Nature Genetics: prior platinum and germline HRD shape clonal hematopoiesis after PARP inhibitors

A research briefing in Nature Genetics dated 29 September 2026 summarises a peer-reviewed paper by Baeten, Chan, Moukarzel and colleagues (DOI 10.1038/s41588-026-02752-2; article dated 28 September 2026) on how PARP inhibitors (PARPi) and platinum chemotherapy affect clonal hematopoiesis (CH) — expansion of blood stem-cell clones carrying mutations associated with therapy-related myeloid neoplasms (tMN).

What the investigators reported

In a retrospective MSK-IMPACT analysis and a prospective serial-sampling cohort (PARPi n = 100; carboplatin n = 150; age-matched untreated controls n = 176), both carboplatin and PARPi increased growth of DNA-damage-response (DDR) CH mutations (including TP53, PPM1D, CHEK2), with carboplatin driving significantly greater expansion than PARPi. Adjusting for prior cytotoxic exposure attenuated the apparent PARPi–CH association. Unexpectedly, patients with pathogenic germline homologous recombination deficiency (HRD) showed reduced DDR CH growth during both PARPi and carboplatin. Mouse models of Trp53-mutant CH supported stronger expansion after cisplatin (and to a lesser extent talazoparib) than olaparib, and heterozygosity for Brca1 attenuated that fitness advantage.

Study type and limitations — read carefully

This is translational research combining observational human sequencing, growth-rate modelling and mouse experiments — not a randomized trial proving who will develop leukemia. Therapy-related myeloid neoplasm risk varies widely in published PARPi experience; prior platinum exposure remains a major confounder. CH is a risk marker, not a diagnosis. This article is not personal medical advice — discuss cancer therapy risks with your oncology and hematology teams.