Alterations in homologous recombination repair genes in prostate cancer brain metastases

• Type of Material: Article
• Authors: Antonio Rodriguez-Calero, University of Bern; John Gallon, Universitat Basel; Dilara Akhoundova, University of Bern; Sina Maletti, University of Bern; Alison Ferguson, University of Bern; Joanna Cyrta, Université PSL; Ursula Amstutz, University Hospital Bern; Andrea Garofoli, Universitätsspital Basel; Viola Paradiso, Universitätsspital Basel; Scott A Tomlins, University of Michigan Medical School; Ekkehard Hewer, University of Bern, Institute of Pathology; Vera Genitsch, University of Bern, Institute of Pathology; Achim Fleischmann, University of Bern, Institute of Pathology; Erik Vassella, University of Bern, Institute of Pathology; Elisabeth J Rushing, Universitätsspital Zürich Institut für Neuropathologie; Rainer Grobholz, Kantonsspital Aarau; Ingeborg Fischer, Kantonsspital Aarau; Wolfram Jochum, Kantonsspital St Gallen; Gieri Cathomas, Kantonsspital Liestal; Adeboye Osunkoya, Emory University; Lukas Bubendorf, Universitätsspital Basel; Holger Moch, UniversitatsSpital Zurich; George Thalmann, University Hospital Bern; Charlotte KY Ng, University of Bern; Silke Gillessen, Faculty of Biomedical Sciences; Salvatore Piscuoglio, Universitat Basel; Mark A Rubin, University of Bern
• Language: English
• Date: 2022-12-01
• Publisher: Springer Nature
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2022
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-022-30003-5
• Title of Journal or Parent Work: Nature Communications
• Volume: 13
• Issue: 1
• Start Page: 2400
• End Page: 2400
• Grant/Funding Information: This study was supported by an NCI (NIH) grant P50 CA211024 (S.A.T. and M.A.R.); Swiss Personalized Health Network grant SOCIBP (H.M., M.A.R.), and the Swiss Cancer League (C.K.Y.N., S.P., and M.A.R.). S.P. is supported by The Prof. Dr. Max Cloëtta foundation.
• Keywords: Mutation; Prostatic Neoplasms; Recombinational DNA Repair; Humans; Male; Poly(ADP-ribose) Polymerase Inhibitors; Brain Neoplasms
• Research Categories: Health Sciences, Pathology; Health Sciences, Oncology

Abstract

Improved survival rates for prostate cancer through more effective therapies have also led to an increase in the diagnosis of metastases to infrequent locations such as the brain. Here we investigate the repertoire of somatic genetic alterations present in brain metastases from 51 patients with prostate cancer brain metastases (PCBM). We highlight the clonal evolution occurring in PCBM and demonstrate an increased mutational burden, concomitant with an enrichment of the homologous recombination deficiency mutational signature in PCBM compared to non-brain metastases. Focusing on known pathogenic alterations within homologous recombination repair genes, we find 10 patients (19.6%) fulfilling the inclusion criteria used in the PROfound clinical trial, which assessed the efficacy of PARP inhibitors (PARPi) in homologous recombination deficient prostate cancer. Eight (15.7%) patients show biallelic loss of one of the 15 genes included in the trial, while 5 patients (9.8%) harbor pathogenic alterations in BRCA1/2 specifically. Uncovering these molecular features of PCBM may have therapeutic implications, suggesting the need of clinical trial enrollment of PCBM patients when evaluating potential benefit from PARPi.