Convergent evolution of BRCA2 reversion mutations under therapeutic pressure by PARP inhibition and platinum chemotherapy

Reversion mutations that restore wild-type function of the BRCA gene have been described as a key mechanism of resistance to Poly(ADP-ribose) polymerase (PARP) inhibitor therapy in BRCA-associated cancers. Here, we report a case of a patient with metastatic castration-resistant prostate cancer (mCRP...

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Veröffentlicht in:NPJ precision oncology Jg. 8; H. 1; S. 34 - 6
Hauptverfasser: Walmsley, Charlotte S., Jonsson, Philip, Cheng, Michael L., McBride, Sean, Kaeser, Christopher, Vargas, Herbert Alberto, Laudone, Vincent, Taylor, Barry S., Kappagantula, Rajya, Baez, Priscilla, Richards, Allison L., Noronha, Anne Marie, Perera, Dilmi, Berger, Michael, Solit, David B., Iacobuzio-Donahue, Christine A., Scher, Howard I., Donoghue, Mark T. A., Abida, Wassim, Schram, Alison M.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 14.02.2024
Nature Publishing Group
Nature Portfolio
Schlagworte:
692/4028/67/1059/2326
692/4028/67/2329
Cancer Research
Case Report
Case reports
Chemotherapy
Drug resistance
Gene Therapy
Human Genetics
Inhibitor drugs
Internal Medicine
Medicine
Medicine & Public Health
Metastasis
Mutation
Oncology
Prostate cancer
Targeted cancer therapy
ISSN:2397-768X, 2397-768X
Online-Zugang:Volltext
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Zusammenfassung:Reversion mutations that restore wild-type function of the BRCA gene have been described as a key mechanism of resistance to Poly(ADP-ribose) polymerase (PARP) inhibitor therapy in BRCA-associated cancers. Here, we report a case of a patient with metastatic castration-resistant prostate cancer (mCRPC) with a germline BRCA2 mutation who developed acquired resistance to PARP inhibition. Extensive genomic interrogation of cell-free DNA (cfDNA) and tissue at baseline, post-progression, and postmortem revealed ten unique BRCA2 reversion mutations across ten sites. While several of the reversion mutations were private to a specific site, nine out of ten tumors contained at least one mutation, suggesting a powerful clonal selection for reversion mutations in the presence of therapeutic pressure by PARP inhibition. Variable cfDNA shed was seen across tumor sites, emphasizing a potential shortcoming of cfDNA monitoring for PARPi resistance. This report provides a genomic portrait of the temporal and spatial heterogeneity of prostate cancer under the selective pressure of a PARP inhibition and exposes limitations in the current strategies for detection of reversion mutations.
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ISSN:2397-768X
2397-768X
DOI:10.1038/s41698-024-00526-9