APOBEC mutagenesis is a common process in normal human small intestine

APOBEC mutational signatures SBS2 and SBS13 are common in many human cancer types. However, there is an incomplete understanding of its stimulus, when it occurs in the progression from normal to cancer cell and the APOBEC enzymes responsible. Here we whole-genome sequenced 342 microdissected normal...

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Bibliographic Details
Published in:	Nature genetics Vol. 55; no. 2; pp. 246 - 254
Main Authors:	Wang, Yichen, Robinson, Philip S., Coorens, Tim H. H., Moore, Luiza, Lee-Six, Henry, Noorani, Ayesha, Sanders, Mathijs A., Jung, Hyunchul, Katainen, Riku, Heuschkel, Robert, Brunton-Sim, Roxanne, Weston, Robyn, Read, Debbie, Nobbs, Beverley, Fitzgerald, Rebecca C., Saeb-Parsy, Kourosh, Martincorena, Iñigo, Campbell, Peter J., Rushbrook, Simon, Zilbauer, Matthias, Buczacki, Simon James Alexander, Stratton, Michael R.
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01-02-2023 Nature Publishing Group
Subjects:	38/91 45 45/23 631/114/2164 631/208/212 Adrenal glands Agriculture Animal Genetics and Genomics APOBEC-1 Deaminase - genetics Apolipoproteins B - genetics Biomedical and Life Sciences Biomedicine Biopsy Cancer Cancer Research Cancer therapies Chemotherapy Child Child, Preschool Confidence intervals Crypts Cytidine Deaminase - genetics Epithelium Gene Function Genomes Human Genetics Humans Intestine Intestine, Small Large intestine Life span mRNA Mutagenesis Mutagenesis - genetics Mutation Pancreas Phylogenetics Prostate RNA, Messenger - genetics Small intestine Stem cells Thyroid gland
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Summary:	APOBEC mutational signatures SBS2 and SBS13 are common in many human cancer types. However, there is an incomplete understanding of its stimulus, when it occurs in the progression from normal to cancer cell and the APOBEC enzymes responsible. Here we whole-genome sequenced 342 microdissected normal epithelial crypts from the small intestines of 39 individuals and found that SBS2/SBS13 mutations were present in 17% of crypts, more frequent than most other normal tissues. Crypts with SBS2/SBS13 often had immediate crypt neighbors without SBS2/SBS13, suggesting that the underlying cause of SBS2/SBS13 is cell-intrinsic. APOBEC mutagenesis occurred in an episodic manner throughout the human lifespan, including in young children. APOBEC1 mRNA levels were very high in the small intestine epithelium, but low in the large intestine epithelium and other tissues. The results suggest that the high levels of SBS2/SBS13 in the small intestine are collateral damage from APOBEC1 fulfilling its physiological function of editing APOB mRNA. Whole-genome sequencing of healthy human epithelial crypts from the small intestines of 39 individuals highlights APOBEC enzymes as a common contributor to the overall mutational burden in this tissue.
ISSN:	1061-4036 1546-1718
DOI:	10.1038/s41588-022-01296-5