Germline TP53 noncoding variant (rs78378222) prevalence in cohorts of prostatic adenocarcinoma and benign prostatic hyperplasia: further evidence from southern Brazil and novel insights into its functional impact mediated by the circRNAs-miRNAs-TP53 regulatory axis

Background The TP53 3’UTR germline variant rs78378222 A > C has been associated with several tumors in European populations. It modifies both the polyadenylation signal (PAS) sequence and binding sites for specific miRNAs (miR-382-5p, miR-325-3p, and miR-125b; rs7837822-associated miRNAs) in the TP53 3’UTR, resulting in decreased p53 expression. Its prevalence is not yet fully known in admixed populations. Methods and Results Herein, the germline prevalence of rs7837822 was examined in 320 samples from two cohorts of patients diagnosed with prostatic adenocarcinoma (PAC, n = 153) and benign prostatic hyperplasia (BPH, n = 167) in southern Brazil. Additionally, circRNAs reported in the circRNAdisease v2.0 database as previously validated "sponges” of rs7837822-associated miRNAs were retrieved, and circRNA differential expression analysis was performed based on PAC and BPH tissues using the GEO database. The variant allele was observed in 1/153 (0.65%) of PAC and in 1/167 (0.6%) of BPH cases, a lower frequency compared to the European prostate cancer cohorts. Interestingly, twenty circRNAs regulating rs78378222-associated miRNAs in other human tissues not related to the prostate gland were found, and two specific circRNAs were upregulated in PAC when compared with BPH tissues, namely hsa_circ_0001658 (derived from the ARID1B host gene; p = 0.0378) and hsa_circ_NR3C1 (p = 0.0114). Conclusions This is the first report investigating a novel functional aspect associated with this variant involving the circRNA-miRNA- TP53 regulatory axis, and a hypothesis-generating framework for future experimental studies. Germline analyses, including larger Brazilian cohorts, should be undertaken to confirm our findings and determine whether screening for rs78378222 in non-cancerous (BPH) and cancerous prostate conditions is justified.