Authors
Jeremy T Baeten, Irenaeus C C Chan, Lea Moukarzel, Giulia E M Petrone, Jie Liu, Duc Tran, Jacob Tabs, Imene Tabet, Sumedha Agashe, Elaheh Nasrollahzadeh, Ankush Vasireddy, Amber Carter, Minal Patel, Konrad H Stopsack, Philip W Kantoff, Weiyin Zhou, Armel L Batchi-Bouyou, J Scott Beeler, Griffen Mustion, Paul Pharoah, James Brenton, Kenneth Offit, Ethan Barnett, Bob Li, Wassim Abida, Alison M Schram, Britta Weigelt, David Mutch, Alessandro Vindigni, Mary Mullen, Carlos Cruchaga, Howard Scher, Ross Levine, Elli Papaemmanuil, Mitchell J Machiela, Karen Cadoo, Daniel C Link, Kelly L Bolton
Published in
Nature genetics. Sep 28, 2026. Epub Sep 28, 2026.
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.
PMID:
42806144
Bibliographic data and abstract were imported from PubMed on 29 Sep 2026.
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