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

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

Authors:	Walmsley, C. S.; Jonsson, P.; Cheng, M. L.; McBride, S.; Kaeser, C.; Vargas, H. A.; Laudone, V.; Taylor, B. S.; Kappagantula, R.; Baez, P.; Richards, A. L.; Noronha, A. M.; Perera, D.; Berger, M.; Solit, D. B.; Iacobuzio-Donahue, C. A.; Scher, H. I.; Donoghue, M. T. A.; Abida, W.; Schram, A. M.
Article Title:	Convergent evolution of BRCA2 reversion mutations under therapeutic pressure by PARP inhibition and platinum chemotherapy
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. © The Author(s) 2024.
Keywords:	adult; clinical article; human tissue; middle aged; gene mutation; sequence analysis; exon; prednisone; case report; positron emission tomography; lymph node dissection; prostate specific antigen; carboplatin; gene frequency; brca2 protein; docetaxel; prostate cancer; leuprorelin; prostatectomy; fluorodeoxyglucose f 18; genomics; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor; abiraterone acetate; liver biopsy; abiraterone; germline mutation; enzalutamide; human; male; article; metastatic castration resistant prostate cancer; convergent evolution; revertant; whole exome sequencing; circulating free dna; reading frame
Journal Title:	npj Precision Oncology
Volume:	8
ISSN:	2397-768X
Publisher:	Springer Nature
Date Published:	2024-02-14
Start Page:	34
Language:	English
DOI:	10.1038/s41698-024-00526-9
PROVIDER:	scopus
PMCID:	PMC10866935
PUBMED:	38048325
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85185295462&doi=10.1038%2fs41698-024-00526-9&partnerID=40&md5=ceed4a5ac74b78cfeedc52b21c36bb1e
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK authors: Alison M. Schram -- Source: Scopus