Regulatory Variants in the KRAS 3'UTR and Intron 2 Are Associated with Breast Cancer Susceptibility Through Independent and Combinatorial Effects in a Mexican Population.

Background: Breast cancer (BC) is a leading cause of cancer-related mortality worldwide and a major public health concern in Mexico. Regulatory variants in KRAS, particularly within the 3'UTR and intronic regions, may influence gene expression through microRNA binding and transcriptional regulation. Methods: Five regulatory single-nucleotide variants (SNVs) in KRAS (rs12228277, rs1137196, rs8720, rs12587, and rs12245) were genotyped in BC patients and cancer-free controls. Associations were evaluated using odds ratios (ORs) with 95% confidence intervals (CIs), adjusting for age, alcohol, and tobacco use. Multiple testing was corrected using the Benjamini-Hochberg false discovery rate (FDR). Linkage disequilibrium (LD), multilocus combinations, and in silico functional analyses were also performed. Results: Variants rs12228277, rs1137196, rs8720, and rs12245 showed significant genotype-level associations with BC susceptibility, all remaining significant after FDR correction (pFDR < 0.05). No clinicopathological associations remained significant after correction in single-variant analyses. Multilocus analysis identified specific high-risk combinations (e.g., involving rs12228277, rs1137196, and rs8720) associated with increased BC susceptibility. At the nominal level, these combinations showed associations with clinicopathological features, including hormone receptor-positive status (PR and ER), proliferation markers, and Luminal B subtype; however, none remained significant after FDR correction. LD analysis indicated weak linkage among variants. In silico analyses suggested potential regulatory effects on microRNA binding and KRAS expression. Conclusions: Regulatory variants in KRAS are associated with BC susceptibility through independent effects and potential combinatorial patterns. These findings support the relevance of non-coding variation in cancer risk and warrant further functional and replication studies.