CYP1A1

Gene Summary

Gene:CYP1A1; cytochrome P450, family 1, subfamily A, polypeptide 1
Aliases: AHH, AHRR, CP11, CYP1, P1-450, P450-C, P450DX
Location:15q24.1
Summary:This gene, CYP1A1, encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and its expression is induced by some polycyclic aromatic hydrocarbons (PAHs), some of which are found in cigarette smoke. The enzyme's endogenous substrate is unknown; however, it is able to metabolize some PAHs to carcinogenic intermediates. The gene has been associated with lung cancer risk. A related family member, CYP1A2, is located approximately 25 kb away from CYP1A1 on chromosome 15. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:cytochrome P450 1A1
HPRD
Source:NCBIAccessed: 21 August, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 21 August 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 21 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CYP1A1 (cancer-related)

Wang S, Sun H, Jia Y, et al.
Association of 42 SNPs with genetic risk for cervical cancer: an extensive meta-analysis.
BMC Med Genet. 2015; 16:25 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: A large number of single nucleotide polymorphisms (SNPs) associated with cervical cancer have been identified through candidate gene association studies and genome-wide association studies (GWAs). However, some studies have yielded different results for the same SNP. To obtain a more comprehensive understanding, we performed a meta-analysis on previously published case-control studies involving the SNPs associated with cervical cancer.
METHODS: Electronic searches of PubMed and Embase were conducted for all publications about the association between gene polymorphisms and cervical cancer. One-hundred and sixty-seven association studies were included in our research. For each SNP, three models (the allele, dominant and recessive effect models) were adopted in the meta-analysis. For each model, the effect summary odds ratio (OR) and 95% CI were calculated. Heterogeneity between studies was evaluated by Cochran's Q test. If the p value of Q test was less than 0.01, a random effect model was used; otherwise, a fixed effect model was used.
RESULTS: The results of our meta-analysis showed that: (1) There were 8, 2 and 8 SNPs that were significantly associated with cervical cancer (P < 0.01) in the allele, dominant and recessive effect models, respectively. (2) rs1048943 (CYP1A1 A4889G) showed the strongest association with cervical cancer in the allele effect model (1.83[1.57, 2.13]); in addition, rs1048943 (CYP1A1 A4889G) had a very strong association in the dominant and recessive effect model. (3) 15, 11 and 10 SNPs had high heterogeneity (P < 0.01) in the three models, respectively. (4) There was no published bias for most of the SNPs according to Egger's test (P < 0.01) and Funnel plot analysis. For some SNPs, their association with cervical cancer was only tested in a few studies and, therefore, might have been subjected to published bias. More studies on these loci are required.
CONCLUSION: Our meta-analysis provides a comprehensive evaluation of cervical cancer association studies.

Maayah ZH, Ghebeh H, Alhaider AA, et al.
Metformin inhibits 7,12-dimethylbenz[a]anthracene-induced breast carcinogenesis and adduct formation in human breast cells by inhibiting the cytochrome P4501A1/aryl hydrocarbon receptor signaling pathway.
Toxicol Appl Pharmacol. 2015; 284(2):217-26 [PubMed] Related Publications
UNLABELLED: Recent studies have established that metformin (MET), an oral anti-diabetic drug, possesses antioxidant activity and is effective against different types of cancer in several carcinogen-induced animal models and cell lines. However, whether MET can protect against breast cancer has not been reported before. Therefore, the overall objectives of the present study are to elucidate the potential chemopreventive effect of MET in non-cancerous human breast MCF10A cells and explore the underlying mechanism involved, specifically the role of cytochrome P4501A1 (CYP1A1)/aryl hydrocarbon receptor (AhR) pathway. Transformation of the MCF10A cells into initiated breast cancer cells with DNA adduct formation was conducted using 7,12-dimethylbenz[a]anthracene (DMBA), an AhR ligand. The chemopreventive effect of MET against DMBA-induced breast carcinogenesis was evidenced by the capability of MET to restore the induction of the mRNA levels of basic excision repair genes, 8-oxoguanine DNA glycosylase (OGG1) and apurinic/apyrimidinic endonuclease1 (APE1), and the level of 8-hydroxy-2-deoxyguanosine (8-OHdG). Interestingly, the inhibition of DMBA-induced DNA adduct formation was associated with proportional decrease in CYP1A1 and in
NAD(P)H: quinone oxidoreductase 1 (NQO1) gene expression. Mechanistically, the involvements of AhR and nuclear factor erythroid 2-related factor-2 (Nrf2) in the MET-mediated inhibition of DMBA-induced CYP1A1 and NQO1 gene expression were evidenced by the ability of MET to inhibit DMBA-induced xenobiotic responsive element and antioxidant responsive element luciferase reporter gene expression which suggests an AhR- and Nrf2-dependent transcriptional control. However, the inability of MET to bind to AhR suggests that MET is not an AhR ligand. In conclusion, the present work shows a strong evidence that MET inhibits the DMBA-mediated carcinogenicity and adduct formation by inhibiting the expression of CYP1A1 through an AhR ligand-independent mechanism.

Ishida M, Mikami S, Shinojima T, et al.
Activation of aryl hydrocarbon receptor promotes invasion of clear cell renal cell carcinoma and is associated with poor prognosis and cigarette smoke.
Int J Cancer. 2015; 137(2):299-310 [PubMed] Related Publications
Although exposure to environmental pollutants is one of the risk factors for renal cell carcinoma (RCC), its relationship with carcinogenesis and the progression of RCC remains unknown. The present study was designed to elucidate the role of the aryl hydrocarbon receptor (AhR), a major mediator of carcinogenesis caused by environmental pollutants, in the progression of RCC. The expression of AhR was investigated in 120 patients with RCC using immunohistochemistry, and its relationship with clinicopathological parameters and prognoses was statistically analyzed. RCC cell lines were exposed to indirubin or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), AhR ligands, to activate the AhR pathway, or were transfected with small interfering RNA (siRNA) for AhR. The expression of the AhR target genes CYP1A1 and CYP1B1, matrix metalloproteinases (MMPs), and invasion through Matrigel(TM) were then examined. AhR was predominantly expressed in the nuclei of high-grade clear cell RCC (ccRCC) and tumor-infiltrating lymphocytes (TILs), and its expression levels in cancer cells and TILs correlated with the pathological tumor stage and histological grade. A multivariate Cox analysis revealed that the strong expression of AhR in cancer cells was a significant and independent predictor of disease-specific survival. AhR ligands up-regulated the expression of AhR and CYPs and promoted invasion by up-regulating MMPs. Furthermore, siRNA for AhR down-regulated CYPs, and inhibited cancer cell invasion together with the down-regulation of MMPs. These results suggest that AhR regulates the invasion of ccRCC and may be involved in tumor immunity. Therefore, inhibiting the activation of AhR may represent a potentially attractive therapeutic target for ccRCC patients.

Go RE, Hwang KA, Choi KC
Cytochrome P450 1 family and cancers.
J Steroid Biochem Mol Biol. 2015; 147:24-30 [PubMed] Related Publications
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcriptional factor that dimerizes with aryl hydrocarbon receptor nuclear translocator (ARNT). This complex binds to xenobiotics response element (XREs), and then starts the expressions of downstream genes including cytochrome P450 (CYP) 1 family members: CYP1A1, CYP1A2 and CYP1B1. Role of CYP1 family is involved in the metabolism of endogenous hormones, xenobiotics and drug. The expression of CYP1 family is regulated by estradiol (E2) or xenobiotics in diverse cancers. In breast cancers expressing estrogen receptors (ERs), level of CYP1B1 is increased by E2 and reversed by an estrogen receptor antagonist, ICI 182,780 or 4-hydrotamoxifen, which indicates that the expression of CYP1 family in downstream region of AhR is regulated by an activation of ERα. In metabolic pathways, E2 is converted into 4-hydroxyestradiol by CYP1B1, which can be converted into mainly estradiol-3,4-quinone, a potential carcinogen, by peroxidase. Increased expression of CYP1 family indicates the possibility of carcinogenesis by exposure of xenobiotics in endometrial and ovarian cancers. Apart from roles of CYP1 family in relation with ER pathway, CYP1 family is over-expressed in ER independent cancers. CYP1A1 exhibits hydroxylase activity in oxidation of arachidonic acid, which has been transformed to 12(R)-hydrxyeicosatetraenoic (HETEs), a potent activator of AhR activity. On the basis of results, phytoestrogens and dexamethasone are provided as cancer therapy regulating the expression of CYP1 family. Thus, this review focuses on the role(s) of CYP1 family in ER-dependent or ER-independent cancers and the potential for cancer therapy to target CYP1 family in these cancers.

Spink BC, Bloom MS, Wu S, et al.
Analysis of the AHR gene proximal promoter GGGGC-repeat polymorphism in lung, breast, and colon cancer.
Toxicol Appl Pharmacol. 2015; 282(1):30-41 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
The aryl hydrocarbon receptor (AhR) regulates expression of numerous genes, including those of the CYP1 gene family. With the goal of determining factors that control AHR gene expression, our studies are focused on the role of the short tandem repeat polymorphism, (GGGGC)n, located in the proximal promoter of the human AHR gene. When luciferase constructs containing varying GGGGC repeats were transfected into cancer cell lines derived from the lung, colon, and breast, the number of GGGGC repeats affected AHR promoter activity. The number of GGGGC repeats was determined in DNA from 327 humans and from 38 samples representing 5 species of non-human primates. In chimpanzees and 3 species of macaques, only (GGGGC)2 alleles were observed; however, in western gorilla, (GGGGC)n alleles with n=2, 4, 5, 6, 7, and 8 were identified. In all human populations examined, the frequency of (GGGGC)n was n=4>5≫2, 6. When frequencies of the (GGGGC)n alleles in DNA from patients with lung, colon, or breast cancer were evaluated, the occurrence of (GGGGC)2 was found to be 8-fold more frequent among lung cancer patients in comparison with its incidence in the general population, as represented by New York State neonates. Analysis of matched tumor and non-tumor DNA samples from the same individuals provided no evidence of microsatellite instability. These studies indicate that the (GGGGC)n short tandem repeats are inherited, and that the (GGGGC)2 allele in the AHR proximal promoter region should be further investigated with regard to its potential association with lung cancer susceptibility.

Maurya SS, Katiyar T, Dhawan A, et al.
Gene-environment interactions in determining differences in genetic susceptibility to cancer in subsites of the head and neck.
Environ Mol Mutagen. 2015; 56(3):313-21 [PubMed] Related Publications
Genetic differences in susceptibility to cancer in subsites of the head and neck were investigated in a case-control study involving 750 cases of cancers of the oral cavity, larynx, or pharynx, and an equal number of healthy controls. The prevalence of variant genotypes of cytochrome P450 (CYP) 1A1, 1B1, 2E1, or glutathione-S-transferase M1 (null) in cases suggests that polymorphisms in drug metabolizing enzymes (DMEs) modify cancer risk within subsites of the head and neck. Tobacco or alcohol use was found to increase the risk in cases of laryngeal, pharyngeal, or oral cavity cancers. Interaction between genetic variation in DMEs and tobacco smoke (or smoking) exposures conferred significant risk for laryngeal cancer. Likewise, strong associations of the polymorphic genotypes of DMEs with cases of pharyngeal and oral cavity cancer who were tobacco chewers or alcohol users demonstrate that gene-environment interactions may explain differences in genetic susceptibility for cancers of the oral cavity, larynx, and pharynx.

Mota P, Silva HC, Soares MJ, et al.
Genetic polymorphisms of phase I and phase II metabolic enzymes as modulators of lung cancer susceptibility.
J Cancer Res Clin Oncol. 2015; 141(5):851-60 [PubMed] Related Publications
OBJECTIVES: Tobacco exposure remains the main etiologic factor for lung cancer (LC). Interactions between environment and individual genetic profile are particularly important for this disease. The aim of this study was to evaluate the contribution of CYP1A1*2A, CYP1A1*2C, CYP2D6*4, GSTP1, GSTM1, GSTT1 and NAT2 polymorphisms for the susceptibility to LC in a Portuguese population considering their demographic and clinical characteristics.
MATERIALS AND METHODS: A total of 200 LC and 247 controls subjects from the Centre of Portugal were studied. Clinical and demographic characteristics were collected from clinical files and by individual questionnaires. Polymorphisms of CYP1A1*2A, CYP1A1*2C, CYP2D6*4, GSTP1, GSTM1, GSTT1 and NAT2 were genotyped using PCR-RFLP, PCR multiplex, ARMS and real time.
RESULTS: Gender, family history of cancer, smoke cessation and alcohol consumption were independent risk factors (p < 0.05). Associations found between phases I and II genes and LC population reveal a sex dependent distribution. Logistic regression analysis demonstrates that enhanced activation by CYPs, associated by reduced or loss of function of phase II enzymes, can lead to a greater risk. GSTP1 and NAT2 polymorphisms studied have a significant contribution for the histological tumour types and the presence of metastases, at time of diagnosis, respectively, when males with smoking habits were considered.
CONCLUSION: Multiple interactions between environment and individual characteristics are clearly associated to this disease. Variants of the detoxification genes may act synergistically contributing to this disease and modifying the risk posed by smoking and sex. The GSTT1*0 and GSTP1 (Ile462Val) might contribute to the malignant phenotype through different mechanisms.

Lin J, He B, Cao L, et al.
CYP1A1 Ile462Val polymorphism and the risk of non-small cell lung cancer in a Chinese population.
Tumori. 2014 Sep-Oct; 100(5):547-52 [PubMed] Related Publications
AIMS AND BACKGROUND: Cytochrome P450 (CYP) 1A1 enzyme plays an important role in the metabolism of carcinogens, such as polycyclic aromatic hydrocarbons, nitroaromatics and arylamines.
METHODS: The study examined the association of CYP1A1 Ile462Val polymorphism with the risk of developing non-small cell lung cancer in a Chinese population. We conducted a case-control study including 526 non-small cell lung cancer cases and 526 cancer-free controls. The odds ratios and 95% confidence intervals were calculated by logistic regression models.
RESULTS: Compared with 462Ile/Ile genotype carriers, subjects with CYP1A1 462Ile/Val or Val/Val genotype had a decreased risk of developing non-small cell lung cancer with odds ratios of 0.57 (95% CI, 0.44-0.75) and 0.54 (95% CI, 0.36-0.81), respectively. When stratified by smoking status, the decreased risk of non-small cell lung cancer associated with CYP1A1 462Ile/Val or Val/Val genotype was observed among non-smokers (OR = 0.62, 95% CI, 0.45-0.87) and among smokers (OR = 0.54, 95% CI, 0.37-0.78). When stratified by smoking-dose, the correlation between CYP1A1 genotypes and the risk of non-small cell lung cancer was detected among light smokers (OR = 0.30, 95% CI, 0.19-0.48) but not among heavy smokers (OR = 0.93, 95% CI, 0.61-1.43).
CONCLUSIONS: The CYP1A1 Ile462Val variant was associated with a low risk of developing non-small cell lung cancer in a Chinese population.

Son BH, Kim MK, Yun YM, et al.
Genetic polymorphism of ESR1 rs2881766 increases breast cancer risk in Korean women.
J Cancer Res Clin Oncol. 2015; 141(4):633-45 [PubMed] Related Publications
PURPOSE: We performed a case-control study to evaluate the association of genetic polymorphisms of estrogen-metabolizing enzyme genes and estrogen receptor genes with breast cancer risk according to age group and subtypes in Korean women.
METHODS: Breast cancer patients (n = 830) and the hospital healthy controls (n = 390) with both clinical information and SNP data were included in the study. Age was divided into three groups: premenopausal under 35 years (n = 64), premenopausal over 35 years (n = 456), and postmenopausal women (n = 310), respectively. Tumor subtype was classified into four subtypes: luminal A, luminal B, HER2-overexpressing, and triple-negative, respectively. Genotyping of the selected SNPs in ESR1, ESR2, CYP1A1, CYP1B1, and COMT was conducted using the VeraCode Golden Gate Genotyping Assay Technology. Multiple logistic regression models (dominant, recessive, and additive) were applied to determine the odds ratio, 95% confidence interval, and p value.
RESULTS: ESR1, rs2881766, rs2077647, rs926778, and rs2273206 polymorphisms increased breast cancer risk, and rs3798377 decreased the risk in overall patients. The association between SNP genotype and breast cancer risk was varied according to age groups and tumor subtypes. For age subgroups, rs2881766 increased breast cancer risk in the all three age groups, and rs926778 increased the risk in premenopausal over 35 years women and in postmenopausal women. For the tumor subtypes, rs2881766 increased breast cancer risk manly in luminal A, HER2-overexpressing, and triple-negative subtypes except for luminal B subtype, and rs926778 increased the risk in luminal A and triple-negative subtypes. Rs3798577 decreased the risk in luminal B and triple-negative subtypes.
CONCLUSION: The results showed that ESR1 rs2881766 polymorphism increased breast cancer risk and rs3798377 decreased the risk in Korean women. Because of wide variation of the association between SNP genotype and breast cancer risk according to age group and tumor subtypes, further studies such as a large-scale cohort study need for validation and test of biologic significance.

Büller NV, Rosekrans SL, Metcalfe C, et al.
Stromal Indian hedgehog signaling is required for intestinal adenoma formation in mice.
Gastroenterology. 2015; 148(1):170-180.e6 [PubMed] Related Publications
BACKGROUND & AIMS: Indian hedgehog (IHH) is an epithelial-derived signal in the intestinal stroma, inducing factors that restrict epithelial proliferation and suppress activation of the immune system. In addition to these rapid effects of IHH signaling, IHH is required to maintain a stromal phenotype in which myofibroblasts and smooth muscle cells predominate. We investigated the role of IHH signaling during development of intestinal neoplasia in mice.
METHODS: Glioma-associated oncogene (Gli1)-CreERT2 and Patched (Ptch)-lacZ reporter mice were crossed with Apc(Min) mice to generate Gli1CreERT2-Rosa26-ZSGreen-Apc(Min) and Ptch-lacZ-Apc(Min) mice, which were used to identify hedgehog-responsive cells. Cyp1a1Cre-Apc (Apc(HET)) mice, which develop adenomas after administration of β-naphthoflavone, were crossed with mice with conditional disruption of Ihh in the small intestine epithelium. Apc(Min) mice were crossed with mice in which sonic hedgehog (SHH) was overexpressed specifically in the intestinal epithelium. Intestinal tissues were collected and analyzed histologically and by immunohistochemistry and quantitative reverse-transcription polymerase chain reaction. We also analyzed levels of IHH messenger RNA and expression of IHH gene targets in intestinal tissues from patients with familial adenomatous polyposis (n = 18) or sessile serrated adenomas (n = 15) and normal colonic tissue from control patients (n = 12).
RESULTS: Expression of IHH messenger RNA and its targets were increased in intestinal adenomas from patients and mice compared with control colon tissues. In mice, IHH signaling was exclusively paracrine, from the epithelium to the stroma. Loss of IHH from Apc(HET) mice almost completely blocked adenoma development, and overexpression of SHH increased the number and size of adenomas that developed. Loss of IHH from Apc(HET) mice changed the composition of the adenoma stroma; cells that expressed α-smooth muscle actin or desmin were lost, along with expression of cyclooxygenase-2, and the number of vimentin-positive cells increased.
CONCLUSIONS: Apc mutant epithelial cells secrete IHH to maintain an intestinal stromal phenotype that is required for adenoma development in mice.

Takeda S, Ikeda E, Su S, et al.
Δ(9)-THC modulation of fatty acid 2-hydroxylase (FA2H) gene expression: possible involvement of induced levels of PPARα in MDA-MB-231 breast cancer cells.
Toxicology. 2014; 326:18-24 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
We recently reported that Δ(9)-tetrahydrocannabinol (Δ(9)-THC), a major cannabinoid component in Cannabis Sativa (marijuana), significantly stimulated the expression of fatty acid 2-hydroxylase (FA2H) in human breast cancer MDA-MB-231 cells. Peroxisome proliferator-activated receptor α (PPARα) was previously implicated in this induction. However, the mechanisms mediating this induction have not been elucidated in detail. We performed a DNA microarray analysis of Δ(9)-THC-treated samples and showed the selective up-regulation of the PPARα isoform coupled with the induction of FA2H over the other isoforms (β and γ). Δ(9)-THC itself had no binding/activation potential to/on PPARα, and palmitic acid (PA), a PPARα ligand, exhibited no stimulatory effects on FA2H in MDA-MB-231 cells; thus, we hypothesized that the levels of PPARα induced were involved in the Δ(9)-THC-mediated increase in FA2H. In support of this hypothesis, we herein demonstrated that; (i) Δ(9)-THC activated the basal transcriptional activity of PPARα in a concentration-dependent manner, (ii) the concomitant up-regulation of PPARα/FA2H was caused by Δ(9)-THC, (iii) PA could activate PPARα after the PPARα expression plasmid was introduced, and (iv) the Δ(9)-THC-induced up-regulation of FA2H was further stimulated by the co-treatment with L-663,536 (a known PPARα inducer). Taken together, these results support the concept that the induced levels of PPARα may be involved in the Δ(9)-THC up-regulation of FA2H in MDA-MB-231 cells.

Sudenga SL, Shrestha S, Macaluso M, et al.
Functional variants in CYP1A1 and GSTM1 are associated with clearance of cervical HPV infection.
Gynecol Oncol. 2014; 135(3):560-4 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
OBJECTIVE: We evaluated time to clearance of high risk (HR) HPV infection in relation to functional variants in three genes (CYP1A1, GSTT1, and GSTM1).
METHODS: The study group consisted of 450 HR-HPV infected women from the Atypical squamous cells of undetermined significance-low-grade squamous intraepithelial Lesion Triage Study (ALTS) cohort followed up at the clinical center at Birmingham, Alabama. The Cox proportional hazard model with the Wei-Lin-Weisfeld (WLW) approach was used, controlling for relevant covariates.
RESULTS: Women who were polymorphic for CYP1A1 experienced an HR-HPV clearance rate that was 20% (HR=0.80, p=0.04) lower than women without the polymorphism for CYP1A1, adjusting for all other cofactors. The GSTM1 null genotype was associated with higher HR-HPV clearance rate (HR=1.39, p=0.006). The polymorphism in GSTT1 was not significantly associated with time to clearance of HR-HPV.
CONCLUSIONS: Xenobiotic metabolism genes may influence the natural history of HR-HPV infection and its progression to cervical cancer.

L'Héritier F, Marques M, Fauteux M, Gaudreau L
Defining molecular sensors to assess long-term effects of pesticides on carcinogenesis.
Int J Mol Sci. 2014; 15(9):17148-61 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
The abundance of dioxins and dioxin-like pollutants has massively increased in the environment due to human activity. These chemicals are particularly persistent and accumulate in the food chain, which raises major concerns regarding long-term exposure to human health. Most dioxin-like pollutants activate the aryl hydrocarbon receptor (AhR) transcription factor, which regulates xenobiotic metabolism enzymes that belong to the cytochrome P450 1A family (that includes CYP1A1 and CYP1B1). Importantly, a crosstalk exists between estrogen receptor α (ERα) and AhR. More specifically, ERα represses the expression of the CYP1A1 gene, which encodes an enzyme that converts 17β-estradiol into 2-hydroxyestradiol. However, (ERα) does not repress the CYP1B1 gene, which encodes an enzyme that converts 17β-estradiol into 4-hydroxyestradiol, one of the most genotoxic estrogen metabolites. In this review, we discuss how chronic exposure to xenobiotic chemicals, such as pesticides, might affect the expression of genes regulated by the AhR-ERα crosstalk. Here, we focus on recent advances in the understanding of molecular mechanisms that mediate this crosstalk repression, and particularly on how ERα represses the AhR target gene CYP1A1, and could subsequently promote breast cancer. Finally, we propose that genes implicated in this crosstalk could constitute important biomarkers to assess long-term effects of pesticides on human health.

Tseng TS, Park JY, Zabaleta J, et al.
Role of nicotine dependence on the relationship between variants in the nicotinic receptor genes and risk of lung adenocarcinoma.
PLoS One. 2014; 9(9):e107268 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Several variations in the nicotinic receptor genes have been identified to be associated with both lung cancer risk and smoking in the genome-wide association (GWA) studies. However, the relationships among these three factors (genetic variants, nicotine dependence, and lung cancer) remain unclear. In an attempt to elucidate these relationships, we applied mediation analysis to quantify the impact of nicotine dependence on the association between the nicotinic receptor genetic variants and lung adenocarcinoma risk. We evaluated 23 single nucleotide polymorphisms (SNPs) in the five nicotinic receptor related genes (CHRNB3, CHRNA6, and CHRNA5/A3/B4) previously reported to be associated with lung cancer risk and smoking behavior and 14 SNPs in the four 'control' genes (TERT, CLPTM1L, CYP1A1, and TP53), which were not reported in the smoking GWA studies. A total of 661 lung adenocarcinoma cases and 1,347 controls with a smoking history, obtained from the Environment and Genetics in Lung Cancer Etiology case-control study, were included in the study. Results show that nicotine dependence is a mediator of the association between lung adenocarcinoma and gene variations in the regions of CHRNA5/A3/B4 and accounts for approximately 15% of this relationship. The top two CHRNA3 SNPs associated with the risk for lung adenocarcinoma were rs1051730 and rs12914385 (p-value = 1.9×10(-10) and 1.1×10(-10), respectively). Also, these two SNPs had significant indirect effects on lung adenocarcinoma risk through nicotine dependence (p = 0.003 and 0.007). Gene variations rs2736100 and rs2853676 in TERT and rs401681 and rs31489 in CLPTM1L had significant direct associations on lung adenocarcinoma without indirect effects through nicotine dependence. Our findings suggest that nicotine dependence plays an important role between genetic variants in the CHRNA5/A3/B4 region, especially CHRNA3, and lung adenocarcinoma. This may provide valuable information for understanding the pathogenesis of lung adenocarcinoma and for conducting personalized smoking cessation interventions.

Brauze D, Fijalkiewicz K, Szaumkessel M, et al.
Diversified expression of aryl hydrocarbon receptor dependent genes in human laryngeal squamous cell carcinoma cell lines treated with β-naphthoflavone.
Toxicol Lett. 2014; 231(1):99-107 [PubMed] Related Publications
The aryl hydrocarbon receptor (AhR) mediates a variety of biological responses to ubiquitous environmental pollutants. In this study the effect of administration of β-naphthoflavone (BNF), potent AhR ligand, on the expression of AhR, AhRR, CYP1A1, CYP1A2, CYP1B1, NQO1, GSTA1, ALDH3A1 and UGT1A genes encoding the enzymes controlled by AhR were examined in thirteen laryngeal tumor cell lines and in HepaRG cell line. The analyzed cell lines were derived from patients with squamous laryngeal cancer, with history of cigarette smoking and without signs of human papillomavirus types 16 and 18 infection in investigated cells. Quantitative real-time RT-PCR analysis revealed huge interindividual differences in expression of genes from AhR regulatory network. Our results strongly suggest predominant effect of DNA methylation on induction of CYP1A1 expression by AhR ligands as well. Our results indicate that differentiated HepaRG cell line appeared to be very good substitute for human liver in studies on xenobiotic metabolism by AhR regulated enzymes.

Zakiullah, Saeed M, Ali S, et al.
Genetic susceptibility to esophageal cancer due to CYP1A1 gene variant rs4646903 in tobacco addicted patients of Pashtun ethnicity: a case control study in Khyber Pakhtunkhwa province of Pakistan.
Asian Pac J Cancer Prev. 2014; 15(16):6715-20 [PubMed] Related Publications
The purpose of this study was to evaluate associations of the CYP1A1 gene variant rs4646903 polymorphism with the risk of developing esophageal cancer (EC). A case-control study was carried out in Pashtun population of Khyber Pakhtunkhwa province of Pakistan in which 140 hospital based EC cases and 196 population based healthy controls exposed to similar environmental conditions were included. A specific method based on the real time polymerase chain reaction (RT-PCR) was used to detect genotypes in case and control groups and results were then analyzed with SPSS version 20. In our population, individuals with CC and TC genotypes of the CYP1A1 rs4646903 polymorphism had significantly higher risk of EC (adjusted odds (OR): 15.709, 95%CI: 6.065-40.686, OR: 3.256 95%CI: 1.902-5.574 respectively). The 'C' allele was strongly associated with the disease (p< 0.0001). Adjusted OR was higher (1.5 times in C/C) in case of variant alleles that show the contribution of environmental and nutritional factors towards the development of EC. Our findings suggest that presence of the 'C' allele of rs4646903 (T>C) may be one of the risk alleles for EC susceptibility in Pashtun population.

Han J, Wang L, Yang Y, Zhang J
Meta-analyses of the effect of CYP1A1 and CYP2D6 polymorphisms on the risk of head and neck squamous cell carcinoma.
Oncol Res Treat. 2014; 37(7-8):406-11 [PubMed] Related Publications
BACKGROUND: CYP1A1 and CYP2D6 are important genes encoding enzymes involved in the metabolism of toxic chemicals and carcinogens. However, inconclusive results for the association between CYP1A1 and CYP2D6 polymorphisms and the risk of head and neck squamous cell carcinoma (HNSCC) have been reported. We conducted a meta-analysis to evaluate the association of CYP1A1 and CYP2D6 polymorphisms with the risk of HNSCC.
METHODS: A database search yielded 19 relevant studies. 3 polymorphisms were included in the meta-analysis: CYP1A1, CYP2D6*4 and CYP2D6*10. Random or fixed effect models were used in the analysis.
RESULTS: The CYP1A1 polymorphism was associated with HNSCC (for m1m1 vs. m1m2: odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.030-1.542, pheterogeneity = 0.025; for the recessive model: OR = 1.316, 95% CI = 1.065-1.625, pheterogeneity = 0.001). The analysis showed evidence for association between the CYP2D6*4 polymorphism and HNSCC in Asian populations; however, negative results were also observed in other models. A significant association was also observed between CYP2D6*10 polymorphism and HNSCC risk.
CONCLUSIONS: The current study demonstrates that the CYP1A1 and CYP2D6 polymorphisms are associated with susceptibility to both development and progression of HNSCC.

Do MT, Kim HG, Tran TT, et al.
Metformin suppresses CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating aryl hydrocarbon receptor expression.
Toxicol Appl Pharmacol. 2014; 280(1):138-48 [PubMed] Related Publications
Induction of cytochrome P450 (CYP) 1A1 and CYP1B1 by environmental xenobiotic chemicals or endogenous ligands through the activation of the aryl hydrocarbon receptor (AhR) has been implicated in a variety of cellular processes related to cancer, such as transformation and tumorigenesis. Here, we investigated the effects of the anti-diabetes drug metformin on expression of CYP1A1 and CYP1B1 in breast cancer cells under constitutive and inducible conditions. Our results indicated that metformin down-regulated the expression of CYP1A1 and CYP1B1 in breast cancer cells under constitutive and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced conditions. Down-regulation of AhR expression was required for metformin-mediated decreases in CYP1A1 and CYP1B1 expression, and the metformin-mediated CYP1A1 and CYP1B1 reduction is irrelevant to estrogen receptor α (ERα) signaling. Furthermore, we found that metformin markedly down-regulated Sp1 protein levels in breast cancer cells. The use of genetic and pharmacological tools revealed that metformin-mediated down-regulation of AhR expression was mediated through the reduction of Sp1 protein. Metformin inhibited endogenous AhR ligand-induced CYP1A1 and CYP1B1 expression by suppressing tryptophan-2,3-dioxygenase (TDO) expression in MCF-7 cells. Finally, metformin inhibits TDO expression through a down-regulation of Sp1 and glucocorticoid receptor (GR) protein levels. Our findings demonstrate that metformin reduces CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating AhR signaling. Metformin would be able to act as a potential chemopreventive agent against CYP1A1 and CYP1B1-mediated carcinogenesis and development of cancer.

Yu KT, Ge C, Xu XF, et al.
CYP1A1 polymorphism interactions with smoking status in oral cancer risk: evidence from epidemiological studies.
Tumour Biol. 2014; 35(11):11183-91 [PubMed] Related Publications
The cytochrome CYP1A1 gene has been implicated in the etiology of oral cancer. However, the results have been inconsistent. In this study, a meta-analysis was performed to clarify the associations of polymorphisms in CYP1A1 gene with oral cancer risk. Published literatures from PubMed, MEDLINE, EMBASE, and China National Knowledge infrastructure (CNKI) databases were retrieved. A total of 12 studies were included in this meta-analysis. We found that significant positive associations between CYP1A1*2A polymorphism and oral cancer risk in recessive model (CC vs. TC + TT, OR = 1.93), dominant model (CC + TC vs. TT, OR = 1.33), and additive model (CC vs. TT, OR = 1.97). In subgroup analysis based on the ethnicity of study population, significant associations were found in all three genetic models for Asians (recessive OR = 2.29, 95% CI =  .42-3.71; dominant OR = 1.54, 95% CI = 1.03-2.31; additive OR  2.39, 95% CI = 1.47-3.88) but not non-Asians. For the smoking stratification, the result indicated a significant association between CYP1A1*2A polymorphism and oral cancer among the smoking subjects (OR = 1.83, 95% CI = 1.47-2.26). This meta-analysis indicated a marked association of CYP1A1*2A polymorphisms with oral cancer risk, particularly among Asians, whereas there were significant interactions between the polymorphisms and cigarette smoking on oral cancer risk.

Cotterchio M, Mirea L, Ozcelik H, Kreiger N
Active cigarette smoking, variants in carcinogen metabolism genes and breast cancer risk among pre- and postmenopausal women in Ontario, Canada.
Breast J. 2014 Sep-Oct; 20(5):468-80 [PubMed] Related Publications
Cigarette smoking is strongly associated with various diseases including many cancers; however, evidence regarding breast cancer risk remains inconclusive with some studies reporting no association, and others an increased risk with long duration and early initiation of smoking. Genetic variation in carcinogen-metabolizing enzymes may modify these associations. Breast cancer cases were identified from the Ontario Cancer Registry (OCR) during 2003-2004 and population controls through random digit dialing methods. All subjects completed self-administered questionnaires. Subsequently, saliva samples were obtained from cases (N = 1,776) and controls (N = 1,839) for deoxyribonucleic acid (DNA) extraction. Multivariate logistic regression was used to estimate odds ratio (OR) and 95% confidence intervals (CI) for active smoking variables, and interactions were assessed between smoking and 36 carcinogen-metabolizing candidate gene variants. No statistically significant association was found between active smoking and breast cancer risk among all women nor when stratified by menopausal status; however, nonsignificant increased premenopausal breast cancer risk was observed among current smokers and women smoking before first pregnancy. Several statistically significant interactions were observed between smoking and genetic variants (CYP1A2 1548C>T, CYP1A1 3801T>C, CYP1B1 4326G>C, NAT1 c.-85-1014T>A, UGT1A7 W208R 622T>C, SOD2 c.47T>C, GSTT1 deletion). However, in analyses stratified by these genotypes, smoking ORs had wide confidence intervals (and with few exceptions included 1.0) making interpretations difficult. Active smoking was not associated with breast cancer risk, although several significant interactions were observed between smoking, carcinogen-metabolizing genetic variants, and breast cancer risk.

Gong FF, Lu SS, Hu CY, et al.
Cytochrome P450 1A1 (CYP1A1) polymorphism and susceptibility to esophageal cancer: an updated meta-analysis of 27 studies.
Tumour Biol. 2014; 35(10):10351-61 [PubMed] Related Publications
Cytochrome P450 1A1 (CYP1A1) polymorphisms are known to play a crucial role in the development and metastasis of malignant diseases including esophageal cancer. However, the results of previous studies investigating the association between CYP1A1 polymorphisms and esophageal cancer risk have been inconsistent. This meta-analysis of 27 eligible studies, encompassing 4,215 esophageal cancer cases and 6,339 control subjects, pooled the odds ratios (ORs) with corresponding 95 % confidence intervals (95 % CI) to assess this association. The effects of ethnicity (Caucasian and Asian) and histopathology type (esophageal squamous cell carcinoma and esophageal adenocarcinoma) were considered in subgroup analyses. A significant association was observed between the CYP1A1 Ile/Val gene polymorphism and esophageal cancer in all of the genetic models (Ile/Val vs. Ile/Ile, OR = 1.41, 95 % CI = 1.25-1.58; Val/Val vs. Ile/Ile, OR = 1.94, 95 % CI = 1.34-2.82; Ile/Val + Val/Val vs. Ile/Ile, OR = 1.49, 95 % CI = 1.33-1.66). The subgroup analysis based on ethnicity showed that the association between the CYP1A1 Ile/Val polymorphism and esophageal cancer existed in Asian and Caucasian populations. However, no association was observed between the CYP1A1 MspI polymorphism and esophageal cancer in either subgroup or in the overall population. These results suggested that the CYP1A1 Ile/Val polymorphism was associated with an increased risk of esophageal cancer, whereas the CYP1A1 MspI polymorphism may not have increased susceptibility to esophageal cancer. Further studies are required to confirm these findings.

Jiang XY, Chang FH, Bai TY, et al.
Susceptibility of lung cancer with polymorphisms of CYP1A1, GSTM1, GSTM3, GSTT1 and GSTP1 genotypes in the population of Inner Mongolia region.
Asian Pac J Cancer Prev. 2014; 15(13):5207-14 [PubMed] Related Publications
BACKGROUND: To study the relationship of susceptibility to lung cancer with the gene polymorphisms of CYP1A1, GSTM1, GSTM3, GSTT1, GSTP1 and smoking status in Han and Mongolian populations of Inner Mongolia, an autonomous region of China.
MATERIALS AND METHODS: PCR-RFLP, allele-specific and multiplex PCR were employed to identify the genotypes of CYP1A1, GSTM1, GSTM3, GSTT1 and GSTP1 in a case-control study of 322 lung cancer patients diagnosed by bronchoscopy and 456 controls free of malignancy.
RESULTS: There is a significant difference in genotypic frequency of GSTT1 of healthy Mongolian and Han subjects. A statistically prominent association was found between CYP1A1 Msp1 (vt/vt) (OR=4.055, 95%CI:2.107-7.578, p=0.000), GSTM1 (-) (OR=2.290, 95%CI:1.467-3.573, p=0.000) and lung cancer in Mongolians. Similarly, in the Han population, CYP1A1 Msp1 (vt/vt) (OR=3.194, 95%CI:1.893-5.390, p=0.000) and GSTM1 (-) (OR=1.884, 95%CI:1.284-2.762, p=0.001) carriers also had an elevated risk of lung cancer. The smokers were more susceptible to lung cancer 2.144 fold and 1.631 fold than non-smokers in Mongolian and Han populations, respectively. The smokers who carried with CYP1A1 Msp1 (wt/vt+vt/vt), exon7 (Val/Val+Ile /Val), GSTM1 (-), GSTM3 (AB+BB), and GSTT1 (-) respectively were found all to have a high risk of lung cancer.
CONCLUSIONS: CYP1A1 Msp1 (vt/ vt) and GSTM1 (-) are risk factors of lung cancer in Han and Mongolian population in the Inner Mongolia region. The smokers with CYP1A1 Msp1 (wt/vt+vt/vt), CYP1A1 exon7 (Val/Val+Ile /Val), GSTM1 (-), GSTM3 (AB+BB), and GSTT1 (-) genotypes, respectively, are at elevated risk of lung cancer.

Chen H, Shen ZY, Xu W, et al.
Expression of P450 and nuclear receptors in normal and end-stage Chinese livers.
World J Gastroenterol. 2014; 20(26):8681-90 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
AIM: To investigate the expression of P450 enzyme genes by using end-stage liver disease samples and trimmed normal Chinese donor livers.
METHODS: The end-stage liver disease samples [n = 93, including hepatocellular carcinoma (HCC), peri-HCC tissue, hepatitis B virus cirrhosis, alcoholic cirrhosis, and severe cirrhosis] and trimmed normal Chinese donor livers (n = 35) from The Institute of Organ Transplantation in Beijing, China. Total RNA was extracted, purified, and subjected to real-time RT-PCR analysis.
RESULTS: For cytochrome P450 enzymes 1 (CYP1) family, the expression of CYP1A2 was decreased 90% in HCC, 80% in alcoholic cirrhosis, and 65% in severe cirrhosis. For CYP2 family, the expression of CAR was decreased 50% in HCC, but increased 50% in peri-HCC tissues. Similar decreases (about 50%) of CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP2E1 were observed in HCC, as compared to peri-HCC tissues and normal livers. CYP2C19 were decreased in all end-stage liver diseases and CYP2E1 also decreased in alcoholic cirrhosis and severe cirrhosis. For CYP3 family, the expression of PXR was decreased 60% in HCC, together with decreases in CYP3A4, CYP3A5, and CYP3A7. In contrast, the expression of CYP3A7 was slightly increased in HBV cirrhosis. The expression of CYP4A11 was decreased 85% in HCC, 7% in alcoholic cirrhosis and severe liver cirrhosis, along with decreases in PPARα. The 93 end-stage livers had much higher inter-individual variations in gene expression than 35 normal livers.
CONCLUSION: The expression of CYP enzyme genes and corresponding nuclear receptors was generally decreased in end-stage liver diseases, and significant differences in gene expression were evident between peri-HCC and HCC.

Gil J, Gaj P, Misiak B, et al.
CYP1A1 Ile462Val polymorphism and colorectal cancer risk in Polish patients.
Med Oncol. 2014; 31(7):72 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Colorectal cancer (CRC) is an epidemiological problem of a great importance in Poland; each year approximately 14,600 new cases of the disease are diagnosed. Mortality associated with CRC reaches approximately 10,400 cases per year (according to the National Cancer Registry). The 5-year survival rate is approximately 25 %, which is one of the lowest rates in Europe. The etiology of sporadic colorectal cancer (CRC) is multifactorial and has been attributed to an interplay between both environmental and genetic risk factors. In addition, there is a general consensus that genetic factors may modulate the influence of environmental insults. Following these assumptions, we performed a study on widely described polymorphisms in xenobiotic-metabolizing enzymes and DNA repair genes which may influence individual susceptibility to cancer. We selected five candidate polymorphisms in following genes: ERCC1 Asp118Asn (rs11615), XPC i11C/A (rs2279017), XRCC3 Met241Thr (rs861539) CYP1A1 Ile462Val (rs1048943) and NAT2 A803G (rs1208) and assessed the importance of chosen SNPs on groups consisting of 478 CRC patients and 404 controls. Only CYP1A1 Ile462Val was statistically significant in CRC patients over 50 years old: OR 2.05 (1.29-3.28); p = 1.25E-02 and this association was more pronounced in the female group of CRC patients after the age of 50: OR 2.72 (1.43-5.14); p = 1.14E-02.

Li W, Song LQ, Tan J
Combined effects of CYP1A1 MspI and GSTM1 genetic polymorphisms on risk of lung cancer: an updated meta-analysis.
Tumour Biol. 2014; 35(9):9281-90 [PubMed] Related Publications
Genetic polymorphisms of cytochrome P450 1A1 (CYP1A1) and glutathione S-transferase M1 (GSTM1) genes might contribute to the variability in individual susceptibility to lung cancer, but the reported results from individual studies are not always consistent. We therefore conducted a meta-analysis to systematically estimate the associations between polymorphisms of these two genes and risk of lung cancer. Twenty-one studies with 8,926 subjects were finally enrolled into this study. Meta-analysis was performed by RevMan 5.2. Odds ratio (OR) and its 95 % confidence interval (CI) were calculated to evaluate the susceptibility to lung cancer. Compared with the wild-type homozygous genotype, significantly elevated risk of lung cancer were associated with variant CYP1A1 MspI (m1/m2 + m2/m2 vs. m1/m1: OR = 1.27, 95 % CI = 1.12-1.43, P < 0.001) and deletion of GSTM1 (null vs. present: OR = 1.26, 95 % CI = 1.13-1.40, P < 0.001). Both the two genetic polymorphisms were independently associated with the risk of lung cancer. The pooled OR of lung cancer for population with both CYP1A1 MspI and GSTM1 mutations (MspI m1/m2 or m2/m2 and GSTM1 null) was 1.62 (95 % CI 1.27-2.07, P < 0.001) when compared with those without any of the above mutations, which is higher than single genetic polymorphism. In the stratified analysis, significantly higher risks of lung cancer associated with above genetic polymorphisms were found only in Asian population. This meta-analysis suggests that the CYP1A1 MspI and GSTM1 polymorphisms correlate with increased lung cancer susceptibility independently, and that there is an interaction between the two genes. However, the associations vary in different ethnic populations.

Brinkman AM, Wu J, Ersland K, Xu W
Estrogen receptor α and aryl hydrocarbon receptor independent growth inhibitory effects of aminoflavone in breast cancer cells.
BMC Cancer. 2014; 14:344 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
BACKGROUND: Numerous studies have implicated the aryl hydrocarbon receptor (AhR) as a potential therapeutic target for several human diseases, including estrogen receptor alpha (ERα) positive breast cancer. Aminoflavone (AF), an activator of AhR signaling, is currently undergoing clinical evaluation for the treatment of solid tumors. Of particular interest is the potential treatment of triple negative breast cancers (TNBC), which are typically more aggressive and characterized by poorer outcomes. Here, we examined AF's effects on two TNBC cell lines and the role of AhR signaling in AF sensitivity in these model cell lines.
METHODS: AF sensitivity in MDA-MB-468 and Cal51 was examined using cell counting assays to determine growth inhibition (GI50) values. Luciferase assays and qPCR of AhR target genes cytochrome P450 (CYP) 1A1 and 1B1 were used to confirm AF-mediated AhR signaling. The requirement of endogenous levels of AhR and AhR signaling for AF sensitivity was examined in MDA-MB-468 and Cal51 cells stably harboring inducible shRNA for AhR. The mechanism of AF-mediated growth inhibition was explored using flow cytometry for markers of DNA damage and apoptosis, cell cycle analysis, and β-galactosidase staining for senescence. Luciferase data was analyzed using Student's T test. Three-parameter nonlinear regression was performed for cell counting assays.
RESULTS: Here, we report that ERα-negative TNBC cell lines MDA-MB-468 and Cal51 are sensitive to AF. Further, we presented evidence suggesting that neither endogenous AhR expression levels nor downstream induction of AhR target genes CYP1A1 and CYP1B1 is required for AF-mediated growth inhibition in these cells. Between these two ERα negative cell lines, we showed that the mechanism of AF action differs slightly. Low dose AF mediated DNA damage, S-phase arrest and apoptosis in MDA-MB-468 cells, while it resulted in DNA damage, S-phase arrest and cellular senescence in Cal51 cells.
CONCLUSIONS: Overall, this work provides evidence against the simplified view of AF sensitivity, and suggests that AF could mediate growth inhibitory effects in ERα-positive and negative breast cancer cells, as well as cells with impaired AhR expression and signaling. While AF could have therapeutic effects on broader subtypes of breast cancer, the mechanism of cytotoxicity is complex, and likely, cell line- and tumor-specific.

Sharma KL, Rai R, Srivastava A, et al.
A multigenic approach to evaluate genetic variants of PLCE1, LXRs, MMPs, TIMP, and CYP genes in gallbladder cancer predisposition.
Tumour Biol. 2014; 35(9):8597-606 [PubMed] Related Publications
Gallbladder cancer (GBC) is a violent neoplasm associated with late diagnosis, unsatisfactory treatment, and poor prognosis. The disease shows complex interplay between multiple genetic variants. We analyzed 15 polymorphisms in nine genes involved in various pathways to find out combinations of genetic variants contributing to GBC risk. The genes included in the study were matrix metalloproteinases (MMP-2, MMP-7, and MMP-9), tissue inhibitor of metalloproteinases (TIMP-2), cytochrome P450 (CYP)1A1, CYP1B1, phospholipase C epsilon 1 (PLCE1), liver X receptor (LXR)-alpha, and LXR-beta. Genotypes were determined by PCR-RFLP and TaqMan probes. Statistical analysis was done by SPSS version 16. Multilocus analysis was performed by Classification and Regression Tree (CART) analysis and multifactor dimensionality reduction (MDR) to gene-gene interactions in modifying GBC risk. In silico analysis was done using various bioinformatics tools (F-SNP, FAST-SNP). Single locus analysis showed association of MMP-2 (-735 C > T, -1306 C > T), MMP-7 - 181 A > G, MMP-9 (P574R, R668Q), TIMP-2 - 418 G > C, CYP1A1-MspI, CYP1A1-Ile462Val, PLCE1 (rs2274223 A > G, rs7922612 T > C) and LXR-beta T > C (rs3546355 G > A, rs2695121 T > C) polymorphisms with GBC risk (p < 0.05) whereas CYP1B1 and LXR-α variants were not associated with GBC risk. Multidimensional reduction analysis revealed LXR-β (rs3546355 G > A, rs2695121 T > C), MMP-2 (-1306 C > T), MMP-9 (R668Q), and PLCE1 rs2274223 A > G to be key players in GBC causation (p < 0.001, CVC = 7/10). The results were further supported by independent CART analysis (p < 0.001). In silico analysis of associated variants suggested change in splicing or transcriptional regulation. Interactome and STRING analysis showed network of associated genes. The study found PLCE1 and LXR-β network interactions as important contributory factors for genetic predisposition in gallbladder cancer.

Sugita S, Aoyama T, Kondo K, et al.
Diagnostic utility of NCOA2 fluorescence in situ hybridization and Stat6 immunohistochemistry staining for soft tissue angiofibroma and morphologically similar fibrovascular tumors.
Hum Pathol. 2014; 45(8):1588-96 [PubMed] Related Publications
Soft tissue angiofibroma (STA), a recently suggested new histologic entity, is a benign fibrovascular soft tissue tumor composed of bland spindle-shaped tumor cells with abundant collagenous to myxoid stroma and branching small vessels. The lesion has a characteristic AHRR-NCOA2 fusion gene derived from chromosomal translocation of t(5;8)(p15;q13). However, morphologically similar tumors containing abundant fibrovascular and myxoid stroma can complicate diagnosis. We designed an original DNA probe for detecting NCOA2 split signals on fluorescence in situ hybridization (FISH) and estimated its utility with 20 fibrovascular tumors: 4 each of STAs, solitary fibrous tumors (SFTs), and cellular angiofibromas and 3 each of low-grade myxofibrosarcomas, myxoid liposarcomas, and low-grade fibromyxoid sarcomas. We also performed FISH for 13q14 deletion and immunohistochemistry (IHC) staining for estrogen receptor, progesterone receptor, retinoblastoma protein, and MUC-4 expression. Furthermore, IHC for Stat6 was conducted in the 20 cases analyzed by FISH and in an additional 26 SFTs. We found moderate to strong nuclear Stat6 expression in all SFTs but no expression in the other tumors. Both estrogen receptor and progesterone receptor expressions were observed in STAs, SFTs, and cellular angiofibromas. Expression of retinoblastoma protein was found in less than 10% of cells in all tumor types except myxoid liposarcoma. The low-grade fibromyxoid sarcomas were strongly positive for MUC-4. All STAs showed NCOA2 split signals on FISH. All tumors, regardless of histologic type, had 13q14 deletion. The NCOA2 FISH technique is a practical method for confirming STA diagnosis. The combination of NCOA2 FISH and Stat6 IHC proved effective for the differential diagnosis of STA, even when using small biopsy specimens.

Mandić S, Horvat V, Marczi S, et al.
Association study of cytochrome P450 1A1*2A polymorphism with prostate cancer risk and aggressiveness in Croatians.
Coll Antropol. 2014; 38(1):141-6 [PubMed] Related Publications
Cytochrome P450 1A1 (CYP1A1) is an enzyme participating in the bioactivation of various endogenous and environmental reactive compounds that can bind to DNA and thus induce cancerogenesis. Gene encoding the enzyme is expressed in the prostate tissue and is polymorphic. CYP1A1*2A gene polymorphism is associated with elevated enzyme activity and/or inducibility which can lead to accumulation of genotoxic compounds and consequently to cancerogenesis. We examined the association of this polymorphism with prostate cancer (PCa) risk and aggressiveness. The case-control study consisted of 120 PCa patients and 120 benign prostatic hyperplasia (BPH) controls, in Croatian population. Regarding aggressiveness, PCa patients were grouped according to the Gleason score (GS), tumor stage (T) and existence of distant metastasis (M). The polymorphism was analyzed using real-time polymerase chain reaction (PCR). We did not observe association of mutated allele with PCa risk, neither with PCa aggressiveness. Furthermore, frequency of polymorphic genotype was slightly higher in BPH group (16.6% vs. 14.2%, respectively) and also in less aggressive form of PCa (20.4% vs. 9.6% for GS < 7; 15.6% vs. 9.1% for T < 3; 16.7% vs. 10.0% for no distant metastasis). Comparing our findings with other published results, we can assume that the ethnicity influence the genotype distribution and thus may affect the etiology of PCa, even possibly in the way to cause an opposite effect among different ethnic groups. Given the small number of participants, results should be validated on the larger sample size.

Shen Y, Ren ML, Xu J, et al.
A multicenter case-control study on screening of single nucleotide polymorphisms in estrogen-metabolizing enzymes and susceptibility to uterine leiomyoma in han chinese.
Gynecol Obstet Invest. 2014; 77(4):224-30 [PubMed] Related Publications
Uterine leiomyoma (UL) is an estrogen-responsive benign tumor in the female reproductive system and the main risk of hysterectomy for women. However, gene polymorphism of estrogen-metabolizing enzymes may lead to the different susceptibility to UL. We detected 10 single mucleotide polymorphisms in three key estrogen metabolite enzymes (COMT, CYP1A1, CYP1B1) in a Chinese Han population consisting of 800 patients and 800 healthy women from five different medical centers. The genetic polymorphism of rs3087869 (IVS1+2329C>T) (OR 3.200, 95% CI 1.614-6.345) and rs4680 (Val158Met) (OR 5.675, 95% CI 2.696-11.942) loci on COMT, rs1048943 (Ile462Val) (OR 4.629, 95% CI 2.216-9.672) and rs4646422 (Gly45Asp) (OR 3.240, 95% CI 1.624-6.461) loci on CYP1A1 and rs1065827 (Ala119Ser) (OR 5.635, 95% CI 2.990-10.619) locus on CYP1B1 were the risk factors to UL development and rs1056836 (Leu432Val) (OR 0.188, 95% CI 0.061-0.575) locus on CYB1B1 may be the protective factor to UL. The results provide a theoretical basis for genetic screening and early intervention to UL-susceptible populations.

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