“Accidental mistakes” during stem cell divisions explain cancer risks in different organs

stem cell

In human adult stem cells, the gradual accumulation of genetic mutations during life is associated with age-related diseases, including cancer.

Cancer risk can be very different across tissues, and recent research shows that the risk depends on the lifetime number of adult stem cell divisions. However, the rates and patterns of mutations in normal adult stem cells remain unknown.

In a recent study, scientists find that the DNA code of human stem cells acquires errors at a fairly constant rate, even in organs with differing cancer incidence. The finding is published in Nature.

Researchers from University Medical Center Utrecht in The Netherlands, Wellcome Trust Sanger Institute in the UK, Erasmus MC-University Medical Center in The Netherlands, and Foundation Hubrecht Organoid Technology in The Netherlands conducted the study.

They determined genome-wide mutation patterns in adult stem cells of the small intestine, colon and liver of human donors. These donors aged between 3 to 87 years.

The result showed 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 adult stem cells, however, had different mutation spectra compared to those of the colon and small intestine.

Mutational signature analysis revealed that this difference could be attributed to spontaneous deamination of methylated cytosine residues in the colon and small intestine, probably reflecting their high adult stem cell division rate.

In liver, a signature with an unknown underlying mechanism is predominant. Mutation spectra of driver genes in cancer showed high similarity to the tissue-specific adult stem cell mutation spectra.

Researchers suggest that intrinsic mutational processes in adult stem cells can initiate tumor growth. In addition, the inter-individual variation in mutation rate and spectra are low, and this suggests tissue-specific activity of common mutational processes throughout life.

A controversial idea published last year suggested that most of the risk for many cancers is due to a build-up of accidental random DNA mutations accumulated during normal stem cell division.

This means organs with faster rates of stem cell division would naturally accrue more random mutations and carry a higher cancer risk. In other words, for these organs the risk of developing cancer is mainly a matter of ‘bad luck’.

The current finding suggests that ‘bad luck’ is definitely part of the story. But researchers need more evidence to find out how, and to what extent.

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Citation: Blokzijl F, et al. (2016). Tissue-specific mutation accumulation in human adult stem cells during life. Nature, published online. DOI: 10.1038/nature19768.
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