Case Control Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Nov 15, 2021; 13(11): 1766-1780
Published online Nov 15, 2021. doi: 10.4251/wjgo.v13.i11.1766
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
Noyko Stanilov, Oncoplastic Unit, University College London Hospital, London NW1 2BU, United Kingdom
Antonia Grigorova, Spaska Angelova Stanilova, Department of Molecular Biology, Immunology and Medical Genetics, Medical Faculty, Trakia University, Stara Zagora 6000, Bulgaria
Tsvetelina Velikova, Department of Clinical Immunology, University Hospital Lozenetz, Sofia 1407, Bulgaria
Tsvetelina Velikova, Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
Author contributions: Grigorova A was involved in the conceptualization, data curation, funding acquisition, investigation, project administration, and writing (original draft); Stanilov N was involved in the data curation, investigation, resources, writing (review & editing); Velikova T was involved in writing (review & editing); Stanilova SA performed the conceptualization, funding acquisition, investigation, methodology, project administration, supervision, validation, visualization, writing (review & editing).
Supported by the Research Grants from Trakia University, Medical Faculty, Stara Zagora, Bulgaria, No. 1/2017 and 2/2019.
Institutional review board statement: The study was reviewed and approved by the Trakia University Institutional Review Board (Approval No. 560/13.02.2019).
Informed consent statement: The patient provided informed written consent prior to study enrollment.
Conflict-of-interest statement: The authors declare that they have no conflict-of-interest.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Tsvetelina Velikova, MD, PhD, Assistant Professor, Department of Clinical Immunology, University Hospital Lozenetz, Kozyak 1, Sofia 1407, Bulgaria. tsvelikova@medfac.mu-sofia.bg
Received: February 22, 2021
Peer-review started: February 22, 2021
First decision: May 8, 2021
Revised: May 19, 2021
Accepted: September 22, 2021
Article in press: September 22, 2021
Published online: November 15, 2021
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, TGF-ΒR2 gene, TGF-ΒR2G[-875]A, Single nucleotide polymorphism

Core Tip: Disruptions in transforming growth factor beta (TGF-β)-associated cancer mechanisms are essential in early-stage tumor development, whereas activation of TGF-β-signaling can encourage invasion and metastasis of cancer. Our findings from this case-control study suggested that the highest risk for developing colorectal neoplasia was found for the GG genotype. The increased risk for colorectal cancer (CRC) development was associated with male CRC patients homozygous for the GG genotype. In contrast, male carriers of TGF-ΒR2 -875A allele genotypes of TGF-ΒR2 had a lower risk of CRC development and progression. No other studies for this polymorphism and CRC association from the literature are available to the best of our knowledge.