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©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
CYP1A1, CYP2E1 and EPHX1 polymorphisms in sporadic colorectal neoplasms
Glaucia Maria M Fernandes, Anelise Russo, Marcela Alcântara Proença, Nathalia Fernanda Gazola, Gabriela Helena Rodrigues, Patrícia Matos Biselli-Chicote, Ana Elizabete Silva, João Gomes Netinho, Érika Cristina Pavarino, Eny Maria Goloni-Bertollo
Glaucia Maria M Fernandes, Anelise Russo, Nathalia Fernanda Gazola, Gabriela Helena Rodrigues, Patrícia Matos Biselli-Chicote, Érika Cristina Pavarino, Eny Maria Goloni-Bertollo, Genetics and Molecular Biology Research Unit - UPGEM, Department of Molecular Biology, São José do Rio Preto Medical School, FAMERP, São José do Rio Preto, SP 15090-000, Brazil
Marcela Alcântara Proença, Ana Elizabete Silva, Departament of Biology, UNESP - São Paulo State University, São José do Rio Preto, SP 15054-000, Brazil
João Gomes Netinho, Departament of Surgery and Coloproctology Service, São José do Rio Preto Medical School, FAMERP, São José do Rio Preto, SP 15090-000, Brazil
Author contributions: Fernandes GMM planned and conducted the study, collected and interpreted data, drafted and wrote the manuscript; Biselli-Chicote PM performed the haplotype analysis and critically revised the manuscript; Netinho JG collected data on SCRC patients; Russo A participated in the collection of the genetic material, performed the analytical tools and revised the manuscript; Proença MA, Gazola NF and Rodrigues GH participated in the collection of the genetic material and performed the analytical tools; Silva AE and Pavarino ÉC served as scientific advisor; Goloni-Bertollo EM was the guarantor, planned the study and critically revised the manuscript.
Supported by São Paulo Research Foundation (FAPESP), No. 2011/23969-1 and No. 2012/02473-0; Coordination for the Improvement of Higher Education Personnel (CAPES) (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 (CAAE: 0237.0.140.00011)
Informed consent statement: All patients gave informed consent.
Conflict-of-interest statement: The authors declare no conflict of interest.
Data sharing statement: Participants gave written informed consent for data sharing.
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, Genetics and Molecular Biology Research Unit - UPGEM, Department of Molecular Biology, São José do Rio Preto Medical School, FAMERP, São José do Rio Preto, Av. Brigadeiro Faria Lima, 5416 Vila São Pedro, SP 15090-000, Brazil.
eny.goloni@famerp.br
Telephone: +55-17-32015720 Fax: +55-17-32015708
Received: August 10, 2016
Peer-review started: August 12, 2016
First decision: September 12, 2016
Revised: October 8, 2016
Accepted: November 15, 2016
Article in press: November 16, 2016
Published online: December 7, 2016
Processing time: 117 Days and 19.8 Hours
AIM
To investigate the contribution of polymorphisms in the CYP1A1, CYP2E1 and EPHX1 genes on sporadic colorectal cancer (SCRC) risk.
METHODS
Six hundred forty-one individuals (227 patients with SCRC and 400 controls) were enrolled in the study. The variables analyzed were age, gender, tobacco and alcohol consumption, and clinical and histopathological tumor parameters. The CYP1A1*2A, CYP1A1*2C CYP2E1*5B and CYP2E1*6 polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The EPHX1 Tyr113His, EPHX1 His139Arg and CYP1A1*2C polymorphisms were detected by real-time PCR. Chi-squared test and binary logistic regression were used in the statistical analysis. Haplotype analysis was conducted using the Haploview program, version 2.05.
RESULTS
Age over 62 years was a risk factor for SCRC development (OR = 7.54, 95%CI: 4.94-11.50, P < 0.01). Male individuals were less susceptible to SCRC (OR = 0.55, 95%CI: 0.35-0.85, P < 0.01). The CYP2E1*5B polymorphism was associated with SCRC in the codominant (heterozygous genotype: OR = 2.66, 95%CI: 1.64-4.32, P < 0.01), dominant (OR = 2.82, 95%CI: 1.74-4.55, P < 0.01), overdominant (OR = 2.58, 95%CI: 1.59-4.19, P < 0.01), and log-additive models (OR = 2.84, 95%CI: 1.78-4.52, P < 0.01). The CYP2E1*6 polymorphism was associated with an increased SCRC risk in codominant (heterozygous genotype: OR = 2.81, 95%CI: 1.84-4.28, P < 0.01; homozygous polymorphic: OR = 7.32, 95%CI: 1.85-28.96, P < 0.01), dominant (OR = 2.97, 95%CI: 1.97-4.50, P < 0.01), recessive (OR = 5.26, 95%CI: 1.35-20.50, P = 0.016), overdominant (OR = 2.64, 95%CI: 1.74-4.01, P < 0.01), and log-additive models (OR = 2.78, 95%CI: 1.91-4.06, P < 0.01). The haplotype formed by the minor alleles of the CYP2E1*5B (C) and CYP2E1*6 (A) polymorphisms was associated with SCRC (P = 0.002). However, the CYP1A1*2A, CYP1A1*2C, EPHX1 Tyr113His and EPHX1 His139Arg polymorphisms were not associated with SCRC.
CONCLUSION
In conclusion, the results demonstrated that CYP2E1*5B and CYP2E1*6 minor alleles play a role in the development of SCRC.
Core tip: Sporadic colorectal cancer (SCRC) includes malignancies that occur in the colon and rectum. This type of cancer is the third most common cancer worldwide. The main etiological factors are age over 50 years and tobacco and alcohol consumption. The elimination of environmental carcinogens contained in tobacco, as well as alcohol, requires metabolic activation mediated by xenobiotic-metabolizing enzymes (XMEs). The CYP2E1*5B and CYP2E1*6 polymorphisms were associated with SCRC, as well as the CYP2E1*5B (C) and CYP2E1*6 (A) haplotype (minor alleles). Polymorphisms in several genes encoding these XMEs may be involved in alterations in gene expression related to important processes of colorectal carcinogenesis such as inflammation and angiogenesis.
