Alterations in Homologous Recombination Repair Genes in Prostate Cancer Brain Metastases

Overview

Journal Nat Commun

Specialty Biology

Date 2022 May 3

PMID 35504881

Authors

Antonio Rodriguez-Calero

John Gallon

Dilara Akhoundova

Sina Maletti

Alison Ferguson

Joanna Cyrta

Ursula Amstutz

Andrea Garofoli

Viola Paradiso

Scott A Tomlins

Ekkehard Hewer

Vera Genitsch

Achim Fleischmann

Erik Vassella

Elisabeth J Rushing

Rainer Grobholz

Ingeborg Fischer

Wolfram Jochum

Gieri Cathomas

Adeboye O Osunkoya

Lukas Bubendorf

Holger Moch

George Thalmann

Charlotte K Y Ng

Silke Gillessen

Salvatore Piscuoglio

Mark A Rubin

Affiliations

Soon will be listed here.

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.

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