Abstract
Prostate cancer ranks fifth in cancer-related mortality in men worldwide. DNA damage is implicated in cancer and DNA damage response (DDR) pathways are in place against this to maintain genomic stability. Impaired DDR pathways play a role in prostate carcinogenesis and germline or somatic mutations in DDR genes have been found in both primary and metastatic prostate cancer. Among these, BRCA mutations have been found to be especially clinically relevant with a role for germline or somatic testing. Prostate cancer with DDR defects may be sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors which target proteins in a process called PARylation. Initially they were used to target BRCA-mutated tumor cells in a process of synthetic lethality. However, recent studies have found potential for PARP inhibitors in a variety of other genetic settings. In this review, we explore the mechanisms of DNA repair, potential for genomic analysis of prostate cancer and therapeutics of PARP inhibitors along with their safety profile.
Highlights
Prostate cancer was the second most common cancer and ranked fifth in causing cancer-related death in men worldwide in 2020 [1]
This review explores the DNA damage response (DDR) pathways with a particular focus on BRCA mutations, genomic analysis with testing guidelines and the role of poly (ADP-ribose) polymerase (PARP) inhibitors in therapy for prostate cancer
homologous recombination (HR) occurs in the S and G2 phases of the cell cycle as it requires a template of a sister chromatid and will repair the DNA damage error-free; compared to non-homologous end joining (NHEJ) which occurs throughout the cell cycle, but especially in the G1 phase and is error-prone as it ligates the ends of broken DNA without a template [4,41]
Summary
Prostate cancer was the second most common cancer and ranked fifth in causing cancer-related death in men worldwide in 2020 [1]. BER is critical for repair of small base lesions that do not distort the double DNA helix caused by oxidation, methylation and deamination [15,16] In the nucleus, it is usually prominent in the G1 phase of the cell cycle [17]. BER is initiated by one of 11 DNA glycosylases to remove the damaged base lesion and create an abasic or apurinic/apyrimidinic (AP) site [14,18] At this site, an AP-site specific AP endonuclease (APE1) incises the DNA backbone and either of two sub-pathways occur: the missing nucleotide is inserted by DNA polymerase β (POLβ) in a process called short-patch BER (the most dominant pathway usually), or 2–13 nucleotides are replaced by a variety of proteins in the long-patch repair pathway [19]. These results highlight how variant mutations in NER genes can increase prostate cancer risk
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