A comprehensive analysis of phase I and phase II metabolism gene polymorphisms and risk of non-small cell lung cancer in smokers

Lung cancer is a leading cause of cancer mortality worldwide with smoking and occupational exposure to carcinogenic compounds as the major risk factors. Susceptibility to lung cancer is affected by existence of polymorphic genes controlling the levels of metabolic activation and detoxification of carcinogens. We have investigated 105 single nucleotide polymorphisms (SNPs) in 31 genes from the phase I and phase II metabolism genes and antioxidant defense genes for association with the risk of non-small cell lung cancer (NSCLC) in a Norwegian population-based study. Our results indicate that several SNPs in the phase I genes, CYP1B1, CYP2D6, CYP2E1 and CYP3A4, are associated with the risk of NSCLC. Moreover, significant associations with multiple SNPs in the phase II genes ALDH2, COMT, EPHX1, SOD2, NAT1, NAT2, GSTM3, GSTP1, GSTT2 and MPO were also found. We prioritized our findings by use of two different recently developed Bayesian statistical tools, employing conservative prior probabilities of association. When we corrected for multiple testing using these statistical tools, three novel associations of NSCLC risk with SNPs in the CYP1B1 (Arg48Gly), COMT (Val158Met) and GSTT2 (Met139Ile) genes were found noteworthy. However, only four of the previously reported associations with polymorphisms in the GSTP1 (Ala14Val), SOD2 (Val16Ala), EPHX1 (His139Arg) genes and the NAT1 fast acetylator phenotype remained significantly associated with lung cancer.     

Esophageal Cancer Risk by ALDH2 and ADH2 polymorphisms and Alcohol Consumption: Exploration of Gene-Environment and Gene-Gene Interactions

Alcohol drinking is a major risk factor for esophageal cancer in Japan and its impact may be modulated by levels ‍of ALDH2, ADH2 and CYP2E1, three representative alcohol-metabolizing enzymes which display genetic ‍polymorphisms altering individual alcohol-oxidizing capacity and drinking behavior. To assess the actual influence ‍of ADH2 Arg47His, ALDH2 Glu487Lys and CYP2E1 variant c2 allele polymorphisms on esophageal cancer risk ‍with conjunction with alcoholic consumption, the present 1:3 matched case-control study was conducted. The 165 ‍histologically diagnosed Japanese esophageal cancer cases were here compared with 495 randomly selected controls, ‍matched with respect to sex and age. Conditional logistic regression was used to calculated Odds Ratios (ORs) and ‍95% confidence intervals (95% CI). Significant gene-environment interactions between alcohol drinking and both ‍ADH2 and ALDH2 were observed regarding esophageal cancer risk. The ADH2 Arg47His polymorphism showed ‍moderately increased risk (OR for Arg/His and Arg/Arg relative to His/His: 2.01 (1.39-2.90)). In the ALDH2 case, ‍comparing the Glu/Lys with the Glu/Glu genotype, ORs were markedly increased to 9.64 (3.23-28.8) and 95.4 (28.7- ‍317) from 1.88 (0.42-8.37) and 4.62 (0.93-23.1) for moderate drinking and heavy drinking, respectively. No significant ‍alteration in risk was observed with the CYP2E1 polymorphism. In conclusion, the present study revealed a significant ‍gene-environment interaction between alcohol drinking and the ALDH2 polymorphism regarding esophageal cancer ‍risk among a general population in Japan, providing concrete evidence of a role for acetaldehyde in neoplastic ‍development. Interactions between ALDH2 and ADH2 need further clarification.‍ ‍     

Ovarian cancer risk and polymorphisms involved in estrogen catabolism.

Polymorphisms within genes responsible for estrogen catabolism could alter cellular levels of genotoxic 4-hydroxylated catechol estrogens and antiangiogenic 2-methoxyestradiol, thus influencing risk of developing ovarian cancer. We carried out a population-based case-control study of 310 epithelial ovarian cancer cases and 585 controls in African-American and Caucasian women ages 35 to 54 years from Seattle, Atlanta, and Detroit metropolitan areas. Subjects were interviewed and genotyped for CYP1A1 m1, m2, m3, and m4; CYP1B1 Arg(48)Gly, Ala(119)Ser, Val(432)Leu, and Asn(453)Ser; COMT Val(158)Met; UGT1A1 A(TA)nTAA; and SULT1A1 Arg(213)His polymorphisms. Unconditional logistic regression was used to calculate odds ratios (OR). Haplotypes were inferred and analyzed using models based on expectation-maximization with progressive ligation and Bayesian coalescence theory. CYP1B1 Leu(432) carriers were at increased risk of ovarian cancer, with an adjusted OR of 1.5 (95% confidence interval, 1.1-2.3) compared with Val(432) homozygotes. The most common CYP1B1 haplotype was Arg(48)-Ala(119)-Val(432)-Asn(453). All other haplotypes with frequencies >5% contained the Leu(432) allele. In diplotype analyses, relative to women homozygous for Arg(48)-Ala(119)-Val(432)-Asn(453), women with diplotypes containing at least one Leu(432) allele had adjusted ORs ranging from 1.3 to 2.2. Among women homozygous for COMT Met(158), carriers of CYP1B1 Leu(432) had a 2.6-fold increase in risk relative to CYP1B1 Val(432) homozygotes (95% confidence interval, 1.1-5.9). This latter result is opposite in direction from a similar analysis conducted by other investigators in a different study population. No association of ovarian cancer risk was observed with any of the other polymorphisms examined, either alone or in combination.     

Interactions between genetic polymorphism of cytochrome P450-1B1, sulfotransferase 1A1, catechol-o-methyltransferase and tobacco exposure in breast cancer risk

Genetic polymorphisms of enzymes involved in the metabolism of xenobiotics and estrogens might play a role in breast carcinogenesis related to environmental exposures. In a case-only study on 282 women with breast cancer, we studied the interaction effects (ORi) between smoking habits and the gene polymorphisms of Cytochrome P450 1B1 (Val432Leu CYP1B1), Phenol-sulfotransferase 1A1 (Arg213His SULT1A1) and Catechol-O-methyltransferase (Val158Met COMT). The smokers carrying the Val CYP1B1 allele associated with a high hydroxylation activity had a higher risk of breast cancer than never smokers with the Leu/Leu genotype (ORi=2.32, 95%CI: 1.00-5.38). Also, the smokers carrying the His SULT1A1 allele associated with a low sulfation activity had a 2-fold excess risk compared to never smokers carrying Arg/Arg SULT1A1 common genotype (ORi= 2.55, 95%CI: 1.21-5.36). The His SULT1A1 allele increased the risk only in premenopausal patients. The Met COMT allele with a lower methylation activity than Val COMT did not modify the risk among smokers. The excess risk due to joint effect could result from a higher exposure to activated tobacco-compounds for women homo/heterozygous for the Val CYP1B1 allele. Also, a lower sulfation of the tobacco carcinogens among women with His SULT1A1 could increase exposure to genotoxic compounds. Alternatively, the Val CYP1B1 or His SULT1A1 allele with modified ability to metabolize estrogens could increase the level of genotoxic catechol estrogen (i.e., 4-hydroxy-estradiol) among smokers. Our study showed that gene polymorphisms of CYP1B1 and SULT1A1 induce an individual susceptibility to breast cancer among current smokers.     

Cytochrome P450 1B1 and catechol-O-methyltransferase polymorphisms and endometrial cancer susceptibility

Estrogen production and metabolism play critical roles in the development and pathogenesis of endometrial carcinoma. Cytochrome P450 1B1 (CYP1B1) and catechol-O-methyltransferase (COMT) are two key enzymes in the estrogen metabolism pathway that result in the hydroxylation and conjugation of estradiol, respectively. We evaluated the association between the CYP1B1 Leu432Val and CYP1B1 Asn453Ser polymorphisms and the COMT Val158Met polymorphism and invasive endometrial cancer risk in a case-control study nested within the Nurses' Health Study (n = 222 cases, 666 controls). We also evaluated whether body mass index (BMI), postmenopausal hormone (PMH) use and cigarette smoking modified the associations of the CYP1B1 and COMT genotypes and endometrial cancer risk. Conditional logistic regression was used to calculate the adjusted odds ratios (OR) and 95% confidence intervals (CI) to quantify the risk of endometrial cancer among subjects who had at least one variant allele compared with subjects who were homozygous for the wild-type allele. Carriers of the CYP1B1 Ser allele had a statistically significant decreased risk of endometrial cancer (OR = 0.62; 95% CI, 0.42-0.91); there was no significant association between the CYP1B1 Val allele and endometrial cancer risk (OR = 1.10; 95% CI, 0.75-1.59). Compared with the COMT Val/Val wildtype genotype, the adjusted OR of endometrial cancer for women with the COMT Val/Met or COMT Met/Met genotype was 0.96 (95% CI, 0.65-1.43). We did not observe any effect modification by BMI, PMH use and cigarette smoking for the CYP1B1 and COMT genotypes. Our data suggest, that the CYP1B1 Ser allele may decrease endometrial cancer risk by altering the production of catechol estrogens. However, further studies are warranted to elucidate the role of CYP1B1 in endometrial cancer.     

雌激素代谢基因COMT和CYP17单核苷酸多态与女性乳腺癌风险的关系

目的：研究参与雌激素合成的细胞色素P450c17(CYP17)和雌激素代谢解毒的儿茶酚-O-甲基转移酶(COMT)基因多态与乳腺癌发生的关系。方法：以聚合酶链反应和限制性片段长度多态方法,对250例乳腺癌患者和250例正常对照者的COMT基因第4外显子第158位密码子G／A(Val／Met)多态和CYP17基因启动子区-1931T／C多态进行分析。以logistic回归模型计算各种基因型的乳腺癌风险(DR)及其95％可信区限(95％CI)。结果：乳腺癌患者的COMT Met／Met基因型频率为10．4％,显著高于对照组的5．2％(P=0．03)。多因素分析显示,COMT Met／Met基因型患乳腺癌的风险比Val／Val或Val／Met基因型高2．1倍(95％a为1．1～4．5)。分层分析显示,COMT Met／Met基因型主要增加绝经前女性患乳腺癌的风险(OR4．1,95％CI为1．2～17.3),而不增加绝经后女性患乳腺癌的风险(OR 1．3,95％CI为0．5～3．5),提示该基因多态对乳腺癌风险的影响与雌激素水平有关。CYP17基因型频率在病例和对照组中的分布差异无显著性(P=O．83)。结论：COMT基因单核苷酸多态与乳腺癌易感性相关,Met／Met基因型增加乳腺癌风险,而CYP17基因多态与中国女性乳腺癌风险无相关性。     

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.     

Polymorphisms in estrogen bioactivation, detoxification and oxidative DNA base excision repair genes and prostate cancer risk

To date, the potential impact of hormones on prostate cancer has predominantly focused on receptor-mediated events. However, catechol estrogens, if not inactivated by catechol-O-methyltransferase (COMT), can generate large quantities of reactive oxygen species (ROS). ROS may cause a spectrum of damage including oxidative DNA base lesions, which can lead to irreversible mutation(s) if they are not repaired by base excision repair (BER) systems. hOGG1 is a key enzyme in short patch BER because it recognizes and performs initial excision of the most common form of oxidative DNA base damage, 8-hydroxyguanine (8-oxo-dG). To investigate potential non-receptor-mediated estrogen effects, we evaluated the association between COMT Val158Met and hOGG1 Ser326Cys polymorphisms and prostate cancer in a family-based case-control study (439 prostate cancer cases, 479 brother controls). We observed no noteworthy associations between these polymorphisms and prostate cancer risk in the total study population. However, among men with more aggressive prostate cancer, the hOGG1 326 Cys/Cys genotype was inversely associated with disease (OR=0.30; 95% CI=0.09-0.98). Combining the lower activity CYP1B1 432 Leu/Leu or Leu/Val genotypes (which may decrease the level of catechol estrogens and ROS generated) with the hOGG1 326 Cys/Cys genotype and the XRCC1 399 Arg/Arg or Arg/Gln genotypes (which may enhance BER) resulted in an even further reduced risk in Caucasians with more aggressive disease (OR=0.09; 95% CI=0.01-0.56). Including the high-activity COMT 158Val allele to this combination also lowered aggressive prostate cancer risk but the effect was not as strong (OR=0.20; 95% CI=0.05-0.88). The decreased risk we observed with the hOGG1 326 Cys/Cys genotype confirms an earlier report and the further reduced risk found with the CYP1B1 (432 Leu/Leu or Leu/Val)-hOGG1 (326 Cys/Cys)-XRCC1 (Arg/Arg or Arg/Gln) genotype combination may lend new insights to the importance of ROS generated from non-receptor-mediated estrogenic mechanisms in more aggressive prostate cancer.     

An investigation of mammographic density and gene variants in healthy women

This cross-sectional study examined if polymorphisms in genes that code for enzymes involved in the production and metabolism of estrogens are associated with mammographic density, a strong predictor of breast cancer risk. The study included 328 healthy women of different ethnicities who underwent mammographic screening and donated a blood or mouthwash sample for DNA analysis. After digitizing cranio-caudal views of the mammograms, we performed computer-assisted mammographic density assessment. Following DNA extraction, samples were analyzed for polymorphisms in the COMT (Val158Met), CYP1A1 (Ile462Val), CYP1B1 (Val432Leu), CYP1A2 (*1F) and CYP17 (T27C) genes using PCR-RFLP. Breast density was lower in Caucasians than in Asians. Caucasian women were less likely to carry the CYP1A1 variant allele and more likely to carry the variant alleles for CYP1B1 and COMT than women with Asian or Hawaiian ancestry. The low-activity COMT and CYP1A2 variant alleles were weakly related to lower percent mammographic density after adjustment for age, ethnicity, body mass index and reproductive variables (p for gene-dosage =0.08 and 0.05, respectively). These relations were observed in premenopausal women only and were similar in direction and magnitude after stratification by ethnicity. We found no significant associations between breast density and the variant alleles for CYP1A1, CYP1B1 and CYP17. Our data suggest lower mammographic density for women carrying the COMT and CYP1A2 variant alleles than for women carrying the common alleles, though this is the opposite of what is commonly hypothesized from the enzyme function.     

Case-control study of ovarian cancer and polymorphisms in genes involved in catecholestrogen formation and metabolism.

Steroid hormones, such as estrogens, appear to be associated with ovarian carcinogenesis, but the precise biological mechanisms are unclear. Polymorphisms in genes that regulate the concentration of estrogens and their metabolites may contribute directly to the individual variation in ovarian cancer risk through a mechanism involving oxidative stress or indirectly by influencing ovarian cancer susceptibility associated with ovulation and reproduction. We conducted a population-based, case-control study of primary ovarian cancer between 1993 and 1999 in Hawaii to test several genetic and related hypotheses. A personal interview and blood specimen were obtained in the subjects' homes. In a sample of 129 epithelial ovarian cancer cases and 144 controls, we compared the frequencies of several polymorphisms in genes that regulate steroid hormone metabolism and catecholestrogen formation. Multivariate unconditional logistic regression was used to model the association of each genetic polymorphism separately after adjusting for age, ethnicity, and other covariates. The high-activity Val432 allele of the CYP1B1 gene, which may be linked to oxidative stress through elevated 4-hydroxylated catecholestrogen formation, was associated with an increased risk of ovarian cancer. The Val/Leu genotype for CYP1B1 was associated with an odds ratio of 1.8 (95% confidence interval, 1.0-3.3) and the Val/Val genotype with an odds ratio of 3.8 (95% confidence interval, 1.2-11.4) compared with the Leu/Leu genotype (P = 0.005). Tobacco smokers with at least one CYP1A1 (MspI) m2 allele, one CYP1B1 Val allele, one COMT Met allele, or two CYP1A2 A alleles were at significantly increased risk of ovarian cancer compared to never-smokers with CYP1A1 (MspI) ml/ml, CYP1B1 Leu/Leu, COMT Val/Val, or CYP1A2 A/A genotypes, respectively. We found a positive statistical interaction (P = 0.03) between tobacco smoking and the CYP1A1 (MspI) polymorphism on the risk of ovarian cancer. None of the other gene-environment (pregnancy, oral contraceptive pill use) or gene-gene interactions were statistically significant. Although not significant, there was a suggestion that the effect of the CYP1B1 Val allele was reduced substantially in the presence of the high-activity COMT Met allele. These findings suggest that the CYP1B1-Val allele and perhaps other genetic polymorphisms in combination with environmental or hormonal exposures are susceptibility factors for ovarian cancer.     

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.     

Association of CYP17, CYP19, CYP1B1, and COMT polymorphisms with serum and urinary sex hormone concentrations in postmenopausal women.

Women with high circulating estrogen concentrations have an increased risk of breast cancer; thus, it is important to understand factors, including genetic variability, that influence estrogen concentrations. Several genetic polymorphisms that may influence sex hormone concentrations have been identified, including CYP17 (5'-untranslated region T-->C), CYP19 [intron 4 (TTTA)(n = 7-13) and a 3-bp deletion (-3)], CYP1B1 (Val(432)Leu), and COMT (Val(108/158)Met). We examined associations between these polymorphisms and serum concentrations of estrogens, androgens, and sex hormone-binding globulin and urinary concentrations of 2- and 16alpha-hydroxyestrone in 171 postmenopausal women, using data from the prerandomization visit of an exercise clinical trial. Participants were sedentary, not taking hormone therapy, and had a body mass index >24.0. Compared with noncarriers, women carrying two CYP19 7r(-3) alleles had 26% lower estrone (P < 0.001), 19% lower estradiol (P = 0.01), 23% lower free estradiol (P = 0.01), and 22% higher sex hormone-binding globulin concentrations (P = 0.06). Compared with noncarriers, women carrying at least one CYP19 8r allele had 20% higher estrone (P = 0.003), 18% higher estradiol (P = 0.02), and 21% higher free estradiol concentrations (P = 0.01). Women with the COMT Met/Met genotype had 28% higher 2-hydroxyestrone (P = 0.08) and 31% higher 16alpha-hydroxyestrone concentrations (P = 0.02), compared with Val/Val women. Few associations were found for CYP17 and CYP1B1 or with serum androgen concentrations. This study provides further evidence that genetic variation may appreciably alter sex hormone concentrations in postmenopausal women not taking hormone therapy.     

Breast cancer risk and polymorphisms in genes involved in metabolism of estrogens (CYP17, HSD17beta1, COMT and MnSOD): possible protective role of MnSOD gene polymorphism Val/Ala and Ala/Ala in women that never breast fed

Polymorphisms in genes encoding enzymes involved in estrogen metabolism are held to be candidates for associations with breast disease, since there is evidence that circulating estrogens are associated with breast cancer risk. In this study, we evaluated the frequency of different polymorphisms related with estrogen metabolism [COMT Val158Met, CYP17 (5'UTR, T27C); HSD17beta1 Gly313Ser and MnSOD Val16Ala] in a breast cancer resistant population, the Xavante Indians, and the frequencies were compared with the ones reported in other populations where breast cancer case-control studies dealing with these polymorphisms have been carried out. The data obtained showed that, apart from the MnSOD Val16Ala polymorphism where the frequency of the variant allele was much higher than that reported in other populations, all the others were within the range reported in other populations. Considering these data we carried out a case-control study in the Portuguese population (241 cases and 457 controls) in order to evaluate the potential role of this polymorphism in breast cancer susceptibility. The results obtained did not reveal a significant association between individual genotypes and breast cancer risk. However, when the population was stratified for breast feeding, it was observed that for the patients that never breast fed the presence of the variant allele (Ala) was marginally associated with a decreased risk for this pathology (adjusted OR: 0.575 (0.327-1.011). These data seem to suggest that individuals who never breast fed with MnSOD Val16Ala variant allele are at a lower risk for breast cancer, but larger studies are required to confirm these results.     

Multiplex PCR with Confronting Two-pair Primers for CYP1A1 Ile462Val,GSTM1, GSTT1, and NQO1 C609T

Polymerase chain reaction with confronting two-pair primers (PCR-CTPP) is an effective genotyping method ‍for single nucleotide polymorphisms (SNPs) in aspects of reducing time and costs for analysis. So far we have ‍established PCR-CTPP conditions for tens of SNPs, including a triplex genotyping (Kawase et al., 2003). In the ‍present study we report a quadruplex PCR-CTPP to genotype simultaneously four functional polymorphisms of ‍carcinogen-metabolizing enzymes, CYP1A1 Ile462Val, GSTM1 null, GSTT1 null and NQO1 C609T, which were ‍reported that they have significant associations with smoking-related cancers. We applied this method for 475 health ‍check-up examinees to demonstrate the performance. Among the subjects, the genotype frequency of CYP1A1 ‍Ile462Val was 56.8% for Ile/Ile, 38.1% for Ile/Val and 5.1% for Val/Val. The null type frequencies of GSTM1 and ‍GSTT1 were 52.8% and 49.9%, respectively. And the genotype frequency of NQO1 C609T was 41.9% for C/C, ‍41.3% for C/T and 16.8% for T/T. Their distributions were similar to those reported for Japanese by other studies. ‍To the best of our awareness, this is the first paper that reports the success in quadruplex PCR-CTPP. The applied ‍polymorphisms are useful ones, which would be adopted not only for research purposes, but also for risk assessment ‍of individuals exposed to carcinogenic substances. This convenient genotyping would be applied for cancer prevention ‍especially in Asian Pacific regions, where expensive genotyping methods are hardly available.     

中国人群COMT Val158Met基因多态性与乳腺癌易感性Meta分析

目的：系统评价中国人群儿荼酚氧位甲基转移酶（catechol-O-methyltransferase,COMT）Vall58Met基因多态性与乳腺癌易感性的关系。方法：在PubMed、MEDLINE、webofScience、Embase、中国期刊全文数据库（CJFD）及万方数据库中检索1999-10-01-2012-01-01发表的所有有关中国人群COMTVall58Met基因多态性与乳腺癌易感性关系的相关文献,并按STREGA原则对文献进行筛选、评价。纳入文献均为病例对照研究,对照群体基因型分布均符合H-W遗传平衡定律。应用Stata 12．0软件进行Meta分析,计算合并0R值及95％CI,并进行敏感性分析和发表偏倚的估计。结果：按照入选标准,有11项病例对照研究纳入,包括乳腺癌患者3184例,健康对照4065例。Meta分析结果显示,与基因型Val／Val（GG）、Val／Met（GA）比较,基因型Met／Met（AA）均增加中国人群罹患乳腺癌的风险[OR=1．55,95％CI：1.03～2．33,P=0．035;OR-1．63,95％CI：1．10～2．42,P=0．015];在隐性效应模型（Met／Met／vs Val／Val＋Val／Met）中,基因型Met／Met（AA）增加中国人群罹患乳腺癌的风险,0R-1．59,95％CI：1．07～2．36,P=0．021。与等位基因Val（G）比较,等位基因Met（A）不增加中国人群罹患乳腺癌的风险,OR=1．12,95％CI：0．96～1．32,P=0．157。结论：COMTVall58Met基因多态性与中国人群乳腺癌易感性相关,基因型Met／Met（AA）增加中国人群罹患乳腺癌的风险。     

Influence of polymorphism in DNA repair and defence genes on p53 mutations in bladder tumours

We studied the effects of polymorphisms in nine genes involved in DNA repair and detoxification on occurrence and type of p53 mutation in 327 bladder cancer patients. The included polymorphisms are XPC(Lys939Gln), XPD(Lys751Gln), XPG(Asp1104His), XRCC1(Arg3999Gln), XRCC3(Thr241Met), NBS1(Glu185Gln), cyclin D1(Pro241Pro), MTHFR(Ala222Val and Glu429Ala) and NQO1(Arg139Trp and Pro187Ser). We found increased risk for p53 mutation among cyclin D1 variant allele homozygotes (OR 2.4 CI 0.8-6.7). Among non-smokers, 75% (3/4) with p53 mutation but only 12.5% (3/24) without p53 mutations were XRCC3 241Met homozygotes (P=0.03). Among smokers, all p53 transversions (3/3), but only 41.7% (5/12) of p53 transitions were found among carriers of the XPC 939Gln allele. Individuals carrying the NQO1 187Ser allele showed increased risk for p53 transversions (OR 4.7, CI 0.9-26.1). All (2/2) NQO1 139Trp allele carriers but only 17.5% (7/40) of the Arg139 homozygotes had p53 transversions. Our findings suggest that altered repair and detoxification due to genetic polymorphism may influence the occurrence of p53 mutations in bladder cancer.     

Cytochrome P450 1B1 and catechol-O-methyltransferase genetic polymorphisms and breast cancer risk in Chinese women: results from the shanghai breast cancer study and a meta-analysis.

Cytochrome P450 1B1 (CYP1B1) and catechol-O-methyltransferase (COMT) are important estrogen-metabolizing enzymes and, thus, genetic polymorphisms of these enzymes may affect breast cancer risk. A population-based case-control study was conducted to assess the association of breast cancer risk with CYP1B1 and COMT polymorphisms. A meta-analysis was done to summarize the findings from this and previous studies. Included in this study were 1,135 incident breast cancer cases diagnosed from August 1996 through March 1998 among female residents of Shanghai and 1,235 randomly selected, age frequency-matched controls from the same general population. The common alleles of the CYP1B1 gene were Arg (79.97%) in codon 48, Ala (80.53%) in codon 119, and Leu (86.57%) in codon 432. The Val allele accounted for 72.46% of the total alleles identified in codon 108/158 of the COMT gene. No overall associations of breast cancer risk were found with any of the single nucleotide polymorphisms described above. This finding was supported by a meta-analysis of all previous published studies. No gene-gene interactions were observed between CYP1B1 and COMT genotypes. The associations of breast cancer risk with factors related to endogenous estrogen exposure, such as years of menstruation and body mass index, were not significantly modified by the CYP1B1 and COMT genotypes. We observed, however, that women who carried one copy of the variant allele in CYP1B1 codons 48 or 119 were less likely to have estrogen receptor-positive breast cancer than those who carried two copies of the corresponding wild-type alleles. The results from this study were consistent with those from most previous studies, indicating no major associations of breast cancer risk with CYP1B1 and COMT polymorphisms.     

Genetic susceptibility of catechol-O-methyltransferase polymorphism in Japanese patients with breast cancer

Polymorphic catechol-O-methyltransferase (COMT) catalyzes the O-methylation of catechol estrogens. It has been reported that COMT polymorphism is a representative genetic trait related to the susceptibility of an individual to breast cancer. However, there is no consensus concerning the association between breast cancer in Japanese patients and COMT polymorphism. To analyze the polymorphism distribution in Japanese patients with breast cancer, a molecular genotyping method using a polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) was used. Based on an analysis of 201 Japanese patients with breast cancer and 352 healthy control subjects, a significant difference was observed in either the distribution of genotypes (p=0.03) or allele frequencies between the two groups (p=0.01). The relative risk of breast cancer for genotypes (COMT(Met/Met) and COMT(Val/Met)) including the variant allele (COMT(Met)) was 1.47 compared to the wild allele (COMT(Val)) and homozygote (COMT(Val/Val)). Furthermore, the distribution of genotypes in post-menopausal patients with breast cancer showed a significant difference with that of healthy subjects of the same menopausal status (p=0.01). No significant difference was found between the distribution of genotypes and clinicopathological features of the cancer. These results suggest that COMT polymorphism may thus be implicated as a genetic trait affecting the susceptibility of an individual to breast cancer in a Japanese population and be an important genetic risk factor in the development of breast cancer in post-menopausal women.     

DNA Repair Gene Polymorphisms at XRCC1, XRCC3, XPD,and OGG1 Loci in the Hyderabad Population of India

Background: DNA repair is one of the crucial defense mechanism against mutagenic exposure. Inherited SNPs of DNA repair genes may contribute to variation in DNA repair capacity and susceptibility to cancer. Due to thepresence of these variants, inter-individual and ethnic differences in DNA repair capacity have been established in various populations. India harbors enormous genetic and cultural diversity. Materials and Methods: In the present study we aimed to determine the genotypes and allele frequencies of XRCC1 Arg399Gln (rs25487), XRCC3 Thr241Met (rs861539), XPD Lys751Gln (rs13181), and OGG1 Ser326Cys (rs1052133) gene polymorphisms in 186 healthy individuals residing in the Hyderabad region of India and to compare them with HapMap and otherpopulations. Results and Conclusions: The genotype and allele frequency distribution at the four DNA repairgene loci among Hyderabad population of India revealed a characteristic pattern. Comparison of these genepolymorphisms with other populations revealed a distinctiveness of Hyderabad population from the Deccanregion of India. To the best of our knowledge, this is the first report of such DNA repair gene polymorphisms inthe Deccan Indian population.