The gradual accumulation of genetic mutations in human adult stem cells (ASCs) during life is associated with various age-related diseases, including cancer1,2. Extreme variation in cancer risk across tissues was recently proposed to depend on the lifetime number of ASC divisions, owing to unavoidable random mutations that arise during DNA replication1. However, the rates and patterns of mutations in normal ASCs remain unknown. Here we determine genome-wide mutation patterns in ASCs of the small intestine, colon and liver of human donors with ages ranging from 3 to 87 years by sequencing clonal organoid cultures derived from primary multipotent cells3,4,5. Our results show that mutations accumulate steadily over time in all of the assessed tissue types, at a rate of approximately 40 novel mutations per year, despite the large variation in cancer incidence among these tissues1. Liver ASCs, however, have different mutation spectra compared to those of the colon and small intestine. Mutational signature analysis reveals that this difference can be attributed to spontaneous deamination of methylated cytosine residues in the colon and small intestine, probably reflecting their high ASC division rate. In liver, a signature with an as-yet-unknown underlying mechanism is predominant. Mutation spectra of driver genes in cancer show high similarity to the tissue-specific ASC mutation spectra, suggesting that intrinsic mutational processes in ASCs can initiate tumorigenesis. Notably, the inter-individual variation in mutation rate and spectra are low, suggesting tissue-specific activity of common mutational processes throughout life.
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European Nucleotide Archive
The human sequencing data have been deposited at the European Genome-phenome Archive (http://www.ebi.ac.uk/ega/) under accession numbers EGAS00001001682 and EGAS00001000881. The mouse sequencing data have been deposited at the European Nucleotide Archive (http://www.ebi.ac.uk/ena/) under accession number ERP005717.
The authors would like to thank the gastroenterologists of the UMCU/Wilhelmina Children’s Hospital and Diakonessen Hospital for obtaining human duodenal and colon biopsies and R. Eijkemans for his advice on the statistical analyses. This study was financially supported by a Zenith grant of the Netherlands Genomics Initiative (935.12.003) to E.C., the NWO Zwaartekracht program Cancer Genomics.nl and funding of Worldwide Cancer Research (WCR no. 16-0193) to R.B. We declare no competing financial interests.
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Proceedings of the National Academy of Sciences (2019)