Genetic variation of TGF-ΒR2 as a protective genotype for the development of colorectal cancer in men

Noyko Stanilov; Antonia Grigorova; Tsvetelina Velikova; Spaska Angelova Stanilova

doi:10.4251/wjgo.v13.i11.1766

Genetic variation of TGF-ΒR2 as a protective genotype for the development of colorectal cancer in men

World J Gastrointest Oncol. 2021 Nov 15;13(11):1766-1780. doi: 10.4251/wjgo.v13.i11.1766.

Authors

Noyko Stanilov¹, Antonia Grigorova², Tsvetelina Velikova³, Spaska Angelova Stanilova²

Affiliations

¹ Oncoplastic Unit, University College London Hospital, London NW1 2BU, United Kingdom.
² Department of Molecular Biology, Immunology and Medical Genetics, Medical Faculty, Trakia University, Stara Zagora 6000, Bulgaria.
³ Department of Clinical Immunology, University Hospital Lozenetz, Sofia 1407, Bulgaria.

Abstract

Background: 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.

Aim: To investigate the association between promoter polymorphism in TGF-β receptor 2 TGF-ΒR2G^[-875]A 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.

Methods: A cohort of 184 CRC patients and 307 sex and age-matched healthy subjects were recruited in the study. A genotyping of the TGF-ΒR2G^[-875]A (rs3087465) polymorphism was performed by primer-introduced restriction analyses-polymerase chain reaction approaches.

Results: The frequency of TGF-ΒR2G^[-875]A genotype was decreased in male patients with CRC than in healthy men (31.3% vs 44.8%; P = 0.058). Among males, the TGF-ΒR2G^[-509]G genotype was related to a significantly increased risk of CRC development (OR = 1.820, 95%CI: 0.985-3.362, P = 0.055) than the GA + AA genotype. Also, TGF-ΒR2^[-875]*A-allele itself was rarer in men with CRC than healthy men (19.1% vs 26.9%, P = 0.086) and was associated with a protective effect (OR = 0.644; 95%CI: 0.389-1.066; P = 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 vs 22.4 ng/mL IQR 14.8-29.7, P = 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 vs 22.8 ng/mL IQR 14.6-28.6, P = 0.037) and advanced CRC (36.3 ng/mL IQR 19.9-56.5 vs 21.6 ng/mL IQR 15.9-33.9, P = 0.039).

Conclusion: 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.

Keywords: Colorectal carcinoma; Cytokine; Single nucleotide polymorphism; TGF-ΒR2 gene; TGF-ΒR2G[-875]A.