3'UTR Variant rs12245 in KRAS and Its Functional Implications in Breast Cancer Susceptibility

Introduction
The KRAS gene plays a key role in oncogenic signaling. Regulatory variants within its 3' untranslated region (3'UTR) can affect microRNA (miRNA) binding, influencing post-transcriptional regulation. This study evaluated the potential association between the rs12245 variant in the 3'UTR of KRAS and breast cancer (BC) susceptibility and explored this variant's possible functional relevance through in silico analysis.

Methods
A total of 627 individuals were genotyped for rs12245, including 385 BC patients and 242 individuals forming a reference group. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression models. Predictions of altered miRNA binding were obtained from miRNASNP-v3 and PolymiRTS. The expression status of the affected miRNAs was examined in dbDEMC. In addition, eQTL analysis was performed using GTEx data for breast mammary tissue.

Results
The AT genotype was associated with a reduced risk of BC (OR = 0.55; 95% CI: 0.40 to 0.77; p = 0.0003), while the TT genotype and recessive model were associated with an increased risk (OR = 1.44; 95% CI: 1.00 to 2.06; p = 0.023). No significant associations were found with clinicopathological variables. In silico analysis suggested that rs12245 may alter the binding of several miRNAs to the KRAS 3'UTR, including hsa-miR-543, hsa-miR-544a, hsa-miR-4803, hsa-miR-5580-3p, hsa-miR-4686, hsa-miR-6738-3p, and hsa-miR-5096, which are deregulated in BC. The GTEx data indicated that rs12245 shows eQTL activity in breast tissue (p = 0.00069; slope = –0.094).

Conclusion
The rs12245 variant in KRAS may contribute to determining BC susceptibility and shows potential regulatory effects based on eQTL and miRNA binding predictions. These findings warrant further investigation to clarify this variant's biological significance.