Somatic inflammatory gene mutations in human ulcerative colitis epithelium

Nature. 2020 Jan;577(7789):254-259. doi: 10.1038/s41586-019-1844-5. Epub 2019 Dec 18.


With ageing, normal human tissues experience an expansion of somatic clones that carry cancer mutations1-7. However, whether such clonal expansion exists in the non-neoplastic intestine remains unknown. Here, using whole-exome sequencing data from 76 clonal human colon organoids, we identify a unique pattern of somatic mutagenesis in the inflamed epithelium of patients with ulcerative colitis. The affected epithelium accumulates somatic mutations in multiple genes that are related to IL-17 signalling-including NFKBIZ, ZC3H12A and PIGR, which are genes that are rarely affected in colon cancer. Targeted sequencing validates the pervasive spread of mutations that are related to IL-17 signalling. Unbiased CRISPR-based knockout screening in colon organoids reveals that the mutations confer resistance to the pro-apoptotic response that is induced by IL-17A. Some of these genetic mutations are known to exacerbate experimental colitis in mice8-11, and somatic mutagenesis in human colon epithelium may be causally linked to the inflammatory process. Our findings highlight a genetic landscape that adapts to a hostile microenvironment, and demonstrate its potential contribution to the pathogenesis of ulcerative colitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Colitis, Ulcerative / genetics*
  • Colitis, Ulcerative / metabolism
  • Epithelium / metabolism*
  • Humans
  • Interleukin-17 / genetics*
  • Interleukin-17 / metabolism
  • Mutation*
  • Phenotype
  • Signal Transduction


  • Interleukin-17