Germline homologous recombination deficiency influences TP53-mutant clonal hematopoiesis fitness during platinum and PARP inhibitor treatment
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. The authors show that platinum is a greater driver of DNA damage response gene-mutant clonal hematopoiesis than poly(ADP-ribose) polymerase inhibitors and that the presence of germline mutations conferring homologous recombination deficiency reduces the rate of expansion of these clones.
Authors
- Jie Liu (ORCID: https://orcid.org/0000-0001-6365-1888)
- Giulia E.M. Petrone (ORCID: https://orcid.org/0000-0003-3166-4355)
- Imène Tabet (ORCID: https://orcid.org/0000-0002-2172-461X)
- Irenaeus C.C. Chan (ORCID: https://orcid.org/0009-0004-3250-9626)
- Amber Carter
- Ross L. Levine (ORCID: https://orcid.org/0000-0002-7884-1905)
- Kelly L. Bolton (ORCID: https://orcid.org/0000-0001-6584-3357)
- Carlos C Cruchaga (ORCID: https://orcid.org/0000-0002-0276-2899)
- Britta Weigelt (ORCID: https://orcid.org/0000-0001-9927-1270)
- Jeremy T. Baeten (ORCID: https://orcid.org/0000-0002-1466-4604)
- Bob T. Li (ORCID: https://orcid.org/0000-0001-6661-8733)
- Daniel C. Link (ORCID: https://orcid.org/0000-0002-3170-7581)
- Armel Landry Batchi-Bouyou (ORCID: https://orcid.org/0000-0002-7323-9894)
- James D. Brenton (ORCID: https://orcid.org/0000-0002-5738-6683)
- Konrad Hermann Stopsack (ORCID: https://orcid.org/0000-0002-0722-1311)
- Sumedha Agashe (ORCID: https://orcid.org/0000-0002-9138-6169)
- Weiyin Zhou (ORCID: https://orcid.org/0000-0002-0467-3064)
- Mitchell J. Machiela (ORCID: https://orcid.org/0000-0001-6538-9705)
- Howard I. Scher (ORCID: https://orcid.org/0000-0002-6791-9324)
- J. Scott Beeler (ORCID: https://orcid.org/0000-0002-1829-1972)
- David G. Mutch (ORCID: https://orcid.org/0000-0002-6921-1581)
- Elli Papaemmanuil (ORCID: https://orcid.org/0000-0003-1709-8983)
- Elaheh Nasrollahzadeh
- Paul D.P. Pharoah (ORCID: https://orcid.org/0000-0001-8494-732X)
- Alison M. Schram (ORCID: https://orcid.org/0000-0002-6070-2413)
- Duc Tran (ORCID: https://orcid.org/0000-0003-2918-8601)
- Griffen Mustion (ORCID: https://orcid.org/0009-0005-5505-5775)
- Karen Cadoo
- Mary Mullen
- Minal Patel
- Philip W. Kantoff
- Jacob Tabs (ORCID: https://orcid.org/0009-0009-0867-453X)
- Alessandro Vindigni
- Lea Moukarzel
- Wassim Abida
- Ethan Barnett
- Kenneth Offit
- Ankush Vasireddy (ORCID: https://orcid.org/0009-0001-7049-0039)
Institutions
- Cedars-Sinai Medical Center (US)
- Memorial Sloan Kettering Cancer Center (US)
- Harvard University (US)
- Washington University in St. Louis (US)
- University of Cambridge (GB)
- Massachusetts General Hospital (US)
- St. James's Hospital (IE)
- Division of Cancer Epidemiology and Genetics
Publication Details
- Journal
- Nature Genetics
- Published
- 2026-09-28
- DOI
- https://doi.org/10.1038/s41588-026-02752-2
- Primary Topic
- PARP inhibition in cancer therapy
- Type
- article
- Field-Weighted Citation Impact
- 0.00