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Somatic inflammatory gene mutations in human ulcerative colitis epithelium
With ageing, normal human tissues experience an expansion of somatic clones that carry cancer mutations 1 – 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 u...
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Published in: | Nature (London) 2020-01, Vol.577 (7789), p.254-259 |
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Main Authors: | , , , , , , , , , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | With ageing, normal human tissues experience an expansion of somatic clones that carry cancer mutations
1
–
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 mice
8
–
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.
Whole-exome sequencing of colon organoids derived from patients with ulcerative colitis identifies somatic mutations in components of the IL-17 signalling pathway, which may confer a growth advantage to cells under inflammatory conditions. |
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ISSN: | 0028-0836 1476-4687 |
DOI: | 10.1038/s41586-019-1844-5 |