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 Laan; Jeroen de Jonge; Jan N M IJzermans; Robert G Vries; Marc van de Wetering; Michael R Stratton; Hans Clevers; Edwin Cuppen; Ruben van Boxtel

doi:10.1038/nature19768

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

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

657 Citations (Scopus)

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.

Original language	English
Pages (from-to)	260-264
Number of pages	5
Journal	Nature
Volume	538
Issue number	7624
DOIs	https://doi.org/10.1038/nature19768
Publication status	Published - 13 Oct 2016

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Blokzijl, F., de Ligt, J., Jager, M., Sasselli, V., Roerink, S., Sasaki, N., Huch, M., Boymans, S., Kuijk, E., Prins, P., Nijman, I. J., Martincorena, I., Mokry, M., Wiegerinck, C. L., Middendorp, S., Sato, T., Schwank, G., Nieuwenhuis, E. E. S., Verstegen, M. M. A., ... van Boxtel, R. (2016). Tissue-specific mutation accumulation in human adult stem cells during life. Nature, 538(7624), 260-264. https://doi.org/10.1038/nature19768

@article{634520fa726b4900ade45ccb026d3202,

title = "Tissue-specific mutation accumulation in human adult stem cells during life",

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.",

author = "Francis Blokzijl and {de Ligt}, Joep and Myrthe Jager and Valentina Sasselli and Sophie Roerink and Nobuo Sasaki and Meritxell Huch and Sander Boymans and Ewart Kuijk and Pjotr Prins and Nijman, {Isaac J} and Inigo Martincorena and Michal Mokry and Wiegerinck, {Caroline L} and Sabine Middendorp and Toshiro Sato and Gerald Schwank and Nieuwenhuis, {Edward E S} and Verstegen, {Monique M A} and {van der Laan}, {Luc J W} and {de Jonge}, Jeroen and IJzermans, {Jan N M} and Vries, {Robert G} and {van de Wetering}, Marc and Stratton, {Michael R} and Hans Clevers and Edwin Cuppen and {van Boxtel}, Ruben",

year = "2016",

month = oct,

day = "13",

doi = "10.1038/nature19768",

language = "English",

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pages = "260--264",

journal = "Nature",

issn = "0028-0836",

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Blokzijl, F, de Ligt, J, Jager, M, Sasselli, V, Roerink, S, Sasaki, N, Huch, M, Boymans, S, Kuijk, E, Prins, P, Nijman, IJ, Martincorena, I, Mokry, M, Wiegerinck, CL, Middendorp, S, Sato, T, Schwank, G, Nieuwenhuis, EES, Verstegen, MMA, van der Laan, LJW, de Jonge, J, IJzermans, JNM, Vries, RG, van de Wetering, M, Stratton, MR, Clevers, H, Cuppen, E & van Boxtel, R 2016, 'Tissue-specific mutation accumulation in human adult stem cells during life', Nature, vol. 538, no. 7624, pp. 260-264. https://doi.org/10.1038/nature19768

TY - JOUR

T1 - Tissue-specific mutation accumulation in human adult stem cells during life

AU - Blokzijl, Francis

AU - de Ligt, Joep

AU - Jager, Myrthe

AU - Sasselli, Valentina

AU - Roerink, Sophie

AU - Sasaki, Nobuo

AU - Huch, Meritxell

AU - Boymans, Sander

AU - Kuijk, Ewart

AU - Prins, Pjotr

AU - Nijman, Isaac J

AU - Martincorena, Inigo

AU - Mokry, Michal

AU - Wiegerinck, Caroline L

AU - Middendorp, Sabine

AU - Sato, Toshiro

AU - Schwank, Gerald

AU - Nieuwenhuis, Edward E S

AU - Verstegen, Monique M A

AU - van der Laan, Luc J W

AU - de Jonge, Jeroen

AU - IJzermans, Jan N M

AU - Vries, Robert G

AU - van de Wetering, Marc

AU - Stratton, Michael R

AU - Clevers, Hans

AU - Cuppen, Edwin

AU - van Boxtel, Ruben

PY - 2016/10/13

Y1 - 2016/10/13

N2 - 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.

AB - 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.

U2 - 10.1038/nature19768

DO - 10.1038/nature19768

M3 - Article

C2 - 27698416

SN - 0028-0836

VL - 538

SP - 260

EP - 264

JO - Nature

JF - Nature

IS - 7624

ER -

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

Abstract

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