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.
authors.affiliation: Center for Molecular Medicine, Cancer Genomics Netherlands, Department of Genetics, University Medical Center Utrecht, Heidelberglaan 100, 3584CX Utrecht, The Netherlands.|Hubrecht Institute for Developmental Biology and Stem Cell Research, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.
authors.forename: Francis
authors.initials: F
authors.lastname: Blokzijl
authors.affiliation: Center for Molecular Medicine, Cancer Genomics Netherlands, Department of Genetics, University Medical Center Utrecht, Heidelberglaan 100, 3584CX Utrecht, The Netherlands.|Hubrecht Institute for Developmental Biology and Stem Cell Research, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.
authors.forename: Joep
authors.initials: J
authors.lastname: de Ligt
authors.affiliation: Center for Molecular Medicine, Cancer Genomics Netherlands, Department of Genetics, University Medical Center Utrecht, Heidelberglaan 100, 3584CX Utrecht, The Netherlands.|Hubrecht Institute for Developmental Biology and Stem Cell Research, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.
authors.forename: Myrthe
authors.initials: M
authors.lastname: Jager
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.
authors.forename: Valentina
authors.initials: V
authors.lastname: Sasselli
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
authors.forename: Sophie
authors.initials: S
authors.lastname: Roerink
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Sasaki
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.
authors.forename: Meritxell
authors.initials: M
authors.lastname: Huch
authors.affiliation: Center for Molecular Medicine, Cancer Genomics Netherlands, Department of Genetics, University Medical Center Utrecht, Heidelberglaan 100, 3584CX Utrecht, The Netherlands.|Hubrecht Institute for Developmental Biology and Stem Cell Research, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.
authors.forename: Sander
authors.initials: S
authors.lastname: Boymans
authors.affiliation: Center for Molecular Medicine, Cancer Genomics Netherlands, Department of Genetics, University Medical Center Utrecht, Heidelberglaan 100, 3584CX Utrecht, The Netherlands.|Hubrecht Institute for Developmental Biology and Stem Cell Research, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.
authors.forename: Ewart
authors.initials: E
authors.lastname: Kuijk
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.
authors.forename: Pjotr
authors.initials: P
authors.lastname: Prins
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.
authors.forename: Isaac J
authors.initials: IJ
authors.lastname: Nijman
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
authors.forename: Inigo
authors.initials: I
authors.lastname: Martincorena
authors.affiliation: Department of Pediatrics, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, The Netherlands.
authors.forename: Michal
authors.initials: M
authors.lastname: Mokry
authors.affiliation: Department of Pediatrics, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, The Netherlands.
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Wiegerinck
authors.affiliation: Department of Pediatrics, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, The Netherlands.
authors.forename: Sabine
authors.initials: S
authors.lastname: Middendorp
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Sato
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.
authors.forename: Gerald
authors.initials: G
authors.lastname: Schwank
authors.affiliation: Department of Pediatrics, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, The Netherlands.
authors.forename: Edward E S
authors.initials: EE
authors.lastname: Nieuwenhuis
authors.affiliation: Department of Surgery, Erasmus MC-University Medical Center, Postbus 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Monique M A
authors.initials: MM
authors.lastname: Verstegen
authors.affiliation: Department of Surgery, Erasmus MC-University Medical Center, Postbus 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Luc J W
authors.initials: LJ
authors.lastname: van der Laan
authors.affiliation: Department of Surgery, Erasmus MC-University Medical Center, Postbus 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: de Jonge
authors.affiliation: Department of Surgery, Erasmus MC-University Medical Center, Postbus 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Jan N M
authors.initials: JN
authors.lastname: IJzermans
authors.affiliation: Foundation Hubrecht Organoid Technology (HUB), Uppsalalaan 8, 3584CT Utrecht, The Netherlands.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Vries
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.
authors.forename: Marc
authors.initials: M
authors.lastname: van de Wetering
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.affiliation: Center for Molecular Medicine, Cancer Genomics Netherlands, Department of Genetics, University Medical Center Utrecht, Heidelberglaan 100, 3584CX Utrecht, The Netherlands.|Hubrecht Institute for Developmental Biology and Stem Cell Research, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.
authors.forename: Edwin
authors.initials: E
authors.lastname: Cuppen
authors.affiliation: Center for Molecular Medicine, Cancer Genomics Netherlands, Department of Genetics, University Medical Center Utrecht, Heidelberglaan 100, 3584CX Utrecht, The Netherlands.|Hubrecht Institute for Developmental Biology and Stem Cell Research, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.
authors.forename: Ruben
authors.initials: R
authors.lastname: van Boxtel
mesh_terms: D000293:Adolescent; D000328:Adult; D053687:Adult Stem Cells / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D000818:Animals; D002648:Child; D002675:Child, Preschool; D003106:Colon / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D052138:Genes, Neoplasm / Q000235:genetics; D006801:Humans; D015994:Incidence; D007421:Intestine, Small / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D039902:Multipotent Stem Cells / Q000378:metabolism; D000067552:Mutation Accumulation; D059645:Mutation Rate; D009369:Neoplasms / Q000453:epidemiology / Q000235:genetics; D009928:Organ Specificity; D009940:Organoids / Q000378:metabolism; D017354:Point Mutation / Q000235:genetics; D055815:Young Adult