1. APOBEC mutagenesis is a common process in normal human small intestine
- Author
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Wang, Yichen, Robinson, Philip S, Coorens, Tim HH, 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, ATG - Applied Tumor Genomics, Lauri Antti Aaltonen / Principal Investigator, Research Programs Unit, Wang, Yichen [0000-0001-5122-7545], Robinson, Philip S [0000-0002-6237-7159], Coorens, Tim HH [0000-0002-5826-3554], Moore, Luiza [0000-0001-5315-516X], Lee-Six, Henry [0000-0003-4831-8088], Fitzgerald, Rebecca C [0000-0002-3434-3568], Saeb-Parsy, Kourosh [0000-0002-0633-3696], Martincorena, Iñigo [0000-0003-1122-4416], Campbell, Peter J [0000-0002-3921-0510], Zilbauer, Matthias [0000-0002-7272-0547], Stratton, Michael R [0000-0001-6035-153X], and Apollo - University of Cambridge Repository
- Subjects
45 ,APOBEC-1 Deaminase ,Family proteins ,Signatures ,article ,1184 Genetics, developmental biology, physiology ,45/23 ,Dna ,Stem-cells ,38/91 ,631/114/2164 ,Mutagenesis ,Somatic mutations ,Child, Preschool ,Cytidine Deaminase ,Intestine, Small ,631/208/212 ,Genetics ,Humans ,RNA, Messenger ,Child ,Mutational processes ,Selection ,Apolipoproteins B ,Cancer - Abstract
Funder: Core funding from the Wellcome Sanger Institute (Wellcome Trust, No. 206194)., Funder: Wellcome PhD Studentship (Wellcome Trust, No. 206194), Funder: Wellcome Clinical PhD fellowship (Wellcome Trust, No. 206194), Funder: Pathological Society of Great Britain and Ireland; doi: https://doi.org/10.13039/501100000672, Funder: Jean Shank/Pathological Society of Great Britain and Ireland Intermediate Clinical Fellowship(JSPS IF 2019 01), Funder: Finnish Center of Excellence Program 2018–2025, No. 312041, Funder: NIHR Cambridge Biomedical Research Centre, Funder: Core funding from The Pharsalia Trust., 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.
- Published
- 2023