Genetic Aberrations of DNA Repair Pathways in Prostate Cancer: Translation to the Clinic

• Main Authors: Aruni Ghose, Michele Moschetta, George Pappas-Gogos, Matin Sheriff, Stergios Boussios
• Format: Article
• Language: English
• Published: MDPI AG 2021-09-01
• Series: International Journal of Molecular Sciences
• Subjects: prostate cancer; DNA damage repair; PARP; BRCA; next-generation sequencing
• Online Access: https://www.mdpi.com/1422-0067/22/18/9783

Prostate cancer (PC) is the second most common cancer in men worldwide. Due to the large-scale sequencing efforts, there is currently a better understanding of the genomic landscape of PC. The identification of defects in DNA repair genes has led to clinical studies that provide a strong rationale for developing poly (ADP-ribose) polymerase (PARP) inhibitors and DNA-damaging agents in this molecularly defined subset of patients. The identification of molecularly defined subgroups of patients has also other clinical implications; for example, we now know that carriers of breast cancer 2 (<i>BRCA2</i>) pathogenic sequence variants (PSVs) have increased levels of serum prostate specific antigen (PSA) at diagnosis, increased proportion of high Gleason tumors, elevated rates of nodal and distant metastases, and high recurrence rate; <i>BRCA2</i> PSVs confer lower overall survival (OS). Distinct tumor PSV, methylation, and expression patterns have been identified in <i>BRCA2</i> compared with non-<i>BRCA2</i> mutant prostate tumors. Several DNA damage response and repair (DDR)-targeting agents are currently being evaluated either as single agents or in combination in patients with PC. In this review article, we highlight the biology and clinical implications of deleterious inherited or acquired DNA repair pathway aberrations in PC and offer an overview of new agents being developed for the treatment of PC.