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

Abstract

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.

Role of Betaglycan in TGF-β Signaling and Wound Healing in Human Endometriotic Epithelial Cells and in Endometriosis

“…Although BG has been demonstrated to participate in multiple diseases [17,19,20,32,33] including endometrial cancer [23,33,34], its role in endometriosis is unknown. Thus, we investigated the involvement of BG in endometriosis with endometriotic 12Z cells in vitro, explored the modulation of BG shedding by TGF-β1/-β2, TIMPs and MMPs, and the influence of TGF-βs and BG on wound healing.…”

Canonical TGFβ Signaling and Its Contribution to Endometrial Cancer Development and Progression—Underestimated Target of Anticancer Strategies

“…An additional mechanism with potential impact on the declined expression of the TGFBR3 gene involves three intronic SNPs, i.e., rs12566180 (c.-114 + 2392C > T) and rs2296621 (c.2285 − 99G > T), which correlate with TGFBR3 transcript loss in endometrial cancer. Moreover, these SNPs and an additional one, rs6680463 (c.-114 + 7008C > G), are significantly associated with increased risk of endometrial cancer, respectively in the case of genotypes CT (rs12566180; OR = 2.22; 95% CI = 1.15-4.30; p = 0.0177), GC (rs6680463; OR = 2.34; 95% CI = 1.20-4.53; p = 0.0120) and TT (rs2296621; OR = 6.40; 95% CI = 1.18-34.84; p = 0.0317) [241] (Table 1). In the context of clinicopathological parameters, only rs2296621 seems to favor an increased tumor 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).…”

“…The evaluation of betaglycan expression at the transcriptomic level in the context of clinicopathological features of studied material indicates that its loss occurs as an early event in neoplastic transformation of human endometrium [222] (Table 1). Further studies have revealed that observed betaglycan down-regulation results from different genetic mechanisms, including LOH and single nucleotide polymorphisms (SNPs) in the locus of the TGFBR3 gene [240,241]. LOH, assessed using three microsatellite markers (D1S188, D1S435 and D1S1588), is a relatively frequent event and occurs in 52% of all analyzed primary endometrial carcinomas (Table 1).…”

TGF‐β superfamily co‐receptors in cancer

“…[30][31][32][33][34] Allelic loss of TβRIII is a frequent genetic event in many of these cancers, and loss of TβRIII is associated with cancer progression and a poor prognosis. 35,36 Additionally, there are polymorphisms of the TβRIII gene (TGFBR3) associated with increased cancer risk, 37 and multiple microRNAs have been implicated in promoting cancer progression and metastasis via downregulation of TβRIII. [38][39][40][41] The mechanism of action is due in large part to the TβRIII ectodomain shedding from the cell surface, releasing sTβRIII, which antagonizes the tumor-promoting and immunosuppressive effects of TGF-β signaling.…”