The aim of our study was to investigate the association between common SNP rs1056836 CYP1B1 and the risk of CRC in the population of Central Russi

Moskalev, A. S.

DSpace at Belgorod State University

Краткое сообщение Short communication Научные результаты биомедицинских исследований. 2020;6(3):318-322 Research Results in Biomedicine. 2020;6(3):318-322 318 DOI: 10.18413/2658-6533-2020-6-3-0-3 Association of L432V (rs1056836)  polymorphism of the CYP1B1 gene with the increased risk of colorectal cancer in the population of Central Russia Alexander S. MoskalevKursk Regional Clinical Oncology Center, 1 Eliseeva St., Kislino, 305524, Russian Federation Corresponding author: Alexander S. Moskalev (moskalev-46@yandex.ru) Abstract Background: Colon malignancies are one of the most common worldwide. Different pro-carcinogenic agents such as polycyclic aromatic hydrocarbons (PAH) and heter-ocyclic aromatic amines can potentially play a key role in the malignant transfor-mation of cells by interacting with DNA. The enzyme of the 1st phase of xenobioticbiotransformation CYP1B1 is involved in the metabolic activation of various carcin-ogens. The aim of the study: The aim of our study was to investigate the association between common SNP rs1056836 CYP1B1 and the risk of CRC in the population of Central Russia. Materials and methods: A total of 256 patients with colorectal can-cer (134 males, 122 females) and 608 age- and sex-matched healthy controls (279 males, 329 females) were recruited for the study. Genotyping of single nucleotide polymorphism L432V (rs1056836) CYP1B1 were done using Taq-Man-based assays. Results: Single nucleotide polymorphism rs1056836 (substitution L432V) CYP1B1 was associated with the increased risk of colorectal cancer in the population of Cen-tral Russia after adjustment for gender, age: ORadj=1.34; 95%CIadj=1.08–1.66; Padj=0.01. Bioinformatic analysis showed the spectrum of transcription factors bind-ing with low-risk C (L) allele are involved in regulation of differentiation of CD8+ alpha-beta T cells (FDR=7.57×10-3) and activation of CD8+ of alpha-beta T cells(P=3.47×10-5, FDR=2.63×10-2). Transcription factors binding with high-risk V alleleare not involved in T cell dependent mechanisms of cancer immunoediting. Conclu-sion: Thus, SNP rs1056836 CYP1B1 is associated with the increased risk of colorec-tal cancer in the population from Central Russia. Keywords: colorectal cancer; SNP; biotransformation of xenobiotics; rs1056836; CYP1B1 For citation: Moskalev AS. Association of L432V (rs1056836) polymorphism of the CYP1B1 gene with the increased risk of colorectal cancer in the population of Cen-tral Russia. Research Results in Biomedicine. 2020;6(3):318-322. DOI: 10.18413/2658-6533-2020-6-3-0-3 Introduction. Colon malignancies are one of the most common worldwide [1, 2]. Neoplasms with localization in the colon and rectum are combined into the general concept Краткое сообщение Short communication Moskalev AS. Association of L432V (rs1056836) polymorphism … 319 of colorectal cancer (CRC). Colorectal cancer is generally originate from epithelial cells of the intestinal wall and is of multifactorial na-ture, reflecting the complex interaction of en-vironmental factors with an individual genetic background that significantly causes the risk of the disease [3]. Known environmental risk factors for developing colorectal cancer are the follow-ing: high fat diet, alcohol, cigarette smoke, red meat cooked at high temperature; they are sources of high levels of polycyclic aromatic hydrocarbons (PAH) and heterocyclic aro-matic amines. These pro-carcinogenic agents can potentially play a key role in the malig-nant transformation of cells by interacting with DNA [4]. The conversion of carcinogen-ic compounds entering into the body is carried out thanks to the xenobiotic biotransformation system which is presented in the body with the group of genetically determined enzymes. The enzyme of the 1st phase of xenobioticbiotransformation CYP1B1 is encoded by a gene CYP1B1 and is involved in the metabol-ic activation of PAH. CYP1B1 plays an im-portant role in carcinogenesis as it activates various carcinogens and it is usually overex-pressed in malignant neoplasms. For example, CYP1B1 catalyses the formation of dihydro-diols of specific PAH as well as their subse-quent oxidation to carcinogenic epoxides of dihydrodiol [5]. In humans, the CYP1B1 gene includes more than 50 single nucleotide pol-ymorphisms (SNP), one of the most frequent and functionally significant is L432V (rs1056836). Associations between rs1056836 CYP1B1 polymorphism and the risk of colo-rectal cancer in the population of Central Rus-sia have not been studied yet. The aim of our study was to investigate the association between common SNP rs1056836 CYP1B1 and the risk of CRC in the population from Central Russia. Materials and methods. A total of 777 unrelated Russian individuals from the Kursk region was examined; written informed con-sent was obtained from all participants prior to entering the study. The study included 241 CRC patients (129 males and 112 females) who underwent inpatient treatment at the Kursk Regional Clinical Oncology Center be-tween 2013 and 2017 [6,7]. The control group included 536 healthy volunteers (246 males and 290 females) without a history of chronic diseases. The mean age of CRC patients was 66.89±9.43 years; the mean age of the control individuals was 67.56±6.38 years (P=0.10). The groups (CRC patients and controls) were frequency-matched according to gender (P >0.05).  Patients were included in the group of patients after verification of the final diagno-sis of the disease, confirmed by clinical and laboratory-instrumental methods of research (histological examination). The study was ap-proved by the Regional Ethics Committee of Kursk State Medical University. All patients signed a voluntary informed consent to partic-ipate in the study. Venous blood samples were obtained from all individuals. Genomic DNA was isolated from peripheral blood by the standard phenol-chloroform extraction method. Genotyping of rs1056836 CYP1B1 polymorphism was performed by real-time PCR using allelic discrimination assay with TaqMan probes on a CFX96 amplifier (Bio-Rad, United States). Regenotyping of 10% of the studied samples taken randomly and in the absence of information on the status of the disease showed 100% reproducibility of the original results. Associations of alleles with the risk of CRC were performed using logistic regression analysis. To assess association of genotypes with the disease, the odds ratio (OR) and 95% confidence interval (CI) values calculated for the log-additive regression model were used. All calculations were performed, adjusted for gender, age, and smoking in the SNPStats software program, available online (https://www.snpstats.net/start.htm). A value of P≤0.05 was taken as statistically signifi-cant. To study the regulatory potential of the studied SNP, the atSNP online resource was used; it estimates binding  affinity of tran-scription factors (TF) with DNA depending on carriage of reference/alternative allele (http://atsnp.biostat.wisc.edu). TF was includ-ed in the analysis only under the condition of Краткое сообщение Short communication Научные результаты биомедицинских исследований. 2020;6(3):318-322 Research Results in Biomedicine. 2020;6(3):318-322 320 a high and very high degree of SNP influence on the interaction of TF with DNA, which was estimated using a position weight matrix.  The Gene Ontology tool (http://geneontology.org) was used to search for gene ontologies related to the biological functions of TF associated with the refer-ence/alternative allele.  Results and discussion. The genotype frequency distribution of the genotypes rs1056836 CYP1B1 in both control and CRC groups were in Hardy–Weinberg equilibrium (P>0.05). The frequency of the V allele in pa-tients with CRC was higher compared with the control group (OR=1.32; 95%CI=1.07–1.64; P=0.01) (Table 1). A comparative anal-ysis of genotype frequencies also showed that rs1056836 CYP1B1 polymorphism is associ-ated with an increased risk of CRC (Table).  Table Analysis of associations of rs1056836 CYP1B1 with the risk of colorectal cancer SNP/Gene Genotypes/minor allele N (%) P1 corOR (95% CI)2Controls (n=536) Patients (n=241) L432V (rs1056836) CYP1B1 L/L 170 (31.7%) 66 (27.4%) 0.01* 1.34 (1.08-1.66) V/L 273 (50.9%) 110 (45.6%) V/V 93 (17.4%) 65 (27.0%) V 0.427 0.498 0.01*! 1.32! (1.07 – 1.64)! Note: 1 – P is a value with adjustment for gender, age; 2 – Odds ratio and 95% confidence interval; * – Statistically significant differences between groups are demonstrated; ! – Indices calculated for the log-additive regression model with adjustment for gender, age. The atSNP bioinformatic resource showed that the allele L creates DNA binding sites for 11 transcription factors: ZBTB7B (P=0.001), NFY (P=0.001), ZBTB7C (P=0.003), PAX5 (P=0.005), GLIS2 (P=0.01), RUNX1 (P=0.01), HOXA5 (P=0.02), TBX2 (P=0.03), ELK1 (P=0.04), RUNX1 (P=0.04), AP1 (P=0.05). Allele V creates binding sites for 7 transcription factors: MYC (P=0.003), LBX2 (P=0.004), NFE2L1::MAFG (P=0.02), NFY (P=0.03), EN2 (P=0.04), MYB (P=0.04), Nfe2l2 (P=0.05). Subsequent en-richment analysis of the biological processes using the Gene Ontology Database showed that TF binding with protective C(L) allele are included in the co-regulation of differentiation of CD8+ alpha-beta T cells (P=5.70×10-6,FDR=7.57×10-3) and activation of CD8+ al-pha-beta T cells (P=3.47×10-5, FDR=2.63×10-2). Moreover, the carriage of the V allele leads to a loss of DNA binding to TFs involved in the regulation of CD8+ alpha-beta T cells. It is known that cancer immune-editing (the process due to which the immune system controls tumor growth and forms the tumor immunogenicity) is largely determined by T-cell immunity. Cytotoxic T lymphocytes are one of the most important effector mecha-nisms of antitumor immunity as they are able to recognize a tumor through their clonal T cell receptors and provide specific destruction of tumor cells by the release of lytic compo-nents and direct intercellular interaction [8]. It is remarkable that, cytolytic activity is per-formed predominantly by CD8+ T-cells [9]. All mentioned above presents important evi-dence of influence of rs1056836 CYP1B1 on the formation of antitumor immune defenses.  At the same time most of conducted ge-netic and epidemiological studies have been focused on other association mechanisms of rs1056836 CYP1B1 with colorectal cancer, they reflected functioning and enzymatic ac-tivity of the protein encoded by CYP1B1. Taking into account that colorectal cancer is connected with various environmental carcin-ogens influence and CYP1B1 is a key enzyme of xenobiotics biotransformation and it is Краткое сообщение Short communication Moskalev AS. Association of L432V (rs1056836) polymorphism … 321 highly expressed in the large intestine, we may suppose that rs1056836 CYP1B1 leads to excessive activation of intermediate biotrans-formation products which are highly DNA damage reagent [10]. CYP1B1 rs1056836 is associated with different substrate specificity and catalytic activity of CYP1B1.  It is proved that the variant allele 432V of the CYP1B1 gene determines greater catalytic activity of 4-hydroxylation than a wild-type enzyme [11], it explains the connection of this SNP with increased risk of development of colorectal cancer. The works devoted to investigation of V432L (rs1056836) CYP1B1 polymorphism involvement for colorectal cancer develop-ment are few and contradictory. Thus, the in-vestigations held in the Czech Republic [12] and in Spain [13] did not reveal the associa-tions of rs1056836 CYP1B1 colorectal cancer development. Lack of association of rs1056836 CYP1B1 with colorectal cancer was shown also by two meta-analyzes held in 2012 [14] and in 2014 [15]. At the same time our results are consistent with those of a ma-jor study held by The Institute of Cancer Re-search (Great Britain): they revealed the asso-ciation of rs1056836 CYP1B1 with colorectal cancer development [16]. We should also note the recent work by Le Morvan et al., which was held on tumor cell lines, and it revealed higher proliferative and invasive activity of tumor cells upon expression of the variant form of rs1056836 CYP1B1, and also in vivo. Besides, it was found out that resistance to antitumor drugs significantly increases under the V allele inheritance [17]. Conclusion. Thus, our investigation has revealed an association of the rs1056836 CYP1B1 single nucleotide variant with in-creased risk for colorectal cancer in the popu-lation in Central Russia. The mechanisms of this association may be related to the influ-ence of rs1056836 on functional effects of CYP1B1 which reflect its participation in the activation of xenobiotic with procarcinogenic effects as well as to the involvement of this SNP in the mechanisms of regulation of anti-tumor T-cell immunity. Financial support No financial support has been provided for this work. Conflict of interests The author has no conflict of interest to de-clare. References 1. Favoriti P, Carbone G, Greco M, et al.Worldwide burden of colorectal cancer: a review. Updates in Surgery. 2016;68(1):7-11. DOI: https://doi.org/10.1007/s13304-016-0359-y 2. Petrash EA. Social identity disorders inpatients with colorectal cancer (colostomy). Kursk Scientific and Practical Bulletin "Man and His Health". 2015;(2):120-125. Russian.  3. Jeon J, Du M, Schoen RE, et al. Deter-mining risk of colorectal cancer and starting age of screening based on lifestyle, environmental, and genetic factors. Gastroenterology. 2018;154(8):2152‐ 2164. DOI: http://dx.doi.org/10.1053/j.gastro.2018.02.021 4. Góngora VM, Matthes KL, Castaño PR,et al. Dietary heterocyclic amine intake and colo-rectal adenoma risk: A systematic review and me-ta-analysis. Cancer Epidemiology Biomarkers and Prevention. 2019;28(1):99-109. DOI: 10.1158/1055-9965.EPI-17-1017 5. Ewa B, Danuta MŠ. Polycyclic aromatichydrocarbons and PAH-related DNA adducts. Journal of applied genetics. 2017;58(3):321‐ 330. DOI: https://doi.org/10.1007/s13353-016-0380-3 6. Moskalev AS, Soldatov VO, VdovinaIN, et al. The relationship between polymorphism I462V of the CYP1A1 gene and -9-154C>A of the CYP1A2 gene and colorectal cancer risk in the population of Central Russia. Medical Genetics. 2017;16(3):41-45. Russian. 7. Moskalev AS, Barysheva EM, SoldatovVO, et al. Association of C3435T (rs1045642) polymorphism of the MDR1 gene with the in-creased risk of colorectal cancer in Russian fe-males from Central Russia. Russian Journal of Genetics. 2019;55(12):1514-1519. DOI: 10.1134/S1022795419120093 8. Figueroa C, Gálvez-Cancino F, OyarceC, et al. Inhibition of dopamine receptor D3 sig-naling in dendritic cells increases antigen cross-presentation to CD8+ T-cells favoring anti-tumor immunity. Journal of Neuroimmunology. 2017;303:99-107. DOI: http://dx.doi.org/10.1016/j.jneuroim.2016.12.014  Краткое сообщение Short communication Научные результаты биомедицинских исследований. 2020;6(3):318-322 Research Results in Biomedicine. 2020;6(3):318-322 322 9. Zander R, Schauder D, Xin G, et al.CD4+ T cell help is required for the formation of a cytolytic CD8+ T cell subset that protects against chronic infection and cancer. Immunity. 2019;51(6):1028‐ 1042.e4. DOI: https://doi.org/10.1016/j.immuni.2019.10.009 10. Murray GI, Melvin WT, Greenlee WF, etal. Regulation, function, and tissue-specific expres-sion of cytochrome P450 CYP1B1. Annual Review of Pharmacology and Toxicology. 2001;41:297-316. DOI: https://doi.org/10.1146/annurev.pharmtox.41.1.297 11. Hanna IH, Dawling S, Roodi N, et al.Cytochrome P450 1B1 (CYP1B1) pharmaco-genetics: association of polymorphisms with func-tional differences in estrogen hydroxylation ac-tivity. Cancer Res. 2000;60(13):3440-3444. 12. Hlavata I, Vrana D, Smerhovsky Z, et al.Association between exposure-relevant polymor-phisms in CYP1B1, EPHX1, NQO1, GSTM1, GSTP1 and GSTT1 and risk of colorectal cancer in a Czech population. Oncology Reports. 2010;24(5):1347-1353. DOI: https://doi.org/10.3892/or_00000992 13. Landi S, Gemignani F, Moreno V, et al.Colorectal Cancer Study Group. A comprehensive analysis of phase I and phase II metabolism gene polymorphisms and risk of colorectal cancer Pharmacogenetics and Genomics. 2005;15(8):535-546. DOI: 10.1097/01.fpc.0000165904.48994.3d 14. Xie Y, Liu GQ, Miao XY, et al.CYP1B1 Leu432Val polymorphism and colorec-tal cancer risk among Caucasians: a meta-analysis. Tumor Biology. 2012;33(3):809-816. DOI: https://doi.org/10.1007/s13277-011-0298-7 15. He XF, Wei J, Liu ZZ, et al. Associationbetween CYP1A2 and CYP1B1 polymorphisms and colorectal cancer risk: a meta-analysis. PLoS One. 2014;9(8):e100487. DOI: https://doi.org/10.1371/journal.pone.0100487 16. Bethke L, Webb E, Sellick G, et al.Polymorphisms in the cytochrome P450 genes CYP1A2, CYP1B1, CYP3A4, CYP3A5, CYP11A1, CYP17A1, CYP19A1 and colorectal cancer risk. BMC Cancer. 2007;7:123. DOI: https://doi.org/10.1186/1471-2407-7-123 17. Laroche-Clary A, Le Morvan V,Yamori T, et al. Cytochrome P450 1B1 gene pol-ymorphisms as predictors of anticancer drug ac-tivity: studies with in vitro models. Molecular Cancer Therapeutics. 2010;9(12):3315‐ 3321. DOI: 10.1158/1535-7163.MCT-10-0673 Received 21 May 2020 Revised 28 June 2020  Accepted 3 July 2020 Information about the author Alexander S. Moskalev, Oncologist, Kursk Re-gional Clinical Oncology Center, E-mail: mos-kalev-46@yandex.ru, ORCID: 0000-0001-6237-9130. 

Association of L432V (rs1056836) polymorphism of the CYP1B1 gene with the increased risk of colorectal cancer in the population of Central Russia

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Association of L432V (rs1056836) polymorphism of the CYP1B1 gene with the increased risk of colorectal cancer in the population of Central Russia

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