cancers Review Pathogenic BRCA Variants as Biomarkers for Risk in Prostate Cancer Ciara S. McNevin 1,2 , Karen Cadoo 2,3 , Anne-Marie Baird 3 , Pierre Murchan 1,4 , Orla Sheils 3 , Ray McDermott 5,6 and Stephen Finn 1,2, *   Citation: McNevin, C.S.; Cadoo, K.; Baird, A.-M.; Murchan, P.; Sheils, O.; McDermott, R.; Finn, S. Pathogenic BRCA Variants as Biomarkers for Risk in Prostate Cancer. Cancers 2021, 13, 5697. https://doi.org/10.3390/ cancers13225697 Academic Editors: Lisa M. Butler and Lisa G. Horvath Received: 3 September 2021 Accepted: 28 October 2021 Published: 14 November 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Department of Histopathology and Morbid Anatomy, Trinity Translational Medicine Institute, Trinity College Dublin, D08 W9RT Dublin, Ireland; MCNEVINC@tcd.ie (C.S.M.); murchanp@tcd.ie (P.M.) 2 Department of Medical Oncology, St. James Hospital, D08 NHY1 Dublin, Ireland; kcadoo@stjames.ie 3 School of Medicine, Trinity Translational Medicine Institute, St. James’s Hospital, D08 W9RT Dublin, Ireland; bairda@tcd.ie (A.-M.B.); osheils@tcd.ie (O.S.) 4 Science Foundation Ireland Centre for Research Training in Genomics Data Science, School of Mathematics, Statistics and Applied Mathematics, National University of Ireland, H91 TK33 Galway, Ireland 5 Department of Medical Oncology, Tallaght University Hospital, D24 NR0A Dublin, Ireland; ray.mcdermott@tuh.ie 6 Department of Medical Oncology, St. Vincent’s University Hospital, D04 YN26 Dublin, Ireland * Correspondence: stephen.Finn@tcd.ie Simple Summary: Historically, the treatment of prostate cancer was a blanket approach for all. Prostate cancer has not benefitted from targeted treatments based on specific tumour characteristics (ie. Particular genetic or molecular patterns) the way other cancers have. This is important as studies have shown that prostate cancer patients with certain errors in their genes, such as BRCA2 or BRCA1, are more likely to have worse disease and poorer outcome. These patients can be treated successfully with a group of drugs called ‘PARP inhibitors’. This paper examines the prognostic, clinical and therapeutic role of BRCA2/BRCA1 mutations across the evolution of PCa. The impact of the inclusion of BRCA genes on genetic screening will also be outlined. Abstract: Studies have demonstrated that men with Prostate Cancer (PCa) harboring BRCA2/BRCA1 genetic aberrations, are more likely to have worse disease and a poorer prognosis. A mutation in BRCA2 is known to confer the highest risk of PCa for men (8.6 fold in men ≤65 years) making BRCA genes a conceivable genomic biomarker for risk in PCa. These genes have attracted a lot of research attention however their role in the clinical assessment and treatment of PCa remains complex. Multiple studies have been published examining the relationship between prostate cancer and BRCA mutations. Here BRCA mutations are explored specifically as a biomarker for risk in PCa. It is in this context, we examined the prognostic, clinical and therapeutic role of BRCA2/BRCA1 mutations across the evolution of PCa. The impact of the inclusion of BRCA genes on genetic screening will also be outlined. Keywords: BRCA2; BRCA1; biomarker; prostate cancer; gene mutation; screening; treatment strategies 1. Introduction Prostate Cancer (PCa) was the second most common cancer diagnosis made in men (14.1%) and the fifth leading cause of death (6.8%) worldwide in 2020 [1]. Population expansion and improved life expectancies across the globe are set to contribute to an increase in PCa [2] rendering it an major worldwide health concern. While there has been an emergence of novel treatments in the last ten years, even now PCa is a major source of cancer deaths in males [3]. Older age is the chief risk factor with greater than three quarters of all PCa detection made in men over the age of 65 years [4]. Family history and genetic predisposition such as pathogenic variants BRCA1/BRCA2 have also been identified as important risk factors [5,6]. Other genes important for DNA repair can also play a role Cancers 2021, 13, 5697. https://doi.org/10.3390/cancers13225697 https://www.mdpi.com/journal/cancers