Betaglycan Gene (TGFBR3) Polymorphism Is Associated with Increased Risk of Endometrial Cancer.

We investigated single nucleotide polymorphism (SNP) of the betaglycan gene (TGFBR3) encoding the TGFβ co-receptor in endometrial cancer (EC) and its association with betaglycan expression. The study group included 153 women diagnosed with EC and 248 cancer-free controls. SNP genotyping and gene expression were analyzed using TaqMan probes. Three out of the eight SNPs tested, i.e., rs12566180 (CT; OR = 2.22; 95% CI = 1.15-4.30; p = 0.0177), rs6680463 (GC; OR = 2.34; 95% CI = 1.20-4.53; p = 0.0120) and rs2296621 (TT; OR = 6.40; 95% CI = 1.18-34.84; p = 0.0317) were found to be significantly associated with increased risk of EC (adjusted to age, body mass index, menarche and parity). Among the analyzed SNPs, only rs2296621 demonstrated the impact on the increased cancer aggressiveness evaluated by the WHO grading system (G3 vs. G1/2, GT-OR = 4.04; 95% CI = 1.56-10.51; p = 0.0026; T-OR = 2.38; 95% CI = 1.16-4.85; p = 0.0151). Linkage disequilibrium (LD) analysis revealed high LD (r2 ≥ 0.8) in two haploblocks, constructed by rs2770186/rs12141128 and rs12566180/rs6680463, respectively. In the case of C/C haplotype (OR = 4.82; 95% CI = 1.54-15.07; p = 0.0116-Bonferroni corrected) and T/G haplotype (OR = 3.25; 95% CI = 1.29-8.15; p = 0.0328-Bonferroni corrected) in haploblock rs12566180/rs6680463, significantly higher frequency was observed in patients with EC as compared to the control group. The genotype-phenotype studies showed that SNPs of the TGFBR3 gene associated with an increased risk of EC, i.e., rs12566180 and rs2296621 may affect betaglycan expression at the transcriptomic level (rs12566180-CC vs. TT, p < 0.01; rs2296621-GG vs. TT, p < 0.001, GT vs. TT, p < 0.05). Functional consequences of evaluated TGFBR3 gene SNPs were supported by RegulomeDB search. In conclusion, polymorphism of the TGFBR3 gene may be associated with an increased EC occurrence, as well as may be the molecular mechanism responsible for observed betaglycan down-regulation in EC patients.