Impact of genetic variation in microRNA binding site on susceptibility to colorectal cancer

Aim/Background

The present study analyzed SNPs located at putative miRNA-binding sites of the 3'-UTR in various genes and investigated their impact on the susceptibility to CRC.

Methods

Ninety-two SNPs were selected using an in Silico analysis of 3'-UTR SNPs in a SNP database and calculating their miRNA bind efficiency using several miRNA databases and the HapMap database. Two independent study sets were used: 380 healthy control subjects and 371 colorectal adenocarcinoma patients for the discovery set, and 521 healthy control subjects and 524 colorectal adenocarcinoma patients for the replication set. The SNP genotyping was performed using a Sequenom MassARRAY. Plus, a luciferase assay was used to investigate whether miR-370 modulated DOK3 gene expression when rs2279398G > A was included in the DOK3 3'-UTR region.

Results

For the discovery set, 16 out of 92 SNPs were significantly associated with the risk of CRC in at least one of the genetic models. Meanwhile, the replication set showed that among these 16 SNPs, DOK3 rs2279398G > A was significantly associated with the risk of CRC in a recessive model (adjusted odds ratio (OR) = 0.65, 95% confidence interval (CI) = 0.44-0.97, P = 0.03). In a combined analysis, DOK3 rs2279398G > A was associated with a significantly decreased risk of CRC in a codominant and recessive model (adjusted OR = 0.84, 95% CI = 0.73-0.96, P = 0.012, adjusted OR = 0.65, CI = 0.49-0.88, P = 0.004, respectively). A significantly lower Renilla activity was also observed with the rs2279398 AA construct when compared with the rs2279398 GG construct (P < 0.001).

Conclusions

DOK3 rs2279398G > A may affect the expression of DOK3 by altering the miRNA binding efficiency at the miRNA-binding sites of the 3'-UTR in DOK3, thereby impacting CRC tumorigenesis.

Clinical trial identification

Disclosure

All authors have declared no conflicts of interest.