Alterations in homologous recombination repair genes in prostate cancer brain metastases

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

doi:10.1038/s41467-022-30003-5

Alterations in homologous recombination repair genes in prostate cancer brain metastases

Nat Commun. 2022 May 3;13(1):2400. doi: 10.1038/s41467-022-30003-5.

Authors

Antonio Rodriguez-Calero^#^{1

2}, John Gallon^#³, Dilara Akhoundova^{1

4}, Sina Maletti¹, Alison Ferguson^{1

5}, Joanna Cyrta⁶, Ursula Amstutz⁷, Andrea Garofoli⁸, Viola Paradiso⁸, Scott A Tomlins⁹, Ekkehard Hewer^{2

10}, Vera Genitsch², Achim Fleischmann^{2

11}, Erik Vassella², Elisabeth J Rushing¹², Rainer Grobholz¹³, Ingeborg Fischer¹³, Wolfram Jochum¹⁴, Gieri Cathomas¹⁵, Adeboye O Osunkoya¹⁶, Lukas Bubendorf⁸, Holger Moch¹⁷, George Thalmann¹⁸, Charlotte K Y Ng¹, Silke Gillessen^{19

20

21}, Salvatore Piscuoglio^{22

23}, Mark A Rubin^{24

25}

Affiliations

¹ Department for BioMedical Research, University of Bern, Bern, Switzerland.
² Institute of Pathology, University of Bern, Bern, Switzerland.
³ Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland.
⁴ Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland.
⁵ Department of Oncology, Ludwig Cancer Centre, University of Lausanne, Lausanne, Switzerland.
⁶ Department of Pathology, Institut Curie, University Paris Sciences et Lettres, Paris, France.
⁷ Department of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
⁸ Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.
⁹ Departments of Pathology and Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
¹⁰ Institute of Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
¹¹ Institute of Pathology, Cantonal Hospital Thurgau, Münsterlingen, Switzerland.
¹² Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
¹³ Institute of Pathology, Cantonal Hospital Aarau, Aarau, Switzerland.
¹⁴ Institute of Pathology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.
¹⁵ Institute of Pathology, Cantonal Hospital Baselland, Liestal, Switzerland.
¹⁶ Departments of Pathology and Laboratory Medicine, and Urology, Emory University School of Medicine, Atlanta, USA.
¹⁷ Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland.
¹⁸ Department of Urology, Inselspital, Bern University Hospital, Bern, Switzerland.
¹⁹ Faculty of Biomedical Sciences, USI, Lugano, Switzerland.
²⁰ Department of Oncology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.
²¹ Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom.
²² Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland. s.piscuoglio@unibas.ch.
²³ Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland. s.piscuoglio@unibas.ch.
²⁴ Department for BioMedical Research, University of Bern, Bern, Switzerland. mark.rubin@dbmr.unibe.ch.
²⁵ Bern Center for Precision Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. mark.rubin@dbmr.unibe.ch.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Brain Neoplasms* / drug therapy
Brain Neoplasms* / genetics
Humans
Male
Mutation
Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use
Prostatic Neoplasms* / drug therapy
Prostatic Neoplasms* / genetics
Recombinational DNA Repair / genetics

Substances

Poly(ADP-ribose) Polymerase Inhibitors

Grants and funding

P50 CA211024/CA/NCI NIH HHS/United States