Rs12516 A allele elevates the risk of colorectal cancer via functional CeRNA network of BDNF-AS, miR-4704-5p and BRCA1.

DNA double-strand break repair has emerged as a vital pathway to repair DNA damage seriously related to the risk of colorectal cancer (CRC). To explore valid susceptible biomarkers of CRC via investigating the association of single nucleotide polymorphisms in DSBR genes with CRC risk, seven polymorphisms located in 3'-untranslated regions of DSBR genes including RAD51 rs11852786, RAD51B rs963917, BRCA1 rs12516 and rs8176318, BRCA2 rs15869, XRCC4 rs2035990 and XRCC5 rs2440 were detected and analyzed in a CRC case-control study (cases (202) and also controls (202)). The PolymiRTs and miRSNP database were used to predict the microRNAs that can bind to 3'UTR SNPs. Since long non-coding RNA as a miRNA "sponge" played the role of competing endogenous RNA, DAVID database was used to find the lncRNAs that can bind to the candidate miRNA seed sequences. BRCA1 rs12516 minor A allele was found to be linked with a higher risk of CRC than its major G allele (OR = 2.716, 95%CI: 1.394-5.292, P = 0.003). The stratified analyses demonstrated rs12516 AA genotype with a more elevated risk of CRC in male (OR = 3.089, 95% CI:1.315 ~ 7.255) or age > 50 population (OR = 3.318, 95%CI:1.571 ~ 7.006) than its GG genotype. BRCA1 rs12516 A allele created a novel miR-4704-5p binding target, and there was a negative correlation between miR-4704-5p and BRCA1 expression (r =-0.7199, P = 0.0440). Based on the theory of ceRNA network, it was predicted that lncRNA BDNF-AS can competitively bind to miR-4704-5p, whose expression was exhibited to be negatively correlated with BDNF-AS (r=-0.3481, P = 0.0375). On the contrary, BDNF-AS expression showed a positive correlation with BRCA1 mRNA level in colorectal tissue carrying rs12516 of A allele (adjacent tissue: r = 0.7269, P = 0.0411; cancer tissue: r = 0.7134, P = 0.0469). ROC curve showed both BDNF-AS (AUC = 0.651, P = 0.0277) and miR-4704-5p (AUC = 0.7215, P = 0.0012) can distinguish CRC tissues from their adjacent tissues. BRCA1 rs12516 is characterized as a potential biomarker associated with CRC risk, via a possible functional ceRNA network of BDNF-AS, miR-4704-5p and BRCA1. The interaction of a lower expression of BDNF-AS, a higher expression of miR-4704-5p and rs12516 A allele could together increase the risk of colorectal cancer.