Cytochrome P450 1B1 Polymorphisms Research Articles

Lower overall survival in male patients with advanced disease undergoing allogeneic hematopoietic stem cell transplantation is associated with CYP1B1 Leu432Val polymorphism.

Human cytochrome P450 1B1 (CYP1B1) is an extrahepatic key enzyme involved in estrogen metabolism, steroid synthesis, and pro-carcinogen activation. In a single-center retrospective study, 382 patients who underwent allogeneic hematopoetic stem cell transplantation and their donors were genotyped for CYP1B1 C432G polymorphism by reverse transcription polymerase chain reaction. One hundred and sixty-nine patients (44%) were homozygous wild-type (wt) gene CC, 157 (41%) heterozygous CG and 56 (15%) homozygous gene mutated GG. Of interest, mutated CYP1B1 was more common in male (62%) than in female patients (48%) P=0.006, unlike in donors. Five-year estimate for overall survival (OS) was 58±4% (CC) versus 48±3% (CG and GG), P=0.048. Surprisingly, this difference was only evident in males (P=0.024): OS 58±6% versus 42±4%, whereas it was virtually absent in females. Importantly, this difference was only evident in male patients with advanced disease (AD) (n=118, P=0.002): OS 44±8% (CC) versus 32±6% (CG) versus 6±6% (GG), whereas it was virtually absent in male patients with early disease. One-year non-relapse mortality in male patients with AD was 8±4% (CC) versus 21±5% (CG) versus 50±12% (GG), P=0.002. Three-year relapse rate in male patients with AD was 31±7% (wt) versus 42±6% (mut), P=0.04. Multivariate analysis for OS in male patients with AD revealed CYP1B1 polymorphism as the only prognostic factor: RR 1.78, P=0.001. In conclusion, these results suggest that male patients with AD and mutant CYP1B1 polymorphism have lower OS after allogeneic hematopoetic stem cell transplantation due to a higher non-relapse mortality and a higher relapse rate.

Cytochrome P450 1B1 polymorphism drives cancer cell stemness and patient outcome in head-and-neck carcinoma

BackgroundCytochrome P450 1B1 (CYP1B1) is mostly expressed in tumours and displays unusual properties. Its two polymorphic forms were differently associated with anticancer drug sensitivity. We decipher here the role of this polymorphism in anticancer drug efficacy in vitro, in vivo and in the clinical setting.MethodsFrom head-and-neck squamous cell carcinoma cell lines not expressing CYP1B1, we generated isogenic derivatives expressing the two forms. Proliferation, invasiveness, stem cell characteristics, sensitivity to anticancer agents and transcriptome were analysed. Tumour growth and chemosensitivity were studied in vivo. A prospective clinical trial on 121 patients with advanced head-and-neck cancers was conducted, and a validation-retrospective study was conducted.ResultsCell lines expressing the variant form displayed high rates of in vitro proliferation and invasiveness, stemness features and resistance to DNA-damaging agents. In vivo, tumours expressing the variant CYP1B1 had higher growth rates and were markedly drug-resistant. In the clinical study, overall survival was significantly associated with the genotypes, wild-type patients presenting a longer median survival (13.5 months) than the variant patients (6.3 months) (p = 0.0166).ConclusionsThis frequent CYP1B1 polymorphism is crucial for cancer cell proliferation, migration, resistance to chemotherapy and stemness properties, and strongly influences head-and-neck cancer patients’ survival.

Influence of lifestyle choices on risks of CYP1B1 polymorphisms for prostate cancer.

Cytochrome P450 1B1 (CYP1B1) converts xenobiotics to carcinogens and how lifestyle choices may interact with CYP1B1 polymorphisms and affect prostate cancer risk was assessed. Blood genomic DNA from a Caucasian population was analysed at polymorphic sites of the 5′ untranslated region of CYP1B1 using TaqMan genotyping assays. Overall, drinker status and minor alleles at rs2551188, rs2567206 and rs10175368 were associated with prostate cancer. Linkage was observed between rs2551188, rs2567206, rs2567207 and rs10175368, and the G‐C‐T‐G haplotype (major allele at respective sites) was decreased in cancer. Interestingly when classified by lifestyle factors, no associations of genotypes were found for non‐smokers and non‐drinkers, whereas on the contrary, minor type at rs2567206 and rs10175368 increased and major G‐C‐T‐G decreased risk for cancer among smokers and drinkers. Interestingly, rs2551188, rs2567206 and rs10175368 minor genotypes correlated with increased tissue CYP1B1 as determined by immunohistochemistry. Further, rs10175368 enhanced luciferase activity and mobility shift show stronger binding of nuclear factor for the minor allele. These results demonstrate smoking and alcohol consumption to modify the risks of CYP1B1 polymorphisms for prostate cancer which may be through rs10175368, and this is of importance in understanding their role in the pathogenesis and as a biomarker for this disease.

Abstract 1242: Differences of cytochrome P450 1B1 polymorphisms on prostate cancer risk between races

Abstract Prostate cancer is the most common cancer among men in the United States but when comparing between races, rates are much higher in African-Americans (AfA) compared to Caucasians (Cau). Reasons for this discrepancy are unknown but studies have shown that polymorphisms of cytochrome P450 1B1 (CYP1B1), a gene that activates carcinogens, to be involved in prostate cancer pathogenesis. In this study, how race influences CYP1B1 polymorphisms and prostate cancer risk were investigated. Blood genomic DNA from a Cau (469 controls, 500 prostate cancer), AfA (152 controls, 218 cases) and Japanese (JPN) (131 controls, 177 cases) population were obtained. Eight polymorphic sites of the promoter or 5'-untranslated region of CYP1B1 (rs2551188 G to A, rs2567206 C to T, rs2567207 T to C, rs162556 T to C, rs10175368 G to A, rs163090 T to A, rs162330 T to G, and rs162331 A to G) were analyzed using Taqman genotyping assays and sequence-specific PCR, and genotyping results tabulated. Also, CYP1B1 protein expression was determined in 52 Cau benign prostatic hyperplasia specimens and levels categorized by polymorphic sites. Racial differences for prostate cancer risk due to CYP1B1 polymorphisms were observed. In Cau, minor alleles rs2551188 A, rs2567206 T and rs10175368 A showed increased risk for cancer (P<0.05). Linkage was observed between rs2551188-rs2567206-rs2567207-rs10175368 and the major G-C-T-G haplotype was reduced in cancer cases (P<0.001). Interestingly when analyzing prostatic tissue specimens, minor genotypes of rs2551188 (P<0.05), rs2567206 (P<0.05) and rs10175368 (Ptrend=0.065) displayed higher levels and major G-C-T-G haplotype lower levels (P<0.05) of CYP1B1 protein expression, which were consistent with genotyping results. For AfA, minor rs2551188 A allele decreased risk for prostate cancer (P<0.001). Rs163090-rs162331 were linked and the minor A-G haplotype displayed a reduced prostate cancer risk (P<0.05). Among JPN, minor rs2567206 T allele also reduced cancer risk (P<0.05). Two sets of linkages, rs2551188-rs2567206-rs2567207-rs162556-rs10175368 and rs163090-rs162330-rs162331 were observed and the minor A-T-C-T-A and major A-T-A haplotypes respectively, showed a decreased risk for cancer (P<0.01). These results suggest a differential effect of CYP1B1 polymorphisms for prostate cancer risk between races and these results are important in understanding its role in this disease. Citation Format: Taku Kato, Yutaka Hashimoto, Ryan Wong, Yozo Mitsui, Shigekatsu Maekawa, Soichiro Yamamura, Shahana Majid, Sharanjot Saini, Varahram Shahryari, Laura Tabatabai, Hiroaki Shiina, Rajvir Dahiya, Takashi Deguchi, Yuichiro Tanaka. Differences of cytochrome P450 1B1 polymorphisms on prostate cancer risk between races [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1242.

CYTOCHROME P450 CYP1B1*2 GENE AND ITS ASSOCIATION WITH T2D IN TABUK POPULATION, NORTHWESTERN REGION OF SAUDI ARABIA

Objective: Cytochrome P450 1B1 (CYP1B1) is involved in the activation of procarcinogens and steroid metabolism. Genetic variants of CYP1B1are associated with altered catalytic activity and disease phenotypes. The purpose of this study was to investigate the role of CYP1B1 (rs1056827) polymorphism in inducing T2D.Methods: This cross-sectional study enrolled 113 subjects of T2D and 120 controls. DNA was isolated from blood. Genotyping of the rs1056827 wasdone by allele-specific polymerase chain reaction. The frequency of alleles and genotype distribution was compared in T2D cases and healthy controls.Statistical analysis was performed with SPSS, Chi-square, and Fisher exact test. Hardy-Weinberg equilibrium was tested by a χ2 test. The associations between rs1056827 variant genotypes and T2D were estimated by computing the odds ratios and their 95% confidence intervals (CI) from univariate and multivariate logistic regression analysis.Results: A significant association of rs1056827 was found between T2D cases and controls (p<0.0001). When GG genotype was compared with GT genotype a significant association was found with odd ration (OD)0.24 (95% CI: (0.131–0.452) and risk ratio (RR) 0.45 (0.30–0.67) times the risk of T2D heterozygous with the G/T allele (p≤0.0002). In a comparison of GG homozygous with the TT homozygous, there was no significant association with the OD 0.38 (95% CI: (0.02–6.51) RR 0.55(0.13–2.35), p<0.49. When G allele was compared with the T allele a highly significant association with OD 0.54 (95% [CI]: (0.37–0.80) RR 0.75(0.630–0.897) < p≤0.003 suggesting a possible dominant effect of this polymorphism on T2D risk.Conclusion: This result suggests a significant association between rs1056827G>T polymorphism and T2D. This finding is limited due to the smaller sample size and can be validated by large sample size studies.

CYTOCHROME P450 CYP1B1*2 GENE AND ITS ASSOCIATION WITH T2D IN TABUK POPULATION, NORTHWESTERN REGION OF SAUDI ARABIA

Objective: Cytochrome P450 1B1 (CYP1B1) is involved in the activation of procarcinogens and steroid metabolism. Genetic variants of CYP1B1are associated with altered catalytic activity and disease phenotypes. The purpose of this study was to investigate the role of CYP1B1 (rs1056827) polymorphism in inducing T2D.Methods: This cross-sectional study enrolled 113 subjects of T2D and 120 controls. DNA was isolated from blood. Genotyping of the rs1056827 wasdone by allele-specific polymerase chain reaction. The frequency of alleles and genotype distribution was compared in T2D cases and healthy controls.Statistical analysis was performed with SPSS, Chi-square, and Fisher exact test. Hardy-Weinberg equilibrium was tested by a χ2 test. The associations between rs1056827 variant genotypes and T2D were estimated by computing the odds ratios and their 95% confidence intervals (CI) from univariate and multivariate logistic regression analysis.Results: A significant association of rs1056827 was found between T2D cases and controls (p<0.0001). When GG genotype was compared with GT genotype a significant association was found with odd ration (OD)0.24 (95% CI: (0.131–0.452) and risk ratio (RR) 0.45 (0.30–0.67) times the risk of T2D heterozygous with the G/T allele (p≤0.0002). In a comparison of GG homozygous with the TT homozygous, there was no significant association with the OD 0.38 (95% CI: (0.02–6.51) RR 0.55(0.13–2.35), p<0.49. When G allele was compared with the T allele a highly significant association with OD 0.54 (95% [CI]: (0.37–0.80) RR 0.75(0.630–0.897) < p≤0.003 suggesting a possible dominant effect of this polymorphism on T2D risk.Conclusion: This result suggests a significant association between rs1056827G>T polymorphism and T2D. This finding is limited due to the smaller sample size and can be validated by large sample size studies.

MP14-06 RISKS OF CYTOCHROME P450 1B1 POLYMORPHISMS AND LIFESTYLE CHOICES ON PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Epidemiology & Natural History II1 Apr 2017MP14-06 RISKS OF CYTOCHROME P450 1B1 POLYMORPHISMS AND LIFESTYLE CHOICES ON PROSTATE CANCER Taku Kato, Yutaka Hashimoto, Shigekatsu Maekawa, Marisa Shiina, Mitsuho Imai-Sumida, Pritha Dasgupta, Priyanka Kulkarni, Soichiro Yamamura, Shahana Majid, Sharanjot Saini, Varahram Sharryari, Guoren Deng, Rajvir Dahiya, and Yuichiro Tanaka Taku KatoTaku Kato More articles by this author , Yutaka HashimotoYutaka Hashimoto More articles by this author , Shigekatsu MaekawaShigekatsu Maekawa More articles by this author , Marisa ShiinaMarisa Shiina More articles by this author , Mitsuho Imai-SumidaMitsuho Imai-Sumida More articles by this author , Pritha DasguptaPritha Dasgupta More articles by this author , Priyanka KulkarniPriyanka Kulkarni More articles by this author , Soichiro YamamuraSoichiro Yamamura More articles by this author , Shahana MajidShahana Majid More articles by this author , Sharanjot SainiSharanjot Saini More articles by this author , Varahram SharryariVarahram Sharryari More articles by this author , Guoren DengGuoren Deng More articles by this author , Rajvir DahiyaRajvir Dahiya More articles by this author , and Yuichiro TanakaYuichiro Tanaka More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.470AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Cytochrome P450 1B1 (CYP1B1) converts xenobiotics to carcinogens and polymorphic variants have been shown to increase activity levels. Lifestyle choices such as tobacco smoking and alcohol consumption are known to enhance the carcinogenesis process and in this study, how these factors may interact with CYP1B1 polymorphisms and affect prostate cancer risk was assessed. METHODS Blood genomic DNA from a Caucasian population consisting of 405 healthy men and 400 prostate cancer patients were obtained. Of these, 507 were current or former smokers and 407 were alcohol drinkers. Eight polymorphic sites of the promoter region of CYP1B1 (rs2551188 G to A, rs2567206 G to A, rs2567207 A to G, rs162556 A to G, rs10175368 C to T, rs163090 T to A, rs162330 T to G, and rs162331 A to G) were analyzed in samples using Taqman genotyping assays and real-time PCR. Lifestyle factors and its influence on CYP1B1 polymorphisms toward cancer risks were also evaluated. RESULTS Overall, both alcohol (P=0.006) and smoker (P=0.069) status were associated with prostate cancer. CYP1B1 variants were also risks for cancer at rs2551188 (P=0.043), rs2567206 (P=0.008), and rs10175368 (P=0.001). Evaluation of linkage disequilibrium show rs2551188, rs2567206, rs2567207, and rs10175368 to be linked and interestingly, the G-G-A-C haplotype (wildtype at respective sites) was significantly reduced in cancer (P=0.0282). When classified by lifestyle factors, no associations for CYP1B1 variants were found for cancer among non-smokers with rs10175368 (P=0.051) being a risk among non-drinkers. On the other hand, variants at both rs2567206 and rs10175368 showed increased cancer risk among smokers (P=0.032 and 0.002, respectively) as well as drinkers (P=0.044 and 0.019, respectively). No genotyping differences were observed when analyzing cancers by pathological grades. CONCLUSIONS These results demonstrate smoker and alcoholic drinker status to modify the risks of CYP1B1 polymorphisms for prostate cancer and this is of importance in understanding their role in the pathogenesis of this disease. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e164 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Taku Kato More articles by this author Yutaka Hashimoto More articles by this author Shigekatsu Maekawa More articles by this author Marisa Shiina More articles by this author Mitsuho Imai-Sumida More articles by this author Pritha Dasgupta More articles by this author Priyanka Kulkarni More articles by this author Soichiro Yamamura More articles by this author Shahana Majid More articles by this author Sharanjot Saini More articles by this author Varahram Sharryari More articles by this author Guoren Deng More articles by this author Rajvir Dahiya More articles by this author Yuichiro Tanaka More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Cytochrome P450 1B1 polymorphisms and risk of renal cell carcinoma in men.

The cytochrome P450 1B1 (CYP1B1) enzyme activates xenobiotics to reactive forms as well as convert estradiol to 4-hydroxy-estradiol that has been shown to play a role in the carcinogenesis process of the kidney in male but not female animals. Prior reports show polymorphic variants of CYP1B1 to alter catalytic activity, and thus, we hypothesize that polymorphisms of the CYP1B1 gene are involved in the malignant transformation of the renal cell in men. The genetic distributions of five CYP1B1 polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism in 480 normal healthy subjects and 403 sporadic renal cell carcinoma cases. All subjects were Caucasian men. The sites evaluated were codons 48 (C → G, Arg → Gly, rs10012), 119 (G → T, Ala → Ser, rs1056827), 432 (C → G, Leu → Val, rs1056836), 449 (C → T, Asp, rs1056837), and 453 (A → G, Asn → Ser, rs1800440). A trend was demonstrated for the 432 Val/Val (χ2, P = 0.06) and 449 T/T (χ2, P = 0.1) genotypes to play a protective role against renal cancer. Odds ratio (95 % confidence interval) for Val/Val compared to Leu/Leu at codon 432 was 0.65 (0.44-0.95) and T/T compared to C/C at codon 449 was 0.67 (0.45-0.99). Codons 432 and 449 were observed to be linked (D = 0.24), and haplotype involving 432 Val and 449 T was significantly reduced in cancer cases (P = 0.04). No association was found, however, when analyzing polymorphic sites with clinical stage of cancer. These results demonstrate polymorphisms of CYP1B1 to be associated with renal carcinogenesis and are of importance in understanding their role in the pathogenesis of renal cell carcinoma.

Genetic polymorphisms in Cytochrome P 4501B1 and susceptibility to idiopathic preterm labor in North Indian population

ObjectiveThe etiology of preterm labor (PTL) is still unknown, but it may be related to a possible genetic predisposition together with involvement of environmental factors. We investigated the relation between PTL and polymorphisms in Cytochrome P4501B1 (CYP1B1) gene, which is involved in the metabolism of a wide range of environmental toxins and hormones. Design and methodsThree hundred (n=300) cases of PTL and equal number of subjects of full term labor (FTL), after excluding all the known risk factors for PTL were included in the study. A two step allele specific PCR was performed for polymorphic analysis of CYP1B1 gene. ResultsThe homozygous variant genotype of CYP1B1*2 (OR=2.97, 95%CI=1.08–8.08, p=0.033) and heterozygous variant of CYP1B1*3 (OR=2.57, 95%CI=1.88–3.63, p=0.001), and CYP1B1*7 (OR=2.59, 95%CI=1.85–3.62, p=0.001) were found to be significantly higher in PTL cases as compared to FTL. ConclusionsThe present study demonstrates the possible association of homozygous variant of CYP1B1*2 and heterozygous variant of CYP1B1*3 and CYP1B1*7 genes with the increased risk of PTL.

Adipose tissue PCB levels and CYP1B1 and COMT genotypes in relation to breast cancer risk in postmenopausal Danish women

Exposure to PCBs may be an etiologic factor for breast cancer. The cytochrome P450 1B1 (CYP1B1) and catechol-O-methyltransferase (COMT) enzymes are involved in estrogen metabolism and PCB metabolism, both of which may relate to breast cancer susceptibility. Polymorphisms in genes regulating these enzymes control efficiency. Our objective was to assess whether CYP1B1 and COMT gene polymorphisms modulate the effect of PCBs in breast cancer risk, among postmenopausal Danish women. Neither CYP1B1 Leu432Val polymorphisms nor adipose tissue PCBs were independently associated with breast cancer risk. When assessing the independent effect of the COMT Val158Met polymorphism, we observed reduced risk for breast cancer amongst hormone replacement therapy using women who were homozygous carriers of the variant allele compared with those carrying the wild-type variant (RR = 0.41; 95% CI: 0.29–0.89). We found no statistically significant interactions between any of the PCB groups and CYP1B1 or COMT polymorphisms on the risk of breast cancer.

CYP1B1 Polymorphisms and Susceptibility to Prostate Cancer: A Meta-Analysis

BackgroundStudies investigating the association between single-nucleotide polymorphisms (SNPs) of the cytochrome P450 1B1 (CYP1B1) and prostate cancer (PCa) risk report conflicting results. To derive a more precise estimation of the relationship between CYP1B1 polymorphisms and PCa risk, a meta-analysis was performed.Methodology/Principal FindingsA comprehensive literature search was conducted to identify all eligible studies of CYP1B1 polymorphisms and PCa risk. A total of 14 independent studies, including 6380 cases and 5807 controls, were identified. We investigated by meta-analysis the effects of 5 polymorphisms in CYP1B1 L432V (12 studies, 5999 cases, 5438 controls), R48G (6 studies, 1647 cases, 1846 controls), N453S (4 studies, 1407 cases, 1499 controls), −13C/T (4 studies, 1116 cases, 1114 controls), and A119S (4 studies, 1057 cases, 1018 controls). There was no evidence that L432V had significant association with PCa in overall population. After subgroup analyses by ethnicity, we found that L432V was significantly associated with PCa risk in Asians (additive: OR = 2.38, 95%CI = 1.31-4.33, P = 0.004; recessive: OR = 2.11, 95%CI = 1.17–3.79, P = 0.01; dominant: OR = 1.52, 95%CI = 1.14–2.01, P = 0.004; allelic: OR = 1.52, 95%CI = 1.20–1.92, P = 0.0006). When stratified by source of controls, significantly elevated PCa risk was found in all genetic models in population based studies (additive: OR = 1.34, 95%CI = 1.14–1.57, P = 0.0003; recessive: OR = 1.25, 95%CI = 1.09–1.43, P = 0.002; dominant: OR = 1.25, 95%CI = 1.11–1.41, P = 0.0002; allelic: OR = 1.18, 95%CI = 1.09–1.28, P<0.0001). For N453S, there was a significant association between N453S polymorphism and PCa risk in both overall population (dominant: OR = 1.18, 95%CI = 1.00–1.38, P = 0.04) and mixed population (domiant: OR = 1.31, 95%CI = 1.06–1.63, P = 0.01; allelic: OR = 1.27, 95%CI = 1.05–1.54, P = 0.01). For A119S, our analysis suggested that A119S was associated with PCa risk under recessive model in overall population (OR = 1.37, 95%CI = 1.04–1.80, P = 0.03).ConclusionsThe results suggest that L432V, N453S, and A119S polymorphisms of CYP1B1 might be associated with the susceptibility of PCa. Further larger and well-designed multicenter studies are warranted to validate these findings.

Abstract 2200: Relationship between cytochrome P450 1B1 (CYP1B1) and head and neck cancer cells proliferation, dissemination and chemosensitivity to anticancer drugs.

Abstract Contrasting to other cytochromes P450, CYP1B1 is essentially present in tumour tissue and has been suspected to play a role in oncogenesis and drug resistance. We have recently shown that a CYP1B1 single nucleotide gene polymorphism (rs1056836, 1697 G&amp;gt;C, V432L) was significantly associated with the cytotoxicity of DNA-damaging anticancer drugs in two independent panels of tumour cell lines, the NCI-60 panel and the JFCR-45 panel. In order to identify the molecular mechanisms involved in the role of CYP1B1 polymorphism in anticancer drug resistance, we selected head-and-neck cancer cell lines with no basal expression of CYP1B1 due to promoter hypermethylation and generated by lentiviral infection isogenic variants differing only by this single nucleotide in the CYP1B1 gene. Cell proliferation was strongly enhanced in cells re-expressing CYP1B1 and further increased in cells harbouring the C/C genotype (C/C cells) as compared to those harbouring the G/G genotype (G/G cells). The cytotoxicity of a panel of anticancer drugs from all drug classes was evaluated on these established cell lines. Significantly higher IC50s of most of them (excepted oxaliplatin and gemcitabine) were noticed for C/C cells as compared to G/G cells in agreement with what was observed in the NCI and JFCR panels. Migration capacity of these cell lines was studied using the scratch wound assay and proteins involved in cell adhesion were evaluated by Western blotting. Cells re-expressing CYP1B1 were able to migrate significantly more rapidly than original cells and this was further enhanced in C/C cells as compared to G/G cells. E-cadherin expression was decreased in C/C cells while vimentin expression was increased in G/G cells. The clinical consequences of the CYP1B1 L432V gene polymorphism were studied in a prospective population of 123 head-and-neck cancer patients treated by chemotherapy associated with cetuximab in the palliative setting, either with locally advanced or with metastatic disease. There were 48 C/C patients, 40 heterozygotes C/G and 35 G/G patients, giving an allele frequency of 45%. No differences in progression rates as a function of the polymorphism were noticed. Overall median survival (OMS) was significantly worse in C/C patients (6.6 months) than in G/G patients (13.2 months), heterozygotes falling in between (9.8 months) (p = 0.017). Taking into account only the metastatic patients (47 patients) revealed more profound differences between C/C patients (OMS = 3.8 months) and G/G patients (OMS not reached), with heterozygotes in between (OMS = 12.0 months) (p = 0.0003). CYP1B1 V432L gene polymorphism appears as a strong determinant of survival of patients with advanced head-and-neck cancer and treated by chemotherapy associated with cetuximab. Citation Format: Valérie Le Morvan, Céline Auzanneau, Alban Pasquies, Mathilde Brault, Jacques Robert, Amélie Lansiaux. Relationship between cytochrome P450 1B1 (CYP1B1) and head and neck cancer cells proliferation, dissemination and chemosensitivity to anticancer drugs. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2200. doi:10.1158/1538-7445.AM2013-2200

Genetic polymorphism intermingled with environmental factors substantially contributes to the bladder cancer progression

Genetic polymorphism intermingled with environmental factors substantially contributes to the bladder cancer progression

Abstract 2640: Risk of cytochrome P450 1B1 missense polymorphisms in renal cell carcinoma

Abstract In male kidney, 4-hydroxy-estradiol has been shown to play a role in the carcinogenesis process. This metabolite is formed from estradiol and due to the hydroxylation activity of the cytochrome P450 1B1 (CYP1B1) enzyme. Prior reports show polymorphisms of CYP1B1 to result in higher catalytic activity and thus, we hypothesize that single nucleotide polymorphisms of the CYP1B1 gene are involved in the malignant transformation of the renal cell. To test this hypothesis, the genetic distributions of four missense CYP1B1 polymorphisms were analyzed in 383 normal healthy subjects and 384 sporadic renal cell carcinoma (RCC) cases by sequence-specific PCR and sequencing. All subjects were men and from a Caucasian population. The polymorphic sites evaluated were at codons 48 (ArgαGly, rs10012), 119 (AlaαSer, rs1056827), 432 (LeuαVal, rs1056836), and 453 (AsnαSer, rs1800440). Results of these experiments demonstrate a trend for the codon 119 Ser/Ser genotype to be a risk for RCC (χ2, P=0.09). Odds ratio for the Ser/Ser genotype was calculated as 1.85 with 95% confidence interval of 1.07-3.20 as compared to the Ala/Ala genotype. The Leu allele on codon 432 was also found to approach significance as a risk for RCC as compared to Val (χ2, P=0.09). Codons 119 and 432 were observed to be linked (R2=0.25) and haplotype analyses show Ala and Val, representing non-risk alleles at these sites, respectively, to be significantly reduced in RCC cases (P=0.06). No association was found however, when analyzing polymorphic sites with clinical stage of RCC. These results demonstrate missense polymorphisms of CYP1B1 to be associated with renal carcinogenesis and are of importance in understanding their role in the pathogenesis of RCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2640. doi:1538-7445.AM2012-2640

CYP1B1 Asn453Ser polymorphism and colorectal cancer risk: a meta-analysis

Studies investigating the association between cytochrome P450 1B1 (CYP1B1) Asn453Ser (453 A/G, rs1800440) polymorphism and colorectal cancer (CRC) risk report conflicting results. The aim of this study was to quantitatively summarize the evidence for such a relationship. Two investigators independently searched the Medline and Embase Databases. Summary odds ratios (ORs) and 95% confidence intervals (95% CIs) for CYP1B1 polymorphism and CRC were calculated in a fixed-effects model (the Mantel–Haenszel method) and a random-effects model (the DerSimonian and Laird method) when appropriate. The pooled ORs were performed for co-dominant model (GG vs AA, GA vs AA), dominant model (GG+GA vs AA), and recessive model (GG vs GA+AA). This meta-analysis included 7 case-control studies, which included 6375 CRC cases and 7003 controls. Overall, the variant genotypes (GG and GA) of the 453 A/G were not associated with CRC risk when compared with the wild-type AA homozygote (GG vs AA, OR=0.94, 95% CI=0.77–1.14; GA vs AA, OR=0.99, 95% CI=0.87–1.12). Similarly, no associations were found in the dominant and recessive models (dominant model, OR=0.98, 95% CI=0.87–1.09; recessive model, OR=0.94, 95% CI=0.77–1.14). When stratifying for country, study sample size, matched control and source of controls, no evidence of significant association was observed in any subgroup, except among those studies from “Canada”. No publication bias was found in the present study. No association was found between the CYP1B1 Asn453Ser polymorphism and risk of CRC among Caucasians.

CYP1B1 Leu432Val polymorphism and colorectal cancer risk among Caucasians: a meta-analysis

Studies investigating the association between cytochrome P450 1B1 (CYP1B1) Leu432Val (432 C/G, rs1056836) polymorphism and colorectal cancer (CRC) risk report conflicting results. The aim of this study was to quantitatively summarize the evidence for such a relationship. Two investigators independently searched the Medline, Embase, China National Knowledge Infrastructure, and Chinese Biomedicine Databases. Summary odds ratios (ORs) and 95% confidence intervals (95% CIs) for CYP1B1 polymorphism and CRC were calculated in a fixed-effects model and a random-effects model when appropriate. The pooled ORs were performed for co-dominant model (GG vs. CC, GC vs. CC), dominant model (GG + GC vs. CC), and recessive model (GG vs. GC + CC). This meta-analysis included ten case-control studies, which included 8,466 CRC cases and 9,301 controls. Overall, the variant genotypes (GG and GC) of the 432 C/G were not associated with CRC risk when compared with the wild-type CC homozygote (GG vs. CC, OR = 1.01, 95% CI = 0.93-1.10; GC vs. CC, OR = 0.97, 95% CI = 0.90-1.04), without any between-study heterogeneity. Similarly, no associations were found in the dominant and recessive models (dominant model, OR = 0.98, 95% CI = 0.92-1.05; recessive model, OR = 1.03, 95% CI = 0.96-1.11). Limiting the analysis to the studies within Hardy-Weinberg equilibrium, the results were persistent and robust. When stratifying for country, matched control and source of controls, no evidence of significant association was observed in any subgroup. No publication bias was found in the present study. No association is found between the CYP1B1 Leu432Val polymorphism and risk of CRC among Caucasians.

Polymorphisms in CYP1B1 modify the risk of idiopathic male infertility with abnormal semen quality

BackgroundIt is acknowledged that Cytochrome P450 1B1 (CYP1B1) plays a crucial role in metabolism and is involved in lots of diseases. We carried out this study to evaluate the association between CYP1B1 single nucleotide polymorphisms (SNPs) and male infertility in the Han-Chinese population with abnormal semen parameters. MethodsWe genotyped five CYP1B1 polymorphisms by using TaqMan allelic discrimination assay and Genome Lab SNP-stream. A total of 591 idiopathic infertile men and 419 fertile controls were comprised in the research. Semen quality analysis was performed using computer assisted sperm analysis. According to semen parameters, we divided cases into 3 subgroups in the stratified analysis. ResultsIn our study, we only found genetic variant rs1056836 is correlated with idiopathic male infertility (P=0.012). Additionally, in strategy analysis, rs1056836 may decrease the risk of abnormal sperm motility (OR=0.11, 95% CI=0.01, 0.86). While other four variants showed no significant association with male infertility. ConclusionsOur results suggested that polymorphism of CYP1B1 modified the risk of male infertility, and men harboring this polymorphism had lower risk of abnormal sperm parameters. These findings should be validated by more epidemiological and functional studies.

Association between exposure-relevant polymorphisms in CYP1B1, EPHX1, NQO1, GSTM1, GSTP1 and GSTT1 and risk of colorectal cancer in a Czech population

Associations of functional single nucleotide polymorphisms in cytochrome P450 1B1, epoxide hydrolase 1, NAD(P)H:quinone oxidoreductase 1, glutathione S-transferase Pi-1 and deletions of glutathione S-transferases Mu-1 and θ-1 with colorectal cancer risk were investigated in a hospital-based case-control study on 495 matched pairs of Czech Caucasians. Polymorphisms were assessed by polymerase chain reaction restriction fragment length polymorphism-based methods, allele-specific multiplex and allelic discrimination by real-time polymerase chain reaction. Carriers of variant Ser allele in codon 453 of cytochrome P450 1B1 (rs1800440) were at a significantly lower risk of colorectal cancer compared to carriers of the wild-type allele (adjusted odds ratio, aOR=0.68, CI=0.51-0.89, p=0.006). The combination of polymorphisms in codons 453 and 432 (rs1056836) of cytochrome P450 1B1 further increased the protective effect (aOR=0.53, CI=0.34-0.83, p=0.005). The glutathione S-transferase Mu-1 deletion was associated with a moderately elevated colorectal cancer risk (aOR=1.30, CI=1.01-1.68, p=0.044). Combination of glutathione S-transferase Mu-1 and θ-1 deletion was associated with a significantly higher colorectal cancer risk compared to the presence of both full-length genes (aOR=1.58, CI=1.01-2.47, p=0.044). Genetic polymorphisms in glutathione S-transferase Pi-1, NAD(P)H:quinone oxidoreductase 1, epoxide hydrolase 1 and deduced epoxid hydrolase 1 activity did not modify the risk of colorectal cancer. These results provide further evidence that interaction between metabolic gene variants contributes to colorectal carcinogenesis.

Three polymorphisms in cytochrome P450 1B1 (CYP1B1) gene and breast cancer risk: a meta-analysis

Cytochrome P450 1B1 (CYP1B1) is a P450 enzyme implicated in the metabolism of exogenous and endogenous substrates. The metabolism of polycyclic aromatic hydrocarbons and other procarcinogens through CYP1B1 may well lead to their activation. Apart from the extensively studied Val432Leu polymorphism, three single nucleotide polymorphisms in CYP1B1 have been studied concerning their potential implication in terms of breast cancer risk: Arg48Gly, Ala119Ser and Asn453Ser. This meta-analysis aims to examine whether the three aforementioned polymorphisms are associated with breast cancer risk. Eligible articles were identified by a search of MEDLINE bibliographical database for the period up to December 2009. Concerning Arg48Gly polymorphism, 10 studies were eligible (11,321 cases and 13,379 controls); 11 studies were eligible for Ala119Ser (10,715 cases and 11,678 controls); 12 cases were eligible regarding Asn453Ser (11,630 cases and 14,053 controls). Pooled odds ratios (OR) were appropriately derived form fixed-effects or random-effects models. Sensitivity analysis excluding studies whose genotype frequencies in controls significantly deviated from Hardy-Weinberg equilibrium was performed. Concerning Arg48Gly, the pooled ORs (95% CI) were 0.933 (0.808-1.078) for heterozygous and 0.819 (0.610-1.100) for homozygous Gly subjects. Regarding Ala119Ser, the pooled ORs were 0.992 (0.896-1.097) for heterozygous and 0.935 (0.729-1.198) for homozygous Ser subjects. With respect to Asn453Ser, the pooled ORs were 0.961 (0.906-1.019) for heterozygous and 0.984 (0.846-1.144) for homozygous Ser subjects. In conclusion, this meta-analysis suggests that CYP1B1 Arg48Gly, Ala119Ser and Asn453Ser polymorphisms are not associated with breast cancer risk. Studies on Chinese populations are needed, to elucidate race-specific effects on East Asian populations, if any.

Association ofCYP1B1Polymorphisms with Breast Cancer: A Case-Control Study in the Han Population in Ningxia Hui Autonomous Region, P. R. China

Studies investigating possible associations between cytochrome P4501B1 (CYP1B1) polymorphisms and breast cancer risk have been inconsistent. We set out to ascertain whether there might be an association between polymorphisms in exon 2 (codon 119, G-->T) and exon 3 (codon 432, G-->C) of CYP1B1 and breast cancer in a Chinese Han population in the rural region of Ningxia. Using an allele-specific polymerase chain reaction method and direct DNA sequencing, the presence or absence of the two CYP1B1 polymorphisms was investigated. Genotype and allele frequencies were analyzed in breast cancer cases (n = 152) and healthy age-matched controls (n = 156). The odds ratio (OR) of 119G-->T or 432G-->C in breast cancer cases and controls was 3.3 (95% CI: 1.28 to 8.28) and 2.8 (95% CI: 1.04 to 7.51), respectively. In addition, the OR for people with both polymorphisms (119T and 432C) was 4.69 (95% CI: 1.97 to 11.19). Our results suggest that certain polymorphisms in the CYP1B1 gene might increase risk for breast cancer among Han Chinese, perhaps because they influence the efficiency of CYP1B1 bio-transformation of oestrogens or pro-carcinogens into DNA-reactive electrophiles that may act as cancer-initiating agents.