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Dynamics of clonal hematopoiesis under DNA-damaging treatment in patients with ovarian cancer

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Item Type:Article
Title:Dynamics of clonal hematopoiesis under DNA-damaging treatment in patients with ovarian cancer
Creators Name:Arends, C.M. and Kopp, K. and Hablesreiter, R. and Estrada, N. and Christen, F. and Moll, U.M. and Zeillinger, R. and Schmitt, W.D. and Sehouli, J. and Kulbe, H. and Fleischmann, M. and Ray-Coquard, I. and Zeimet, A. and Raspagliesi, F. and Zamagni, C. and Vergote, I. and Lorusso, D. and Concin, N. and Bullinger, L. and Braicu, E.I. and Damm, F.
Abstract:Clonal hematopoiesis (CH) driven by mutations in the DNA damage response (DDR) pathway is frequent in patients with cancer and is associated with a higher risk of therapy-related myeloid neoplasms (t-MNs). Here, we analyzed 423 serial whole blood and plasma samples from 103 patients with relapsed high-grade ovarian cancer receiving carboplatin, poly(ADP-ribose) polymerase inhibitor (PARPi) and heat shock protein 90 inhibitor (HSP90i) treatment within the phase II EUDARIO trial using error-corrected sequencing of 72 genes. DDR-driven CH was detected in 35% of patients and was associated with longer duration of prior PARPi treatment. TP53- and PPM1D-mutated clones exhibited substantially higher clonal expansion rates than DNMT3A- or TET2-mutated clones during treatment. Expansion of DDR clones correlated with HSP90i exposure across the three study arms and was partially abrogated by the presence of germline mutations related to homologous recombination deficiency. Single-cell DNA sequencing of selected samples revealed clonal exclusivity of DDR mutations, and identified DDR-mutated clones as the origin of t-MN in two investigated cases. Together, these results provide unique insights into the architecture and the preferential selection of DDRmutated hematopoietic clones under intense DNA-damaging treatment. Specifically, PARPi and HSP90i therapies pose an independent risk for the expansion of DDR-CH in a dose-dependent manner.
Publisher:Nature Publishing Group
Date:18 April 2024
Additional Information:Erratum in: Leukemia 2024 May 7 (in Press)
Official Publication:https://doi.org/10.1038/s41375-024-02253-3
PubMed:View item in PubMed

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