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Adult Stem Cells and Organoids Combine to Explore the Contribution of Cancer Risk Factors

Review of “Tissue-specific mutation accumulation in human adult stem cells during life” from Nature by Stuart P. Atkinson

A recent study in Science suggested that random errors (“bad-luck”) suffered during DNA replication in normal adult stem cells may represent the main reason for the observed differences in cancer prevalence between distinct tissues [1]. To further refine this hypothesis, researchers from the labs of Edwin Cuppen and Ruben van Boxtel (University Medical Center Utrecht, The Netherlands) sought to investigate the existence of confounding factors which may modify the bad-luck hypothesis.

Their results, published in Nature, now demonstrate that adult stem cells derived from organs with varying cancer incidence actually display a similar mutation rate and mutation spectra, although each tissue features its own specific mutational profile [2]. This suggests that the probability of cancer cannot be fully explained by the number of DNA–errors and, instead, implies that other factors may be of equal or greater importance to cancer development.

So how did they come to this realization? Blokzijl et al isolated single adult stem cells from multiple donors and different tissues that differ greatly in proliferation rate and cancer risk. Then, to generate sufficient material for accurate whole-genome sequencing (WGS) analysis, the authors expanded adult stem cells as epithelial organoids.

This organoid-based analysis demonstrated that, independent of tissue type and cancer risk, adult stem cells gradually accumulated a similar amount of mutations with age although different mutational processes dominated in different adult stem cells. Those adult stem cells derived from the colon and small intestine displayed a mutational landscape linked to the deamination of methylated cytosines and reflects high division rate, while liver adult stem cells presented a different mutation pattern linked to an unidentified mechanism. Interestingly, mutations in specific cancer driver genes arose in all adult stem cells, but occurred via their spectra-specific mechanisms, demonstrating that these intrinsic mutational processes can initiate tumorigenesis.

So rather than bad luck, is the prevalent mutational process in tissue-specific adult stem cells the main cancer risk factor? The likelihood is that adult stem cell-intrinsic processes, “bad-luck”, and lifestyle factors all contribute to the development of cancer, and future studies should tell us the level of contribution for each cancer risk factors


  1. Tomasetti C and Vogelstein B. Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 2015;347:78-81.
  2. Blokzijl F, de Ligt J, Jager M, et al. Tissue-specific mutation accumulation in human adult stem cells during life. Nature 2016;538:260-264.