U1 snRNA in several types of tumour. The primary function of U1 snRNA is to recognize the 5' splice site via base-pairing. This mutation changes the preferential A-U base-pairing between U1 snRNA and the 5' splice site to C-G base-pairing, and thus creates novel splice junctions and alters the splicing pattern of multiple genes-including known drivers of cancer. Clinically, the A>C mutation is associated with heavy alcohol use in patients with hepatocellular carcinoma, and with the aggressive subtype of chronic lymphocytic leukaemia with unmutated immunoglobulin heavy-chain variable regions. The mutation in U1 snRNA also independently confers an adverse prognosis to patients with chronic lymphocytic leukaemia. Our study demonstrates a noncoding driver in spliceosomal RNAs, reveals a mechanism of aberrant splicing in cancer and may represent a new target for treatment. Our findings also suggest that driver discovery should be extended to a wider range of genomic regions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Mutation*
  • Neoplasms / genetics*
  • Neoplasms / pathology
  • Neoplasms / physiopathology
  • RNA Splice Sites
  • RNA Splicing
  • RNA Splicing Factors / genetics
  • RNA, Small Nuclear / genetics*
  • Spliceosomes / genetics*

Substances

  • RNA Splice Sites
  • RNA Splicing Factors
  • RNA, Small Nuclear
  • U1 small nuclear RNA