BRCA2 and Other DDR Genes in Prostate Cancer.

Paz Nombela,David Olmos,Elena Castro,Joaquin Mateo,Rebeca Lozano,Alvaro Aytes

doi:10.3390/cancers11030352

Abstract

Germline and somatic aberrations in DNA damage repair (DDR) genes are more prevalent in prostate cancer than previously recognized, with BRCA2 as the most commonly altered gene. Germline mutations in BRCA2 have been linked to poor prognosis when patients are managed under the protocols currently approved for prostate cancer. The impact of germline mutations in other DDR genes beyond BRCA2 remain unclear. Importantly, a quarter of prostate cancer patients identified as germline mutation carriers lack a family history of cancer. The clinical implications of somatic DDR defects are yet to be elucidated. Poly ADP-ribose polymerase (PARP) inhibitors and platinum-based chemotherapy have proven to be effective in the treatment of other tumor types linked to BRCA1 and BRCA2 alterations and several trials are currently evaluating their efficacy in prostate cancer. Here, we summarize the available evidence regarding the prevalence of somatic and germline DDR defects in prostate cancer; their association with clinical outcomes; the trials assessing the efficacy of new therapies that exploit DDR defects in prostate cancer and briefly discuss some uncertainties about the most appropriate management for these patients.

Highlights

Alterations in the DNA damage repair (DDR) pathways have only recently been recognized as a major hallmark of prostate cancer
The decrease in the cost of sequencing and the broad access to these platforms will presumably result in an increased number of prostate cancer patients identified as DDR mutation carriers, who could benefit from appropriate genetic counseling and personalized management and therapies
DDR defects are present in prostate cancer at a higher prevalence than previously recognized

Summary

Introduction

Alterations in the DNA damage repair (DDR) pathways have only recently been recognized as a major hallmark of prostate cancer. Inherited BRCA2 mutations that impair the gene function have been described in 3–5% of patients with advanced prostate cancer [3,4]. There is strong emerging evidence that some germline and somatic DDR defects may predict the response to poly-ADP ribose polymerase (PARP) inhibitors and platinum-based chemotherapy in prostate cancer [10,11,12,13]. These findings make genetic testing attractive for risk stratification, Cancers 2019, 11, 352; doi:10.3390/cancers11030352 www.mdpi.com/journal/cancers. The decrease in the cost of sequencing and the broad access to these platforms will presumably result in an increased number of prostate cancer patients identified as DDR mutation carriers, who could benefit from appropriate genetic counseling and personalized management and therapies

Alterations in DNA Repair Genes Are Common in Prostate Cancer

Management of Localized Disease

Management of Metastatic Prostate Cancer

Implications for Hereditary Cancer and Germline Testing

Findings

Conclusions and Future Directions