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
Processing time: 262 Days and 20.7 Hours
ARTICLE HIGHLIGHTS
Research background

The role of transforming growth factor beta (TGF-β) signaling, which includes both the cytokine and its receptors, in the etiology of colorectal cancer (CRC) has been investigated recently. TGF-β-associated cancer pathways must be disrupted in the early stages of tumor growth, while TGF-β activation can promote cancer invasion and metastasis.

Research motivation

Given the importance of the TGF-β1 signaling pathway in CRC production and the fact that TGF-β1 exerts its effects through these receptors, we could hypothesize that genetic polymorphisms in the TGF-β1 gene and genes for TGF-β receptors may also play a role in CRC susceptibility. Previously, we recorded that circulating TGF-β1 and the -509C/T functional promoter polymorphism (rs1800469) within the TGF-β1 gene (TGF-Β1) plays a gender-dependent role in the resistance, development, and prognosis of CRC in Bulgarian patients. Therefore, we were interested in gender-associated differences in the frequency of TGF-ΒR2G[-875]A promoter polymorphism and CRC risk.

Research objectives

We performed a case-control gene association research approach to examine the association between TGF-β receptor 2 TGF-ΒR2G[-875]A promoter polymorphism and CRC risk in a cohort of Bulgarian patients, as well as TGF-β1 protein levels in the peripheral blood. We also estimated the role of this polymorphism at different stages of the disease, defined as early and advanced in men and women.

Research methods

One hundred eighty-four CRC patients and 307 sex and age-matched stable participants were recruited in the study. Primer-introduced restriction analysis-polymerase chain reaction methods were used for genotyping the TGF-ΒR2G[-875]A (rs3087465) polymorphism.

Research results

The GG genotype was shown to have the greatest chance of developing colorectal neoplasia in this case-control study. Male CRC patients who were homozygous for the GG genotype had an elevated risk of developing CRC. Male carriers of TGF-ΒR2 -875A allele genotypes, on the other hand, had a lower chance of CRC growth and progression. TGF-β1 serum levels were higher in the GG genotype in people over 50 years old than in CRC patients.

Research conclusions

TGF-ΒR2 AG and AA genotypes were associated with a lower risk of CRC in our study. Besides, circulating TGF-β levels could inhibit CRC production in a gender-specific manner.

Research perspectives

Since we documented that male carriers of TGF-ΒR2 -875A allele genotypes had a lower risk of CRC formation and progression, we can imply that the TGF-ΒR2 -875A/G polymorphism has a direct effect on the protective biological factors that influence the risk of colon and rectal carcinogenesis.