Figure 3. APOBEC3-mediated mutagenesis and disease trajectory.

Clinical progression of a hypothetical ER⁺ patient from preclinical stage [initial outgrowth and initial cancer driver events], to first- and second-line anti-cancer treatments. In this example, APOBEC3-mediated mutation of ESR1 is the first driver mutation. Mutations in PIK3CA provide the tumor with resistance to adjuvant endocrine treatment. Although remission is obtained, further growth and APOBEC3-mediated diversification occurs. Second-line chemotherapeutics provided temporary remission, butfurther APOBEC3-mediated mutagenesis affected genes involved in metastatic behavior, here exemplified with CDH1, leading to treatment failure. The cytosine targeted by APOBEC3 proteins is underlined.