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Mutation burden in cancer cells
▸ Blokzijl F, de Ligt J, Jager M, et al. Tissue-specific mutation accumulation in human adult stem cells during life. Nature 2016;538:260–4.
In cancer, stem cells are thought to be the primary target for genetic defects due to the fact that they live far longer than any differentiated cells; however, no accurate estimation of the mutation rate in human tissue stem cells (particularly colon, small intestine and liver) has been established. Here, the authors have generated 45 organoid cultures, from 19 donors ranging in age from 3 to 87 years, from stem cells extracted from colon, small intestine and liver specimens. There is a much higher rate of cancer incidence in the human colon compared with small intestine and liver and the authors test whether this is reflected in the mutation burden and pattern in the organoids. They performed whole genome sequencing and calculated the mutation rate by using the distribution of patient ages. While in each tissue there was a measurable increase in mutations per genome/time in colon, small intestine and liver, surprisingly, the mutation rate was the same in all tissues despite drastically different cancer susceptibilities. The mutation spectra were identical between small intestine and colonic organoids (with a high incidence of C>T mutations) but in the liver organoids there was a relatively even distribution of all mutation types. Using a methodology that puts each mutation in the context of the surrounding sequence (non-negative matrix factorisation), the authors produced mutational signatures. The colon and small intestinal organoids display a signature associated with spontaneous deamination or methylated cytosine residues that reflect the high turnover of cells. This was not observed in the liver where turnover of hepatocytes is low. Interestingly, the mutation spectra in driver genes such as APC and TP53 reflected the spectra in the genome as a …
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