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

Francis Blokzijl, Joep De Ligt, Myrthe Jager, Valentina Sasselli, Sophie Roerink, Nobuo Sasaki, Meritxell Huch, Sander Boymans, Ewart Kuijk, Pjotr Prins, Isaac J. Nijman, Inigo Martincorena, Michal Mokry, Caroline L. Wiegerinck, Sabine Middendorp, Toshiro Sato, Gerald Schwank, Edward E.S. Nieuwenhuis, Monique M.A. Verstegen, Luc J.W. Van Der LaanJeroen De Jonge, Jan N.M. Ijzermans, Robert G. Vries, Marc Van De Wetering, Michael R. Stratton, Hans Clevers, Edwin Cuppen, Ruben Van Boxtel

研究成果: Article査読

430 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)260-264
ページ数5
ジャーナルNature
538
7624
DOI
出版ステータスPublished - 2016
外部発表はい

ASJC Scopus subject areas

  • 一般

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