Nature genetics · 2023
APOBEC mutagenesis is a common process in normal human small intestine.
СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаНазвание и аннотация: Перевод пока не подготовлен
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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
Аннотация
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.