Seminar: Edwin Cuppen

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

Date:
13 April 2017 11:00 hrs. - 12:00 hrs.
Location:
Figdor Lecture Theatre, 8th floor RIMLS Building, Geert Grooteplein 26-28, route 289
Title:
Tissue-specific mutation accumulation in human adult stem cells during life
Speaker(s):

Edwin Cuppen, Center for Molecular Medicine, Cancer Genomics Netherlands, Department of Genetics, University Medical Center Utrecht

Host(s):

Wiljan Hendriks, Dept. of Cell Biology, RIMLS

13-04-2017 11:00:0013-04-2017 12:00:00Europe/AmsterdamTissue-specific mutation accumulation in human adult stem cells during life Figdor Lecture Theatre, 8th floor RIMLS Building, Geert Grooteplein 26-28, route 289Rimlsrimls@radboudumc.nl

Remarks / more information:

undefinedThe 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. We determined genome-wide mutation patterns in >50 ASCs of the small intestine, colon and liver of human donors with ages ranging from 3 to 87 years by whole genome sequencing of 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. Interestingly, 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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Key publications

  • Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids. PNAS; 114: E2357-E2364, 2017
  • Molecular dissection of germline chromothripsis in a developmental context using patient-derived iPS cells. Genome Med.; vol. 9: 9., 2017
  • Tissue-specific mutation accumulation in human adult stem cells during life. Nature; 260-264, 2016


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