BRCA2 and Other DDR Genes in Prostate Cancer

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.

Activity of Platinum-Based Chemotherapy in Patients With Advanced Prostate Cancer With and Without DNA Repair Gene Aberrations

“…In their cohort, response to taxanes was not different between variation carriers and noncarriers; however, duration of response was shorter in carriers, and treatment sequencing seemed to be of importance. 30 , 31 Therefore, activity of the taxane component has to be taken into some account when interpreting our efficacy data in patients receiving combination treatment.…”

SRSF6 regulates alternative splicing of genes involved in DNA damage response and DNA repair in HeLa cells

“…4D and Table SIX). Collectively, these results suggested that SRSF6 indeed regulated ASEs that were involved in pathways associated with the DDR, which is strongly associated with tumorigenesis (44).…”

Germline and Somatic Mutations in Prostate Cancer: Focus on Defective DNA Repair, PARP Inhibitors and Immunotherapy

“…This requires the adoption of definitive treatment, compared with noncarriers. Upstage at 5 and 10 years is as high as 50%, and 78% in carriers of BRCA2 mutations, when compared with 22 and 40% in noncarriers [11,12]. The poor outcome associated with BRCA-related PCa discourages clinicians to recommend AS to eligible carriers; however, AS may be feasible for BRCA carriers with low-risk PCa if they are monitored very closely and patients are compliant [13].…”