Case Control Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 21, 2018; 24(39): 4462-4471
Published online Oct 21, 2018. doi: 10.3748/wjg.v24.i39.4462
Molecular evaluation of glutathione S transferase family genes in patients with sporadic colorectal cancer
Gabriela Helena Rodrigues-Fleming, Glaucia Maria de Mendonça Fernandes, Anelise Russo, Patrícia Matos Biselli-Chicote, João Gomes Netinho, Érika Cristina Pavarino, Eny Maria Goloni-Bertollo
Gabriela Helena Rodrigues-Fleming, Glaucia Maria de Mendonça Fernandes, Anelise Russo, Patrícia Matos Biselli-Chicote, Érika Cristina Pavarino, Eny Maria Goloni-Bertollo, Genetics and Molecular Biology Research Unit - UPGEM, São José do Rio Preto Medical School, FAMERP, São José do Rio Preto, SP 15090-000, Brazil
João Gomes Netinho, Department of Surgery and Coloproctology, São José do Rio Preto Medical School, FAMERP, São José do Rio Preto, SP 15090-000, Brazil
Author contributions: Rodrigues-Fleming GH planned and conducted the study, collected and interpreted data, and drafted and wrote the manuscript; Fernandes GMM participated in the collection of the genetic material, performed the analytical assessments, and revised the manuscript; Russo A participated in the collection of the genetic material; Biselli-Chicote PM critically revised the analytical tools and the manuscript; Netinho JG collected data on sporadic colorectal cancer patients; Pavarino ÉC served as scientific advisor; Goloni-Bertollo EM was the guarantor, planned the study, and critically revised the manuscript.
Supported by the São Paulo Research Foundation (FAPESP), No. 2011/23969-1 and No. 2012/02473-0; Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001 (Master Grant); and National Council of Technological and Scientific Development (CNPq) No. 310582/2014-8.
Institutional review board statement: The study was reviewed and approved by the FAMERP Institutional Review Board, and it was approved by the Ethics in Research Committee CEP/FAMERP, protocol no. 012/2012.
Informed consent statement: All patients gave informed consent.
Conflict-of-interest statement: The authors declare no conflicts of interest.
Data sharing statement: Participants gave written informed consent for data sharing.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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/
Correspondence to: Eny Maria Goloni-Bertollo, PhD, Adjunct Professor, Postdoc, Genetics and Molecular Biology Research Unit - UPGEM, Department of Molecular Biology, São José do Rio Preto Medical School (FAMERP), Av. Brigadeiro Faria Lima, - 5416 - Vila São Pedro, São José do Rio Preto, SP 15090-000, Brazil. eny.goloni@famerp.br
Telephone: +55-17-32015720 Fax: +55-17-32015708
Received: June 29, 2018
Peer-review started: July 2, 2018
First decision: July 17, 2018
Revised: July 27, 2018
Accepted: August 24, 2018
Article in press: August 24, 2018
Published online: October 21, 2018
Processing time: 111 Days and 20.7 Hours
Abstract
AIM

To evaluate the association between polymorphisms in glutathione S transferases (GSTs) and the risk of sporadic colorectal cancer (SCRC), tumor progression and the survival of patients.

METHODS

A case-control study of 970 individuals from the Brazilian population was conducted (232 individuals from the case group with colorectal cancer and 738 individuals from the control group without a history of cancer). PCR multiplex and PCR-RFLP techniques were used to genotype the GST polymorphisms. The tumors were categorized according to the TNM classification: tumor extension (T), affected lymph nodes (N), and presence of metastasis (M). Logistic regression, multiple logistic regression and survival analysis were used to analyze the data. The results are presented in terms of odds ratio (OR) and 95% confidence interval (CI). The level of significance was set at 5% (P ≤ 0.05).

RESULTS

Age equal to or over 62 years (OR = 8.79; 95%CI: 5.90-13.09, P < 0.01) and female gender (OR = 2.91; 95%CI: 1.74-4.37; P < 0.01) were associated with increased risk of SCRC. Analysis of the polymorphisms revealed an association between the GSTM1 polymorphisms and a risk of SCRC (OR = 1.45; 95%CI: 1.06-2.00; P = 0.02), as well as between GSTT1 and a reduced risk of the disease (OR = 0.65; 95%CI: 0.43-0.98; P = 0.04). An interaction between the presence of the wild-type allele of GSTP1 Ile105Val polymorphism and tobacco consumption on risk of SCRC (OR = 2.33; 95%CI: 1.34-4.05; P = 0.05) was observed. There was an association between the GSTM1 null genotype and the presence of advanced tumors (OR = 2.33; 95%CI: 1.23-4.41; P = 0.009), as well as increased risk of SCRC in the presence of a combination of GSTT1 non-null/GSTM1 null genotypes (OR = 1.50; 95%CI: 1.03-2.19; P = 0.03) and GSTT1 non-null/GSTM1 null/GSTP1 Val* (OR = 1.85; 95%CI: 1.01-3.36, P = 0.04). Combined GSTT1 non-null/GSTM1 null genotypes (OR = 2.40; 95%CI: 1.19-4.85; P = 0.01) and GSTT1 non-null/GSTM1 null/GSTP1 Val* (OR = 2.92; 95%CI: 1.05-8.12; P = 0.04) were associated with tumor progression. Polymorphisms were not associated with the survival of patients with SCRC.

CONCLUSION

Females aged 62 years or older are more susceptible to SCRC. Polymorphisms of GSTT1 and GSTM1 null genotypes modulated the susceptibility to SCRC in the population studied.

Keywords: Colorectal neoplasms; Smoking; Alcohol; Glutathione S transferase; Genetic polymorphisms

Core tip: Sporadic colorectal cancer (SCRC) is the third most common cancer worldwide and includes malignancies that occur in the colon and rectum. Age greater than 60 years, smoking, and alcohol habits are some of the risk factors for SCRC. Detoxification and elimination of carcinogens contained in tobacco and alcohol require metabolic activation mediated by enzymes that metabolize the xenobiotics (XME). Polymorphisms in genes such as GSTP1, GSTT1, and GSTM1 that encode enzymes involved in XMEs may be related to important processes in colorectal carcinogenesis.