Background: Colorectal cancer (CRC) ranks as the third most common malignancy worldwide and the leading cause of cancer-related mortality in 2024. While previous studies have explored the role of intracellular genes in CRC development, there is limited evidence regarding the involvement of fibroblast growth factor receptors (FGFR), particularly FGFR3. This gene, located on chromosome 4p16.3, consists of 19 exons and plays a key role in cell cycle regulation. Three high-variability regions, or hotspots, have been identified within the gene, with exon 7 being the most significant—accounting for approximately 88% of reported mutations. Exon 7 encodes the IgIII domain, which is essential for the formation of receptor isoforms via alternative splicing, affecting ligand-binding specificity. The synonymous variant rs2234909, located in exon 7 (codon 294), involves a T>C transition (p.Asn294Asn). Although it does not change the amino acid sequence, it may promote disulfide bond formation between adjacent monomer receptors or induce structural changes in the tyrosine kinase domain, leading to ligand-independent dimerization.

Objective: To analyze the association between the FGFR3 rs2234909 variant and CRC in the Mexican population.

Materials and Methods: A cross-sectional analytical study was conducted with 472 DNA samples from CRC patients and 395 from healthy donors. The rs2234909 variant was genotyped using real-time PCR (qPCR) with TaqMan® probes on a Bio-Rad CFX96 system. Genotypic and allelic frequencies were calculated by direct counting. Associations between genotypes and CRC risk were assessed using bivariate analysis (odds ratio, 95% CI), with statistical significance set at p < 0.05. Data were analyzed using SPSS v24.

Results: The GG genotype and recessive model of rs2234909 were significantly associated with an increased risk of CRC (OR = 5.34; 95% CI: 3.36–8.47; p < 0.05).

Conclusion: rs2234909 may serve as a potential genetic susceptibility marker for CRC.