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Nature. 2016 Oct 13;538(7624):260-264. doi: 10.1038/nature19768. Epub 2016 Oct 3.

Tissue-specific mutation accumulation in human adult stem cells during life.

Author information

1
Center for Molecular Medicine, Cancer Genomics Netherlands, Department of Genetics, University Medical Center Utrecht, Heidelberglaan 100, 3584CX Utrecht, The Netherlands.
2
Hubrecht Institute for Developmental Biology and Stem Cell Research, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.
3
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
4
Department of Pediatrics, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, The Netherlands.
5
Department of Surgery, Erasmus MC-University Medical Center, Postbus 2040, 3000 CA Rotterdam, The Netherlands.
6
Foundation Hubrecht Organoid Technology (HUB), Uppsalalaan 8, 3584CT Utrecht, The Netherlands.

Abstract

The gradual accumulation of genetic mutations in human adult stem cells (ASCs) during life is associated with various age-related diseases, including cancer. 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 replication. 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 cells. 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 tissues. 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.

PMID:
27698416
PMCID:
PMC5536223
DOI:
10.1038/nature19768
[Indexed for MEDLINE]
Free PMC Article

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