Fig. 1

Mutation rate in adult stem cells and their potential consequences. a Correlation of the number of somatic point mutations in adult stem cells derived from colon, small intestine, and liver with age of the donor (adapted from [66]); there is an increase of ~36 mutations/adult stem cell/year. b Summary of the “Three strikes to cancer model” [68] for colorectal cancer, where mutations occur in specific driver genes. In the breakthrough phase, a mutation occurs in APC and results in abnormal division of the respective cell. Subsequently, a mutation in KRAS may follow in the expansion phase and may give rise to a benign tumor. Occurrence of a further mutation in a driver gene in at least one of the listed pathways SMAD4, TP53, PIK3CA, or FBXW7 may enable the tumor to invade surrounding tissues and to initiate the invasive phase with dissemination of tumor cells and formation of metastases [68]. The mutations may be detectable in cfDNA; furthermore, depending on the ctDNA allele frequency and tumor stage, somatic copy number alterations may become visible (shown exemplarily for chromosome 8: blue: lost; green: balanced; and red: gained region). c As the order of driver gene mutations is important, the consequences differ if a TP53 mutation occurs in a colon stem cell before the initiating mutations have taken place. Such a TP53 mutation alone will not be sufficient to cause increased proliferation or even to transform the cell into a tumor cell. However, due to the stem cell’s capacity of self-renewal, cells with this mutation may be propagated in the respective part of the colon. Depending on how many of these cells are removed by apoptosis or other events, ultra-sensitive ctDNA assays may then detect this mutation in the blood; this will usually not be accompanied by copy number alterations (as indicated by the green scatter-plot for chromosome 8)