Germline HRD limits therapy-driven clonal hematopoiesis

In human cancer patients and a mouse model of Trp53-mutated clonal hematopoiesis, researchers analyzed how therapies drive blood clone growth. They tracked clonal dynamics to investigate why poly(ADP-ribose) polymerase inhibitors (PARPi) link to therapy-related myeloid neoplasms. The authors observed a high frequency of DNA damage response clonal hematopoiesis following PARPi therapy. However, this pattern was largely explained by prior carboplatin exposure. In patients with serial blood sampling, these clones expanded during carboplatin treatment and, to a lesser extent, during PARPi therapy. Notably, this expansion was largely reduced in patients carrying germline homologous recombination deficiency. The researchers validated the findings using Trp53-mutated mice, showing that prior chemotherapy and inherited genetics alter clonal fitness.