TY - JOUR
T1 - APOBEC mutagenesis is a common process in normal human small intestine
AU - Wang, Yichen
AU - Robinson, Philip S.
AU - Coorens, Tim H.H.
AU - Moore, Luiza
AU - Lee-Six, Henry
AU - Noorani, Ayesha
AU - Sanders, Mathijs A.
AU - Jung, Hyunchul
AU - Katainen, Riku
AU - Heuschkel, Robert
AU - Brunton-Sim, Roxanne
AU - Weston, Robyn
AU - Read, Debbie
AU - Nobbs, Beverley
AU - Fitzgerald, Rebecca C.
AU - Saeb-Parsy, Kourosh
AU - Martincorena, Iñigo
AU - Campbell, Peter J.
AU - Rushbrook, Simon
AU - Zilbauer, Matthias
AU - Buczacki, Simon James Alexander
AU - Stratton, Michael R.
N1 - Data availability
DNA sequencing data generated for this study are deposited in the European Genome-Phenome Archive (EGA) with accession code EGAD00001008764. Existing DNA sequencing datasets used in the study are deposited in EGA with accession code EGAD00001004192 (PD37449, PD34200 and PD37266) and EGAD00001006641 (PD28690, PD43850 and PD43851). Existing RNA sequencing datasets were downloaded from Gut Cell Survey (https://www.gutcellatlas.org/), Tabula Sapiens (https://tabula-sapiens-portal.ds.czbiohub.org/) and Gene Expression Omnibus (GSE125970 and GSE116222, read counts and cluster results downloaded from the Human Protein Atlas: https://www.proteinatlas.org/about/download). The cBioPortal MutationMapper database used to annotate cancer hotspot mutations was accessed at https://www.cbioportal.org/mutation_mapper?standaloneMutationMapperGeneTab=ATM.
Code availability
Code required to reproduce the analyses in this paper is available online. Mutation-calling algorithms are available through GitHub (https://github.com/cancerit). Variant calling filters can be found at https://github.com/MathijsSanders/SangerLCMFiltering and https://github.com/TimCoorens/Unmatched_NormSeq. All other custom code used in this study is available online at https://github.com/YichenWang1/small_bowel.
Acknowledgements
We thank the staff of the Wellcome Sanger Institute Sample Logistics, Genotyping, Pulldown, Sequencing and Informatics facilities for their many contributions, especially L. O’Neill, Y. Hooks, C. Latimer, K. Roberts and I. Whitmore for their support with sample management and laboratory work.We thank S. Moody, E. Dunstone, R. Rahbari, S. Behjati and F. Markowetz (University of Cambridge and Cancer Research UK Cambridge Institute) for discussion of the results, C. Suo, W. Wang (Technical University of Munich), W. Zhao (Karolinska Institutet) for discussion regarding single-cell RNA-seq data analysis, S. Olafsson and M. Przybilla for discussion regarding statistical analyses. We gratefully acknowledge the contributions to this study made by the University of Birmingham’s Human Biomaterials Resource Centre, which has been supported through Birmingham Science City—Experimental Medicine Network of Excellence Project; especially, we thank S. Beard and E. Hurlestone for coordination. We thank Cambridge University Hospitals NHS Foundation Trust Tissue Bank for assistance in the acquisition of samples, especially J. R. Davies for assistance in clinical data collection. We thank members of the Phoenix Consortium, in particular I. Debiram-Beecham and N. Grehan for their help with patient recruitment and sample collection. We also thank Royal Papworth Hospital NHS Trust Mortuary, in particular, M. Goddard and S. Preston for help with sample acquisition. We thank L. A. Aaltonen (University of Helsinki) for coordinating small bowel cancer data analysis. We thank all the patients and their families, without their support this work would not have been possible.
The GTEx Project is supported by the Common Fund of the Office of the Director of the National Institutes of Health, NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS. The GTEx data used for the analyses described in this manuscript were obtained from the HPA Project. For the purpose of open access, the authors have applied a CC-BY public copyright license to any author-accepted manuscript version arising from this submission.
PY - 2023/2
Y1 - 2023/2
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85146867610
U2 - 10.1038/s41588-022-01296-5
DO - 10.1038/s41588-022-01296-5
M3 - Article
C2 - 36702998
AN - SCOPUS:85146867610
SN - 1061-4036
VL - 55
SP - 246
EP - 254
JO - Nature Genetics
JF - Nature Genetics
IS - 2
ER -
SDG 3 Good Health and Well-being