Ethnic susceptibility to lung cancer: differences in CYP2E1, CYP1A1 and GSTM1 genetic polymorphisms between French Caucasian and Chilean populations.

Many investigators have reported an association between genetic polymorphisms of cytochromes P-450 CYP2E1, CYP1A1 or glutathione S-transferase Mu (GSTM1) and susceptibility to lung cancer. However, pronounced interethnic variations have been described in the frequencies of these polymorphisms, especially between Asians and Caucasians. The present study was set up to establish CYP2E1 (c1, c2 and C, D), CYP1A1 (m1, m2 and Ile, Val) and GSTM1 (null) allelic frequencies in Chileans (n = 96) who are an admixture of Native Americans and Caucasians (Spaniards). The rare allele frequencies were found to be 0.15 (c2), 0.21 (C), 0.23 (m2), 0.32 (Val) and 0.21 ('null' genotype). These values are significantly higher than those of Caucasians except for the GSTM1 'null' genotype and suggest differences in susceptibility to lung cancer between both populations.     

Genetic Polymorphisms of CYP2E1 and GSTP1 in a South Indian Population - Comparison with North Indians,Caucasians and Chinese

CYP2E1 and GSTP1 enzymes belong to phase I and phase II group of drug metabolizing enzymes respectively ‍which are involved in the metabolic activation and detoxification of various potential genotoxic compounds. The ‍functional polymorphism in these genes exhibit inter-individual variations in susceptibility towards various diseases ‍and difference in therapeutic response. The variant sequences of these genes differ considerably between ethnic ‍groups. Therefore, the objective of the study was to assess the prevalence of CYP2E1 & GSTP1 gene variants in ‍healthy volunteers of Tamilnadu, a population of South India. The genotype distribution of CYP2E1*1B A2A2, A2A1 ‍and A1A1 were 61%, 36% and 3% respectively. The distribution of CYP2E1*5B c1c1, c1c2 genotypes were 99.2%and ‍0.8%. CYP2E1*6 DD, DC and CC genotype frequencies were 72%, 25% and 3% respectively. The allele frequencies ‍of CYP2E1*1B, CYP2E1*5B and CYP2E1*6 were A2- 0.79 A1- 0.21, c1-0.996 c2 - 0.004 and D- 0.84 C- 0.16 respectively. ‍The genotypic distribution of GSTP1 (Ile/Val) were Ile/Ile - 44%, Ile/Val -47% and Val/Val- 9 % whereas, the allelic ‍frequencies were 0.67 for Ile and 0.33 for Val allele. The molecular studies in these enzymes provide basis for further ‍epidemiological investigations in the population where the functional mutations in the genes alter therapeutic response ‍and acts as susceptibility markers for various clinical conditions.     

Polymorphisms in the CYP1A1 gene are associated with prostate cancer risk

CYP1A1 is likely to play an important role in the etiology of CaP through its function in activating environmental procarcinogens and catalyzing the oxidative metabolites of estrogens. To test the hypothesis that genetic polymorphisms in the CYP1A1 gene may be associated with the risk for CaP, we compared the allele, genotype and haplotype frequencies of 3 SNPs (3801T>C, 2455A>G and 2453C>A) of CYP1A1 among 159 HPC probands, 245 sporadic CaP cases and 222 unaffected men. Two SNPs (3801T>C and 2455A>G) were each individually associated with CaP risk when the allele and genotype frequencies were compared between CaP patients and unaffected controls. Furthermore, a combined SNP analysis using a haplotype approach revealed an even stronger association in Caucasians. Specifically, 4 major haplotypes (T-A-C, C-A-C, C-G-C and T-A-A) accounted for 99.8% of all observed haplotypes. These 4 haplotypes correspond to the previously described nomenclature (CYP1A1*1A, CYP1A1*2A, CYP1A1*2B and CYP1A1*4). The frequencies of these 4 haplotypes were significantly different among CaP patients and controls. The haplotype T-A-C (CYP1A1*1A) was significantly associated with increased risk for CaP, and the haplotype C-A-C (CYP1A1*2A) was significantly associated with decreased risk for CaP. These findings suggest that genetic polymorphisms in CYP1A1 may modify the risk for CaP.     

Association of CYP3A5*3 and CYP1A1*2C Polymorphism with Development of Acute Myeloid Leukemia in Egyptian Patients

Aim: Cytochrome P450 (CYP) enzyme catalyzes the phase I metabolism reaction which metabolize endogenous and exogenous DNA-reactive chemical compounds and xenobiotics which could induce genotoxicity and increase the risk for leukemia. We aimed to detect frequency of CYP3A5*3 and CYP1A1*2C polymorphisms in Egyptian acute myeloid leukemia (AML) patients and to determine role of allele’s variants as a risk factor for developing leukemia. Patients and Methods: A case-control study was conducted on seventy acute myeloid leukemia patients and thirty control subjects. Samples were analyzed for prevalence of CYP3A5*3 and CYP1A1*2C polymorphisms using PCR - restriction fragment length polymorphism method. Results: CYP3A5*3 polymorphism (3/3) and (1/3) genotype were significantly elevated in AML group compared to control group (p=0.002). However, no statistical significant differences were found between patients and control group as regard CYP1A1*2C polymorphism. Conclusion: Our results suggest that Egyptians carrying CYP3A5*3 polymorphism might have an increased risk of AML emphasizing the significance of effective phase I detoxification in carcinogenesis.     

CYP1A1, CYP2E1 and GSTM1 genetic polymorphisms. The effect of single and combined genotypes on lung cancer susceptibility in Chilean people.

CYP1A1, CYP2E1 and GSTM1 polymorphisms were evaluated in Chilean healthy controls and lung cancer patients. In the Chilean healthy group, frequencies of CYP1A1 variant alleles for MspI (m2 or CYP1A1*2A) and ile/val (val or CYP1A1*2B) polymorphisms were 0.25 and 0.33, respectively. Frequencies of variant alleles C (CYP2E1*6) and c2 (CYP2E1*5B) for CYP2E1 were 0.21 and 0.16, respectively and frequency for GSTM1(-) was 0.24. The presence of variant alleles for GSTM1, MspI and Ile/val polymorphisms was more frequent in cases than in controls. However, frequencies for the c2 and C alleles were not significantly different in controls and in cases. The estimated relative risk for lung cancer associated to a single mutated allele in CYP1A1, CYP2E1 or GSTM1 was 2.41 for m2, 1.69 for val, 1.16 for C, 0.71 for c2 and 2.46 for GSTM1(-). The estimated relative risk was higher for individuals carrying combined CYP1A1 and GSTM1 mutated alleles (m2/val, OR=6.28; m2/GSTM1(-), OR=3.56) and lower in individuals carrying CYP1A1 and CYP2E1 mutated alleles (m2/C, OR=1.39; m2/c2, OR=2.00; val/C, OR=1.45; val/c2, OR=0.48; not significant). The OR values considering smoking were 4.37 for m2, 4.05 for val, 3.47 for GSTM1(-), 7.38 for m2/val and 3.68 for m2/GSTM1(-), higher values than those observed without any stratification by smoking. Taken together, these findings suggest that Chilean people carrying single or combined GSTM1 and CYP1A1 polymorphisms could be more susceptible to lung cancer induced by environmental pollutants such as polycyclic aromatic hydrocarbons.     

Analysis of CYP3A5*3 and CYP3A5*6 Gene Polymorphismsin Indian Chronic Myeloid Leukemia Patients

CYP3A5 is a member of the CYP3A gene family which metabolizes 50% of therapeutic drugs and steroidhormones. CYP3A5*3 and CYP3A5*6 polymorphisms exhibit inter-individual differences in CYP3A5 expression.The CYP3A5*3 allele (A6986G transition in intron 3) results in loss of CYP3A5 expression and the CYP3A5*6allele (G14690A transition in exon 2, leading to the skipping of exon 7) is associated with lower CYP3A5 catalyticactivity. The aim of the present study was to investigate their influence on susceptibility to chronic myeloidleukemia (CML). 265 CML cases and 241 age and sex matched healthy controls were analyzed by the PCR-RFLPtechnique. The frequencies of homozygous 3/3 genotype and CYP3A5*3 allele were elevated significantly in theCML group compared to controls (χ2=93.15, df=2, p=0.0001). With respect to clinical parameters, CYP3A5*3allele frequency was increased in patients with advanced phase of the disease (0.71) as compared to those inchronic phase (0.65). Patients without hematological response (minor/poor) had higher frequency of 3/3 genotype(54.54%) as compared to those with major hematological response (41.2%). CYP3A5*6 allele was not observed incases as well as in controls. Our study suggests that the CYP3A5*3 gene polymorphism is significantly associatedwith the risk of CML development and disease progression.     

Characteristic CYP2A6 genetic polymorphisms detected by TA cloning-based sequencing in Chinese digestive system cancer patients with S-1 based chemotherapy

S-1 is an oral antitumor agent that contains tegafur, which is converted to fluorouracil (5-FU) in the human body. Cytochrome P450 2A6 (CYP2A6) is the principal enzyme responsible for bioconversion of tegafur to 5-FU. A number of CYP2A6 polymorphisms have been associated with variations in enzyme activity in several ethnic populations. The CYP2A6*4C allele leads to deletion of the entire CYP2A6 gene, and is the main finding in patients with reduced CYP2A6 enzymatic activity. Thus, the aim of our study was to evaluate the allele frequencies of CYP2A6 polymorphisms in a population with cancer of the digestive system. We developed a simple screening method, which combined TA cloning and direct-sequencing, to detect CYP2A6 genetic polymorphisms in Chinese patients with cancers of the digestive system. A total of 77 patients with various types of digestive system cancers were screened for CYP2A6 genetic polymorphisms. The allele frequencies of CYP2A6*1A, CYP2A6*1B and CYP2A6*4C in the 77 patients screened were 62, 42 and 13%, respectively. Frequencies of the homozygous genotypes for CYP2A6*1A and CYP2A6*4C were 27 and 12%, respectively. As expected, patients that were determined to be homozygous for CYP2A6*4C exhibited the characteristic chemotherapy efficacy and toxicity profiles. The TA cloning-based direct sequencing method facilitated allele frequency and genotyping determination for CYP2A6*1A, 1B and 4C of cancer patients. The findings indicated that the population carries a high frequency of the CYP2A6*4C homozygous genotype. Thus, the reduced efficacy of standard chemotherapy dosage in Chinese cancer patients may be explained by the lack of CYP2A6-mediated S-1 bioconversion to 5-FU.     

Genetic Polymorphisms of CYP2E1 and GSTM1 in a Thai Population

Cytochrome P450 2E1 and GSTM1 play major roles in metabolic activation and detoxification of many carcinogensand polymorphisms in the encoding genes have been reported to be individually associated with increased susceptibilityto certain cancer. In the present study, we investigated the RsaI, PstI and DraI polymorphisms of the CYP2E1 geneand the null GSTM1 genotype in a Thai population. DNA samples from 485 individuals were analysed by polymerasechain reaction with restriction fragment length (PCR/RFLP). The frequency of RsaI and PstI predominanthomozygous alleles (c1/c1) was 73.2%, heterozygous allele (c1/c2) was 25.6% and rare homozygous allele (c2/c2)was 1.2%. For the DraI polymorphism, the frequency of the predominant allele (DD) was 59.6%, heterozygous (CD)was 40% and rare allele (CC) was 0.4%. The frequency of GSTM1 null genotype was 62.7%. The distribution andfrequencies of these alleles showed different pattern from those found in Caucasian and some other Asian populations.With the large population in this study, we believed that our results are reliable estimates of the frequencies of thepolymorphic CYP2E1 and GSTM1 alleles in Thai population and should provide a base for further epidemiologicalstudies on their links with cancer development.     

CYP3A4*1B polymorphism and cancer risk: A HuGE review and meta-analysis

CYP450 3A4 (CYP3A4), encoded by the CYP3A4 gene, is a major enzyme catalyzing the metabolism of both endogenous and exogenous agents that may play a role in the etiology of carcinogenesis. Several potentially functional polymorphisms of the CYP3A4 gene have been implicated in cancer risk, but individually published studies have shown inconclusive results. The aim of this Human Genome Epidemiology (HuGE) review and meta-analysis was to investigate the association between CYP3A4*1B (rs2740574 A?>?G) polymorphism and cancer risk. Eleven studies were included with a total of 3,810 cancer patients and 3,173 healthy controls. We found that the G allele and GG genotype of CYP3A4*1B polymorphism were associated with increased risk of cancers using the fixed effects model (allele model: odds ratio (OR)?=?1.24, 95 %CI: 1.09–1.42, P?=?0.001; recessive model: OR?=?1.77, 95 %CI: 1.30–2.41, P?<?0.001; homozygous model: OR?=?1.72, 95 %CI: 1.19–2.47, P?=?0.004). Subgroup analyses by cancer type showed that the G allele and G carrier (AG?+?GG) of CYP3A4*1B polymorphism had significant associations with increased risk of prostate cancer, but not with breast cancer, leukemia, or other cancers. With further subgroup analysis based on different ethnicities, the results indicated that the GG genotype of CYP3A4*1B polymorphism might increase the risk of cancer among African populations. However, similar associations were not observed among Caucasian and Asian populations. Results from the current meta-analysis indicate that the G allele and GG genotype of CYP3A4*1B polymorphism might be associated with increased cancer risk, especially for prostate cancer among African populations.     

CYP1B1 variants are associated with prostate cancer in non-Hispanic and Hispanic Caucasians

Cytochrome P450 1B1 (CYP1B1) is involved in the activation of many carcinogens and in the metabolism of steroid hormones. We compared allele, genotype and haplotype frequencies of six single-nucleotide polymorphisms (SNPs) within CYP1B1 among non-Hispanic Caucasians (496 cases and 498 controls) and Hispanic Caucasians (153 cases and 240 controls). In the Hispanic Caucasians, the GG genotype for rs1056836 decreased the risk for prostate cancer (PCa) when compared with the CC genotype [odds ratio (OR) = 0.31, P = 0.04, 95% confidence interval (CI) = 0.10-0.96]. Among non-Hispanic Caucasian men with more aggressive PCa, the prevalence of several SNPs (rs2567206, rs2551188, rs2617266, rs10012 and rs1056836) was significantly associated with the disease status. A common C-G-C-C-G-A haplotype for rs2567206-rs2551188-rs2617266-rs10012-rs1056836-rs1800440 showed an inverse association with PCa risk in Hispanic Caucasians (OR = 0.19, P = 0.04, 95% CI = 0.04-0.95) and with aggressive disease status (i.e. Gleason score >or=7) in non-Hispanic Caucasian cases (OR = 0.64, P = 0.008, 95% CI = 0.47-0.89). In the non-Hispanic Caucasian cases, a second major haplotype T-A-T-G-C-A was positively associated with the high-grade disease status (OR = 1.77, P = 0.002, 95% CI = 1.24-2.53). Our findings suggest that genetic polymorphisms in CYP1B1 may modify the risk for PCa and support the role of CYP1B1 as a candidate gene for PCa.     

Association of GSTM1, CYP1A1 and CYP2E1 genetic polymorphisms with susceptibility to lung adenocarcinoma: a case-control study in Chinese population

A case-control study of 164 lung adenocarcinoma (AC) patients with 181 age- and gender-matched healthy controls was conducted in order to assess any associations between glutathione- S -transferase M1 (GSTM1), cytochrome P4501A1 (CYP1A1) and cyto-chrome P4502E1 (CYP2E1) polymorphisms and susceptibility to lung AC in Chinese. The presence of CYP2E1 variant allele was significantly less frequent in cases than in controls, while the distribution of GSTM1 null genotype and variant CYP1A1 Msp 1 allele did not vary between cases and controls. After adjustment for age, gender, smoking and all other genotypes, the CYP2E1 Rsa1 variant allele was significantly associated with decreased risk of lung AC [odds ratio 0.534 (95% confidence interval, 0.340–0.837)]. Furthermore, 3.0-fold increased risk was found in individuals with combined GSTM1 null genotype and CYP2E1 Rsa 1 wild type versus those with combined GSTM1 non-null type and CYP2E1 variant allele. Our results suggest that CYP2E1 Rsa 1 variant allele is associated with a decreased risk of lung AC, and combined GSTM1 null genotype and CYP2E1 Rsa1 wild type has a promoting effect on susceptibility to lung AC. (Cancer Sci 2003; 94: 448–452)     

甘肃省人群CYP2E1基因多态性与急性白血病易感性的关系

目的 研究甘肃省人群CYP2E1基因多态性和急性白血病易感性的关系.方法 用1∶1配对病例-对照方法,LDR-PCR方法,对甘肃省人群中100例急性白血病患者和100例对照进行CYP2E1基因突变分析.结果 急性白血病组CYP2E1基因C2等位基因频率(13.5%)和CIC2+C2C2基因型频率(22%)均高于对照组(10.5%和19%),但其差异均无统计学意义.进一步分层分析,急性髓系白血病(AML)组C1C2/C2C2基因型频率(27%)高于对照组(19%),其差异无统计学意义.急性淋巴细胞白血病(ALL)组CYP2E1基因C2等位基因频率和C1C2/C2C2基因型频率均与对照组差异无统计学意义(x2=0.446,P=0.504>0.05).结论 甘肃省研究人群CYP2E1基因多态性与急性白血病(AML和ALL)遗传易感性无关.     

Polymorphism in CYP1A1 and CYP2E1 genes and susceptibility to leukoplakia in Indian tobacco users

Inter-individual genetic differences may contribute to differences in susceptibility to human diseases triggered by environmental exposures. In this study, we investigated polymorphisms at two sites in the CYP1A1 and three sites in the CYP2E1 genes in 99 leukoplakia patients and 227 controls from one Indian population. The frequencies of genotypes at these polymorphic sites (MspI and Ileu/Val) in the CYP1A1 and (PstI, RsaI and DraI) in the CYP2E1 genes, were similar in patient and control groups. But the combined rare and heterozygous genotypes (CC+CD) at the DraI site in the CYP2E1 gene were over-represented among patients compared with controls (age-adjusted odds ratio (OR)=2.02, 95% confidence interval (CI)=1.21-3.35). Light tobacco smokers (i.e. <21 pack-year) and light tobacco chewers (i.e. <104 chewing-year) with a "rare" C allele at the DraI site had high risk of leukoplakia (OR=2.88, 95% CI=1.16-7.22; OR=2.94, 95% CI=1.15-7.65, respectively). The "mixed tobacco" users with "rare" C allele are more susceptible to the disease than "exclusive" tobacco smokers and chewers. The results indicate that the "rare" C allele at the DraI polymorphic site in CYP2E1 gene may enhance susceptibility to leukoplakia among tobacco users in this population. But the low sample size limited the power to precisely estimate the tobacco-genotype interactions.     

CYP2D6 and CYP2E1 Gene Polymorphisms and their Association with Cervical Cancer Susceptibility: A Hospital Based Case-Control Study from South-Western Maharashtra

Background: In last few years several studies all over the world discovered the genetic polymorphisms in different cytochrome P450 genes associated with risk of various cancers, but contradictory outcomes were evidenced in case of cervical cancer risk.  In this case-control study we aimed to see whether the polymorphism of CYP2D6 or CYP2E1 genes may or may not be associated with cervical cancer risk in women of rural Maharashtra. Methods: In this case-control study, the association of CYP2D6 and CYP2E1 gene polymorphism with cervical cancer risk was studied by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The study was conducted with 350 clinically confirmed cervical cancer patients and 350 healthy women in a population of South-Western Maharashtra. The Odds ratio (OR) with 95% confidence interval and p-value were evaluated, where p ≤0.005 was considered as statistically significant. Results: After the analysis of SNP (rs389209) of CYP2D6 and SNPs (rs2031920, rs6413432, rs6413420) of CYP2E1, we noticed that variant allele A of CYP2E1*6 showed significant increase in cervical cancer cases (OR=4.81; 95% CI: 1.57- 14.77; p=0.005). The genotypic distribution of heterozygote G/A genotype of CYP2D6*4 showed negative association with cervical cancer development when age of cancer occurrence (OR=0.41; 95% CI: 0.27- 0.61; p<0.0001) and tobacco history (OR=0.35; 95% CI: 0.20- 0.59; p=0.0001) was considered. Conclusion: The findings from this study supported that rs6413432 SNP of CYP2E1*6 increased cervical cancer risk in the studied rural women population.     

Polymorphisms of GSTP1 and GSTT1, but not of CYP2A6, CYP2E1 or GSTM1, modify the risk for esophageal cancer in a western population

Esophageal cancer is among the most common and fatal tumors in the world. Eighty percent of esophageal tumors are esophageal squamous cell carcinoma (ESCC). Brazil is one of the high incidence areas in the West, where tobacco and alcohol consumption have been associated with ESCC. However, polymorphisms in xenobiotic metabolizing genes may also contribute to the risk. Therefore, in this study, we analyzed the risk of ESCC associated with tobacco and alcohol consumption and with polymorphisms of CYP2A6 (CYP2A6*2), CYP2E1 (CYP2E1*5B, CYP2E1*6), GSTP1 (Ile105Val), GSTM1 and GSTT1 null genotypes in 126 cases and 252 age- and gender-matched controls. Data on the amount, length and type of tobacco and alcohol consumed were collected, and DNA was extracted from blood lymphocytes from all individuals. Polymorphisms were analyzed by polymerase chain reaction (PCR)-multiplex (GSTM1 and T1), PCR-Restriction Fragment Length Polymorphism (CYP2E1*5B and *6 and GSTP1 Ile105Val) or allele-specific PCR amplification (CYP2A6*2). Risks were evaluated by multivariate conditional regression analysis. As expected, tobacco [odds ratio (OR) = 6.71, 95% confidence interval (95% CI) 3.08-14.63] and alcohol (OR = 16.98, CI 7.8-36.98) consumption, independently or together (OR = 26.91, CI 13.39-54.05) were risk factors. GSTP1 Ile105Val polymorphism was an independent risk factor (OR = 2.12, CI 1.37-3.29), whereas GSTT1 wild-type was an independent protective factor for ESCC (OR = 0.37, CI 0.16-0.79). There was approximately 80% statistical power to detect both results. There was no risk associated with CYP2A6, CYP2E1 and GSTM1 polymorphisms. In conclusion, this study suggests an opposite role of GSTP1 and GSTT1 polymorphisms for the risk for ESCC.     

Effects of the ADH3, CYP2E1, and GSTP1 genetic polymorphisms on their expressions in Caucasian lung tissue

Individual differences in lung cancer susceptibility should be considered for effective lung cancer prevention. We investigated the CYP2E1, ADH3, and GSTP1 genetic polymorphisms that biotransform xenobiotic carcinogens, and variations of their enzyme activity in Caucasian lung tissues (N=28), and found a variant distribution in pulmonary ADH and CYP2E1 activity. The ADH3*1/*1 subjects (N=8) showed significantly higher ADH activity than ADH3*2/*2 (N=3) subjects (P<0.01). On the other hand, we found a 5-fold variation in the pulmonary CYP2E1 activity using a sensitive HLPC/EC based technique. A subject with the CYP2E1-c/t allele showed 2-fold higher CYP2E1 activity than subjects with the c/c allele (N=14). GSTP1 expression comprised 83% of the total pulmonary GSTs. However, neither the GSTP1 polymorphism, nor other lifestyle factors, such as age, gender, smoking status, were found to be associated with pulmonary GST expression. In conclusion, subjects with the ADH3*1 allele showed higher ADH activity and acetaldehyde-DNA adducts in lung than other subjects; thus, the ADH3*1 allele could be considered a risk factor for lung cancer.     

Alcohol dehydrogenase 1B and Aldehyde dehydrogenase 2 Polymorphisms in Uzbekistan

The alcohol dehydrogenase 1B (ADH1B) *2 (47His) allele and the aldehyde dehydrogenase 2 (ALDH2) *2(487Lys) allele are seen among some Asian peoples, but rare among other ethnic groups. This study examinedthe allele frequencies in the Uzbekistan Republic, which is located in Central Asia. Subjects were derived froma case-control study on peptic ulcer disease, which included 161 Uzbeks and 23 Russians. They were enrolled atthe Republic Research Center of Emergency Medicine located in the capital, Tashkent City. Genotyping wasperformed for ADH1B Arg47His and ALDH2 Glu487Lys with a polymerase chain reaction with confrontingtwo-pair primers. The frequency for the ADH1B *2 allele was similar among cases and controls. The ALDH2 *2allele was rare in both. Among 161 Uzbeks, the ADH1B *2 allele frequency was 0.286 (95% confidence interval,0.237-0.338) and for the ALDH2 *2 allele was 0.016 (0.005-0.036), while among the 23 Russians the figures were0.083 (0.024-0.208) and 0.000 (0.000-0.077), respectively. There were no significant differences in drinking habitsamong individuals with different genotypes, although ALDH2 *2*2 genotype was not observed. The presentstudy demonstrated that ADH1B *2 allele frequency among Uzbeks was closer to that among Caucasians thanEast Asians, some Uzbeks also demonstrating the ALDH2 *2 allele.     

The role of CYP2D6*4 variant in bladder cancer susceptibility in Tunisian patients

CYP2D6 enzyme is implicated in the metabolism of drugs and nicotine. Genetic variability within CYP2D6, results in different CYP2D6 phenotypes. Inheritance of polymorphic CYP2D6 metabolizing enzyme is likely to be an important determinant of inter-individual variations in susceptibility to cancer. In this work, we have conducted a case control study in order to assess the role of CYP2D6*4 variant in bladder cancer development in a Tunisian cohort. A total of 80 patients with TCC of bladder cancer and 109 healthy controls were included in the present study. The frequency of CYP2D6*4 allele, characterized by loss of BstNI site, was observed in 8.25% of healthy volunteers and in 10.62% of patients. The CYP2D6*4/CYP2D6*4 genotype was observed in only 2.75% of controls and was absent in cases. In all group of patients, the CYP2D6*4 allele did not appear to influence bladder cancer susceptibility (p > 0.05). A similar result was obtained when we stratified cases group according to tobacco status. Conversely, patients carrying the BstNI site at the homozygous state, mostly combined as homozygous wild genotype, could be at more risk of bladder cancer invasiveness than those having the heterozygous genotype.     

Genetic polymorphisms of CYP2D6*10 and CYP2C19*2,*3 are not associated with prognosis,endometrial thickness,or bone mineral density in Japanese breast cancer patients treated with adjuvant tamoxifen

BACKGROUND:

The authors investigated the impact of the genetic polymorphisms cytochrome P450 (CYP) family 2, subfamily D, polypeptide 6, allele *10 (CYP2D6*10) and CYP family 2, subfamily C, polypeptide 19, allele *2,*3 (CYP2C19*2,*3) on disease recurrence in patients with breast cancer who received adjuvant tamoxifen and evaluated the impact of those polymorphisms on endometrial thickness, bone mineral density (BMD), and serum total cholesterol levels.

METHODS:

Patients with primary breast cancer (n=173) who had hormone receptor‐positive tumors and who also received adjuvant tamoxifen were included in the current study. Genetic polymorphisms of CYP2D6*10 and CYP2C19*2,*3 were analyzed.

RESULTS:

Recurrence‐free survival (RFS) rates did not differ significantly between patients with the CYP2D6 *10/*10 genotype (n=40) and patients with the CYP2D6 wild‐type (wt)/wt or wt/*10 genotype (n=133) or between patients with the CYP2C19 *2/*2, *2/*3, or *3/*3 genotypes (n=41) and patients with the CYP2C19 wt/wt, wt/*2, or wt/*3 genotype (n=132). Multivariate analysis indicated that, even after adjustment for well established prognostic factors, these CYP2D6 or CYP2C19 genotypes were not associated significantly with the RFS rate. Moreover, these genotypes did not affect endometrial thickness, BMD, or total cholesterol levels 1 year after the start of tamoxifen treatment.

CONCLUSIONS:

Neither the CYP2D6 *10/*10 genotype nor the CYP2C19 genotype is likely to have a clinically significant impact on prognosis, endometrial thickness, BMD, or total cholesterol levels in Japanese patients with breast cancer who are treated with adjuvant tamoxifen. Cancer 2009. © 2009 American Cancer Society.