Stanilov Noyko, Grigorova Antonia, Velikova Tsvetelina, Stanilova Spaska Angelova
Oncoplastic Unit, University College London Hospital, London NW1 2BU, United Kingdom.
Department of Molecular Biology, Immunology and Medical Genetics, Medical Faculty, Trakia University, Stara Zagora 6000, Bulgaria.
World J Gastrointest Oncol. 2021 Nov 15;13(11):1766-1780. doi: 10.4251/wjgo.v13.i11.1766.
The role of transforming growth factor beta (TGF-β) signaling, including both the cytokine and their receptors, in the etiology of colorectal cancer (CRC) has been of particular interest lately.
To investigate the association between promoter polymorphism in TGF-β receptor 2 TGF-ΒR2GA with a CRC risk in a cohort of Bulgarian patients using a case-control gene association study approach, as well as the protein levels of TGF-β1 in the peripheral blood.
A cohort of 184 CRC patients and 307 sex and age-matched healthy subjects were recruited in the study. A genotyping of the TGF-ΒR2GA (rs3087465) polymorphism was performed by primer-introduced restriction analyses-polymerase chain reaction approaches.
The frequency of TGF-ΒR2GA genotype was decreased in male patients with CRC than in healthy men (31.3% 44.8%; = 0.058). Among males, the TGF-ΒR2GG genotype was related to a significantly increased risk of CRC development (OR = 1.820, 95%CI: 0.985-3.362, = 0.055) than the GA + AA genotype. Also, TGF-ΒR2*A-allele itself was rarer in men with CRC than healthy men (19.1% 26.9%, = 0.086) and was associated with a protective effect (OR = 0.644; 95%CI: 0.389-1.066; = 0.086). Regarding the genotypes, we found that TGF-β1 serum levels were higher in GG genotype in healthy persons above 50 years than the CRC patients [36.3 ng/mL interquartile range (IQR) 19.9-56.5 22.4 ng/mL IQR 14.8-29.7, = 0.014]. We found significant differences between higher levels of TGF-β1 serum levels in healthy controls above 50 years (GG genotype) and CRC patients (GG genotype) at the early stage (36.3 ng/mL IQR 19.9-56.5 22.8 ng/mL IQR 14.6-28.6, = 0.037) and advanced CRC (36.3 ng/mL IQR 19.9-56.5 21.6 ng/mL IQR 15.9-33.9, = 0.039).
In summary, our results demonstrated that TGF-ΒR2 AG and AA genotypes were associated with a reduced risk of CRC, as well as circulating levels of TGF-β could prevent CRC development in a gender-specific manner. Notably, male carriers of TGF-ΒR2 -875A allele genotypes had a lower risk of CRC development and progression, suggesting that TGF-ΒR2 -875A/G polymorphism significantly affects the protective biological factors that also impact the risk of colon and rectal carcinogenesis.
转化生长因子β（TGF-β）信号传导，包括细胞因子及其受体，在结直肠癌（CRC）病因学中的作用近来备受关注。
采用病例对照基因关联研究方法，调查保加利亚患者队列中TGF-β受体2（TGF-ΒR2）基因启动子多态性TGF-ΒR2GA与CRC风险之间的关联，以及外周血中TGF-β1的蛋白水平。
本研究招募了184例CRC患者和307例年龄及性别匹配的健康受试者。采用引物引入限制性分析-聚合酶链反应方法对TGF-ΒR2GA（rs3087465）多态性进行基因分型。
CRC男性患者中TGF-ΒR2GA基因型的频率低于健康男性（31.3%对44.8%；P = 0.058）。在男性中，与GA + AA基因型相比，TGF-ΒR2GG基因型与CRC发生风险显著增加相关（OR = 1.820，95%CI：0.985 - 3.362，P = 0.055）。此外，CRC男性患者中TGF-ΒR2*A等位基因本身比健康男性更罕见（19.1%对26.9%，P = 0.086），且与保护作用相关（OR = 0.644；95%CI：0.389 - 1.066；P = 0.086）。关于基因型，我们发现50岁以上健康人的GG基因型中TGF-β1血清水平高于CRC患者[36.3 ng/mL四分位间距（IQR）19.9 - 56.5对22.4 ng/mL IQR 14.8 - 29.7，P = 0.014]。我们发现50岁以上健康对照（GG基因型）与早期CRC患者（GG基因型）的TGF-β1血清水平较高之间存在显著差异（36.3 ng/mL IQR 19.9 - 56.5对22.8 ng/mL IQR 14.6 - 28.6，P = 0.037）以及晚期CRC患者（36.3 ng/mL IQR 19.9 - 56.5对21.6 ng/mL IQR 15.9 - 33.9，P = 0.039）。
总之，我们的结果表明TGF-ΒR2 AG和AA基因型与CRC风险降低相关，并且TGF-β的循环水平可能以性别特异性方式预防CRC发生。值得注意的是，TGF-ΒR2 -875A等位基因基因型的男性携带者患CRC的风险较低且进展较慢，这表明TGF-ΒR2 -875A/G多态性显著影响保护生物学因素，这些因素也会影响结肠癌和直肠癌发生的风险。
