Germline homologous recombination deficiency influences TP53-mutant clonal hematopoiesis fitness during platinum and PARP inhibitor treatment.
- Abstract:
- Poly(ADP-ribose) polymerase inhibitors (PARPi) are commonly used in tumors with homologous recombination deficiency (HRD) but are associated with an increased risk of therapy-related myeloid neoplasms (tMN). Clonal hematopoiesis (CH) driven by DNA damage response (DDR) mutations is the origin of most tMN. Here, to better understand the causes of tMN following PARPi therapy, we studied the relationship between PARPi use and CH. We observed a high frequency of DDR CH following PARPi therapy, largely explained by prior carboplatin exposure. Among patients with serial blood sampling, DDR CH expanded during carboplatin and to a lesser extent, during PARPi treatment. Surprisingly, this expansion was largely reduced in patients with germline HRD. We validated these findings in a mouse model of Trp53-mutated CH. Our findings suggest that the increased risk of tMN following PARPi is largely influenced by prior oncologic therapies, including carboplatin, and may vary by germline HRD status.
- Authors:
- JT Baeten, ICC Chan, L Moukarzel, GEM Petrone, J Liu, D Tran, J Tabs, I Tabet, S Agashe, E Nasrollahzadeh, A Vasireddy, A Carter, M Patel, KH Stopsack, PW Kantoff, W Zhou, AL Batchi-Bouyou, JS Beeler, G Mustion, P Pharoah, J Brenton, K Offit, E Barnett, B Li, W Abida, AM Schram, B Weigelt, D Mutch, A Vindigni, M Mullen, C Cruchaga, H Scher, R Levine, E Papaemmanuil, MJ Machiela, K Cadoo, DC Link, KL Bolton
- Journal:
- Nat Genet
- Publication date:
- 28th Sep 2026
- Full text
- DOI