| Autor: |
Charlotte S. Walmsley, Philip Jonsson, Michael L. Cheng, Sean McBride, Christopher Kaeser, Herbert Alberto Vargas, Vincent Laudone, Barry S. Taylor, Rajya Kappagantula, Priscilla Baez, Allison L. Richards, Anne Marie Noronha, Dilmi Perera, Michael Berger, David B. Solit, Christine A. Iacobuzio-Donahue, Howard I. Scher, Mark T. A. Donoghue, Wassim Abida, Alison M. Schram |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
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| Zdroj: |
npj Precision Oncology, Vol 8, Iss 1, Pp 1-6 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2397-768X |
| DOI: |
10.1038/s41698-024-00526-9 |
| Popis: |
Abstract 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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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