Genetic aberrations in DNA repair pathways: a cornerstone of precision oncology in prostate cancer

Abstract

Over the past years, several studies have demonstrated that defects in DNA damage response and repair (DDR) genes are present in a significant proportion of patients with prostate cancer. These alterations, particularly mutations in BRCA2, are known to be associated with an increased risk of developing prostate cancer and more aggressive forms of the disease. There is growing evidence that certain DDR gene aberrations confer sensitivity to poly-(ADP ribose) polymerase inhibitors and/or platinum chemotherapy, while other defects might identify cases that are more likely to benefit from immune checkpoint inhibition. The potential prognostic impact and relevance for treatment selection together with the decreasing costs and broader accessibility to next-generation sequencing have already resulted in the increased frequency of genetic profiling of prostate tumours. Remarkably, almost half of all DDR genetic defects can occur in the germline, and prostate cancer patients identified as mutation carriers, as well as their families, will require appropriate genetic counselling. In this review, we summarise the current knowledge regarding the biology and clinical implications of DDR defects in prostate cancer, and outline how this evidence is prompting a change in the treatment landscape of the disease.

Metformin Sensitizes Osteosarcoma Cells to Chemotherapy Through IGF-1R/miR-610/FEN1 Pathway

“…Cytotoxic chemotherapy causes severe DNA damage directly by induction of breaks or indirectly due to the formation of reactive oxygen species (ROS) and ultimately induce cell death 34,35 . In responses to DNA damage, cells recruit DNA repair factors to upregulate mutagenic repair pathways that to maintain survival 36 .…”

The Etiology and Pathophysiology Genesis of Benign Prostatic Hyperplasia and Prostate Cancer: A New Perspective

“…This is the threshold point at the start of "prostate reprogramming" and the "loss" of cell function, homeostasis and regulation pathways [192][193][194][195][196][197]. It marks the beginning of a prostate stagnation tumorigenesis inflammatory microenvironment with heterogeneous events [17] including inflammation [57, [140][141][142]198], genetic aberrations [199][200][201][202][203][204][205], epigenetic dysregulation [206][207][208][209][210], autophagy dysregulation [86,87,89,90,[211][212][213][214][215][216] and lysosomal dysfunction [217][218][219][220].…”

Immune Checkpoint Inhibitors: A Promising Treatment Option for Metastatic Castration-Resistant Prostate Cancer?

“…Alterations in DNA damage repair (DDR) genes, such as those involving the homologous recombination (HR) pathway genes, such as BRCA2, BRCA1, ATM, CDK12 , and PALB2 , occur in approximately 20–25% of mCRPC cases at either the somatic or the germline level [ 27 , 28 ]. In this regard, two Poly (ADP-ribose) polymerase inhibitors (PARPi), rucaparib and olaparib, have been recently approved by the FDA for the treatment of mCRPC [ 29 ].…”

“…Interestingly, defects in HR pathway genes may also be associated with an increase in genomic instability, neoantigen load, PD-L1 expression, and tumor-infiltrating lymphocytes [ 120 ]. Alterations in HR pathway genes, including BRCA2 , BRCA1 , ATM , CDK12 , and PALB2 , occur in approximately 20–25% of mCRPC cases at either the somatic or the germline level [ 27 , 28 ], making these patients potentially more responsive to ICIs and suggesting that HR pathway genes may be potential predictive biomarkers of response to ICIs. Indeed, several studies, including the KEYNOTE-199 and CheckMate-650 trials, have shown a trend towards a higher ORR to pembrolizumab in HR-deficient mCRPC patients [ 59 , 72 ].…”