Identification of DNA Damage Repair-Associated Prognostic Biomarkers for Prostate Cancer Using Transcriptomic Data Analysis

Abstract

In the recent decade, the importance of DNA damage repair (DDR) and its clinical application have been firmly recognized in prostate cancer (PC). For example, olaparib was just approved in May 2020 to treat metastatic castration-resistant PC with homologous recombination repair-mutated genes; however, not all patients can benefit from olaparib, and the treatment response depends on patient-specific mutations. This highlights the need to understand the detailed DDR biology further and develop DDR-based biomarkers. In this study, we establish a four-gene panel of which the expression is significantly associated with overall survival (OS) and progression-free survival (PFS) in PC patients from the TCGA-PRAD database. This panel includes DNTT, EXO1, NEIL3, and EME2 genes. Patients with higher expression of the four identified genes have significantly worse OS and PFS. This significance also exists in a multivariate Cox regression model adjusting for age, PSA, TNM stages, and Gleason scores. Moreover, the expression of the four-gene panel is highly correlated with aggressiveness based on well-known PAM50 and PCS subtyping classifiers. Using publicly available databases, we successfully validate the four-gene panel as having the potential to serve as a prognostic and predictive biomarker for PC specifically based on DDR biology.

A Novel Four Mitochondrial Respiration-Related Signature for Predicting Biochemical Recurrence of Prostate Cancer

“…EME2 can restart a stalled fork and regulate the homologous recombination repair pathway [ 49 , 50 ]. In the present study, we found that EME2 may regulate mitochondrial respiration and affect the BCR in patients with PCa.…”

PSMA Targeted Molecular Imaging and Radioligand Therapy for Prostate Cancer: Optimal Patient and Treatment Issues

“…Therefore, the use of olaparib and 177Lu-PSMA-617 is expected to have a synergistic anti-tumor effect. It has been reported that PSMA expression correlates with DNA damage repair (DDR) mutation [ 64 ], and since patients with DDR mutation are more radiosensitive [ 65 ] and effective to olaparib [ 8 , 62 , 66 , 67 , 68 ], synergistic effects between both agents could be expected. Clinical trials of combination therapy aimed to exploit the “abscopal” effect, which is a benefit of radiotherapy, are also ongoing.…”

Exonucleases: Degrading DNA to Deal with Genome Damage, Cell Death, Inflammation and Cancer

“…EXO1 has been associated with different types of tumours and its overexpression causes an increase in its DNA repair activity and genome instability. Overexpression of EXO1 occurs in prostate [ 89 , 90 ], breast [ 91 , 92 , 93 ], ovarian (cell lines) [ 94 ], lung [ 95 ], liver [ 96 , 97 ], bladder [ 98 ] and melanoma [ 99 ] cancer patients ( Table 1 ). Moreover, mutations in the exonuclease domain resulting in loss of function, such as the A153V and N279S mutations, are found in colorectal and small intestine tumours [ 100 ].…”