Prognostic Value of PARP1 and PARP2 Copy Number Alterations in Prostate Cancer

Abstract

PARP1/2 have overlapping yet nonredundant biological functions in DNA repair and androgen receptor-transcriptional regulation. Studies on PARP alterations in human tumors have yielded conflicting results. In prostate cancer (PCa), PARP1/2 protein overexpression has been related to androgen deprivation therapy resistance, biochemical recurrence, and progression to metastases. PARP inhibitors have been approved for treating metastatic castration-resistant PCa with homologous recombination repair gene mutations. However, the significance of PARP1/2 genomic alterations is not fully studied. We aimed to analyze PARP1/2 alterations in PCa, assess their value as prognostic markers, and explore their relevance for potential therapeutic stratification. PARP1/2 copy number status was evaluated in 121 PCa primary tumors using real-time PCR. In 29 of them, a regional pelvic lymph node involvement was also analyzed. BRCA1/2 somatic mutations were analyzed in 24 PCa cases. Relationship with clinicopathological features, progression to metastases, and prostate-specific antigen recurrence was assessed. PARP1 loss and PARP2 gain were detected in 34.7% and 32.2% of primary tumors, respectively, with a high frequency of co-occurrence (P < .001). Both alterations were statistically associated with locally advanced disease at the time of diagnosis (P = .036; P = .006), metastatic dissemination (P = .014; P = .003), and other aggressive clinicopathological characteristics (such as the presence of Gleason pattern 5, high-grade, and high-stage). Cases with exclusive PARP2 gain had the shortest time to prostate-specific antigen recurrence, whereas double wt patients displayed the best outcome (P = .007). In 29 paired primary tumors and regional pelvic lymph node involvement, PARP1 loss showed strong concordance (P = .001), whereas PARP2 gain did not (P = .411). In conclusion, loss of PARP1 and gain of PARP2 show strong co-occurrence and are associated with clinicopathological characteristics of aggressiveness. PARP2 alterations appear to have a particularly significant impact on disease prognosis. Furthermore, these data suggest that the analysis of PARP1/2 copy number status could be useful in predicting PCa outcomes. Its role in therapy warrants further evaluation.

Keywords: PARP inhibitors; PARP1; PARP2; copy number; prostate cancer.