Alcohol drinking and one-carbon metabolism-related gene polymorphisms on pancreatic cancer risk

Effect of alcohol consumption on pancreatic cancer risk has been investigated in many studies, but results have been inconsistent. We conducted a case-control study to assess the effect of alcohol on pancreatic cancer in conjunction with polymorphisms in one-carbon metabolism enzymes, methylenetetrahydrofolate reductase (MTHFR C677T), methionine synthase (MTR A2756G), methionine synthase reductase (MTRR A66G), and thymidylate synthase (TS) variable number of tandem repeat. A total of 157 pancreatic cancer patients and 785 age- and sex- matched control subjects were genotyped for polymorphisms. Odds ratios (OR) with 95% confidence intervals (95% CI) were estimated using unconditional logistic models adjusted for potential confounders. Heavy alcohol drinking was marginally associated with an increased risk of pancreatic cancer (OR, 1.90; 95% CI, 1.00-3.62). None of the polymorphisms showed any significant effect on pancreatic cancer risk by genotype alone. In stratified analysis, effect of alcohol consumption on pancreatic cancer was observed in individuals with the MTHFR 667 CC, MTR 2756 AA, or MTRR 66 G allele. OR (95% CI) of pancreatic cancer for heavy drinkers compared with never drinkers was 4.50 (1.44-14.05) in the MTHFR 667 CC genotype, 2.65 (1.17-6.00) in the MTR 2756 AA genotype, and 3.35 (1.34-8.36) in the MTRR 66 G allele carriers. These results suggest that the folate-related enzyme polymorphism modifies the association between drinking habit and pancreatic cancer risk.     

One-carbon metabolism-related gene polymorphisms and risk of breast cancer

Environmental exposures and/or genetic background in Japanese population, which might contribute to the relatively low breast cancer incidence rates in Japan, have not been clarified in detail. Folate plays an essential role in DNA methylation and synthesis, and thus may be involved in the development of breast cancer. Functional polymorphisms in genes encoding one-carbon metabolism enzymes, methylenetetrahydrofolate reductase (MTHFR C677T), methionine synthase (MTR A2756G), methionine synthase reductase (MTRR A66G) and thymidylate synthase (TS), influence folate metabolism, but epidemiological studies have yielded inconsistent findings. We therefore conducted a case-control study to clarify their associations with breast cancer risk. A total of 456 breast cancer cases and 912 age-matched and menopausal status-matched non-cancer controls were genotyped for the polymorphisms. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using conditional logistic models adjusted for potential confounders and gene-environment interactions between the polymorphisms and folate consumption were also evaluated. We observed an increased risk of postmenopausal breast cancer with the MTHFR 677TT genotype (OR = 1.83, 95% CI: 1.08-3.11) with a menopausal status-based analysis. In combination analysis, a significantly elevated OR was found among postmenopausal women with the MTHFR 677TT genotype and lower intake of dietary folate compared with those with 677CC genotype and adequate folate consumption (OR = 2.80, 95% CI: 1.11-7.07). In addition, interaction between the MTRR A66G polymorphism and folate intake for risk of postmenopausal breast cancer was observed (interaction P = 0.008). Our findings indicated that the MTHFR and MTRR polymorphisms were associated with individual susceptibility to breast cancer among postmenopausal women.     

Association of polymorphisms in one-carbon metabolizing genes and lung cancer risk: a case-control study in Chinese population

One-carbon metabolism facilitates the cross-talk between genetic and epigenetic processes, making it a good candidate for studying the risk of lung cancer. To investigate the role of common variants of one-carbon metabolizing genes on lung cancer risk, total 25 single nucleotide polymorphisms (SNPs) in 7 genes were genotyped among 500 incident lung cancer patients and 517 cancer-free controls. An increased risk was suggested for the variant allele carriers of MTHFR rs17037396 [odds ratio (OR)=1.39, 95% confidence interval (CI): 1.00-1.94] and rs3753584 (OR=1.46, 95% CI: 1.03-2.08), compared with subjects with wild homozygote, respectively, and the risk was more pronounced among older individuals (>60 years). In contrast, a decreased risk was observed for TYMS rs2853742 variant allele carriers (OR=0.44, 95% CI: 0.19-0.99) and MTHFD rs2236225 variant allele carriers (OR=0.76, 95% CI: 0.59-0.99). Haplotype analysis revealed that MTHFR "ACCACC" haplotype may contribute to the risk of lung cancer (OR=1.49, 95% CI: 1.03-2.14, local test p value 0.032). A data mining method, multifactor dimensionality reduction (MDR), predicted a four-factor interaction model (rs1801133, rs4659731, rs2273029 and rs699517) with the lowest average prediction error (45.08%, p<0.001). These findings suggest that genetic variants in one-carbon metabolizing genes might modulate the risk of lung cancer. Validation of these findings in larger studies is needed.     

FGFR2 intronic polymorphisms interact with reproductive risk factors of breast cancer: Results of a case control study in Japan

Recently, 2 genome‐wide association studies demonstrated that single nucleotide polymorphisms (SNPs) of the fibroblast growth factor receptor 2 (FGFR2) gene at intron 2 are significantly associated with the risk of female breast cancer. As the next step, it is necessary to evaluate the interaction between these SNPs and known risk factors of breast cancer because such an evaluation could elucidate mechanisms of carcinogenesis and lead to preventive advances. We conducted a case‐control study of 456 newly and histologically diagnosed breast cancer cases and 912 age‐ and menopausal status‐matched noncancer controls. The impact of 5 FGFR2 intronic SNPs on the risk of breast cancer and the interactions between these SNPs and various known risk factors of breast cancer were evaluated in both pre and postmenopausal women. We observed a statistically significant association between 4 SNPs and breast cancer risk and these 4 SNPs were in strong linkage disequilibrium in the Japanese population. rs2420946 was associated with a population‐attributable risk of 17.7%. We found that FGFR2 polymorphisms interact with family history of breast cancer (interaction p = 0.003) and reproductive risk factors, namely, age at menarche (interaction p = 0.019) and parity (interaction p = 0.026). Of note, a significant association between body mass index (BMI) ≥ 25 and FGFR2 polymorphism was observed among postmenopausal women (trend p = 0.012), but not among premenopausal women. In contrast, BMI < 25 had no significant association with this polymorphism regardless of menopausal status. These findings suggest that FGFR2 intronic SNPs affect the reproductive hormone‐related pathway and contribute to the development of female breast cancer in the Japanese population. © 2009 UICC     

Genetic polymorphisms in the one-carbon metabolism pathway and breast cancer risk: a population-based case-control study and meta-analyses

Epidemiological evidence suggests that intake of folate and other B-vitamins and genetic variants in the one-carbon metabolism pathway could influence the risk of breast cancer. Previous studies have focused on 2 polymorphisms in the methylenetetrahydrofolate gene (MTHFR A222V and E429A); however, findings are inconclusive. In a large population-based case-control study in Poland (2,386 cases, 2,502 controls), we investigated the association between breast cancer risk and 13 polymorphisms in 6 one-carbon metabolism genes (MTHFR, MTR, MTRR, CBS, SHMT1 and SLC19A1). Data suggested an association between a nonsynonymous change in the gene coding for methionine synthase (MTR D919G) and reduced breast cancer risk: OR (95% CI) = 0.84 (0.73-0.96) and 0.85 (0.62-1.15) for heterozygous and homozygote variant genotypes, respectively, compared with common homozygotes; p-trend = 0.01, false discovery rate = 0.14. We found no significant associations between other variants and breast cancer risk, including MTHFR A222V or E429A. Meta-analyses including published studies of MTHFR A222V (8,330 cases and 10,825 controls) and E429A (6,521 cases and 8,515 controls) supported the lack of an overall association; however, studies suggested an increase in risk among premenopausal women. In conclusion, this report does not support a substantial overall association between the evaluated polymorphisms in the one-carbon metabolism pathway and breast cancer risk.     

One-carbon metabolism-related gene polymorphisms and risk of head and neck squamous cell carcinoma: case-control study

Low consumption of vegetables and fruits, which leads to insufficient folate intake, is associated with increased risk of several types of cancer, including head and neck squamous cell carcinoma (HNSCC). Functional polymorphisms in genes encoding one-carbon metabolism enzymes, such as methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), methionine synthase (MTR A2756G), methionine synthase reductase (MTRR A66G) and thymidylate synthase (TS), influence folate metabolism and thus might impact on HNSCC risk. We conducted a case-control study with 237 HNSCC cases newly and histologically diagnosed and 711 age- and sex-matched non-cancer controls to clarify associations with these five polymorphisms. Gene-environment interactions between polymorphisms and smoking and drinking habit and folate consumption were also evaluated by logistic regression analysis. Dietary folate intake was inversely associated with HNSCC risk. None of the polymorphisms showed any significant impact on HNSCC risk by genotype alone, but we found interactions between drinking habit and MTHFR C667T (P = 0.04), MTR A2756G (P = 0.04) and MTRR A66G (P = 0.03) polymorphisms. The results suggest that there may be interactions between one-carbon metabolism-related polymorphisms and alcohol drinking for HNSCC risk.     

Interleukin gene polymorphisms and breast cancer: a case control study and systematic literature review

Background  

Interleukins and cytokines play an important role in the pathogenesis of many solid cancers. Several single nucleotide polymorphisms (SNPs) identified in cytokine genes are thought to influence the expression or function of these proteins and many have been evaluated for their role in inflammatory disease and cancer predisposition. The aim of this study was to evaluate any role of specific SNPs in the interleukin genes IL1A, IL1B, IL1RN, IL4R, IL6 and IL10 in predisposition to breast cancer susceptibility and severity.     

Associations of one-carbon metabolism-related gene polymorphisms with breast cancer risk are modulated by diet,being higher when adherence to the Mediterranean dietary pattern is low

Purpose

Breast cancer is more likely attributed to a combination of genetic variations and lifestyle factors. Both one-carbon metabolism and diet-related factors could interfere with the carcinogenesis of breast cancer (BC), but whether diet consumed underlie a specific metabolism pathway could influence the impact of genetic variants on breast cancer risk remains equivocal.

Methods

A case–control study of the Chinese female population (818 cases, 935 controls). 13 SNPs in eight one-carbon metabolism-related genes (MTHFD1, TYMS, MTRR, MAT2B, CDO1, FOLR1, UNG2, ADA) were performed. Diet was assessed by a validated food-frequency questionnaire. We examined the associations of the adherence to the Mediterranean dietary pattern (MDP) and single-nucleotide polymorphisms (SNPs) of one-carbon metabolism with breast cancer risk. We constructed an aggregate polygenic risk score (PRS) to test the additive effects of genetic variants and analyzed the gene–diet interactions.

Results

High adherence (highest quartile) to the MDP decreased the risk of breast cancer among post- but not premenopausal women, respectively (OR?=?0.54, 95% CI?=?0.38 to 0.78 and 0.90, 0.53 to 1.53). Neither of the polymorphisms or haplotypes was associated with breast cancer risk, irrespective of menopause. However, a high PRS (highest quartile) was associated with more than a doubling risk in both post- and premenopausal women, respectively (OR?=?1.95, 95% CI?=?1.32 to 2.87 and 2.09, 1.54 to 2.85). We found a gene–diet interaction with adherence to the MDP for aggregate PRS (P-interaction?=?0.000) among postmenopausal women. When adherence to the MDP was low (<?median), carries with high PRS (highest quartile) had higher BC risk (OR?=?2.80, 95% CI?=?1.55 to 5.07) than low PRS (lowest quartile), while adherence to the MDP was high (≥ median), the association disappeared (OR?=?1.57, 95% CI?=?0.92 to 2.66).

Conclusion

High adherence to the MDP may counteract the genetic predisposition associated with one-carbon metabolism on breast cancer risk in postmenopausal women.

     

Aryl hydrocarbon receptor gene polymorphisms affect lung cancer risk

To evaluate the role of genetic polymorphisms of AhR related to the carcinogen metabolism and cell proliferation, genotypes of three AhR polymorphisms Ex1+185A>G, IVS7+33T>G and Ex10+501G>A were determined in 616 lung cancer cases and 616 lung cancer-free controls. When the effect of each AhR allele on lung cancer risk was evaluated, any AhR genotype did not show the association with lung cancer risk. However, when haplotypes were composed of three AhR SNP sites, non-smokers with GGG haplotype (adjusted OR=1.7, 95% CI, 1.06-2.71) and smokers without GGG haplotype (adjusted OR=2.5, 95% CI, 1.64-3.74) showed significantly increased risk of lung cancer compared to non-smokers without GGG haplotype. Moreover, smokers with GGG haplotype showed the highest risk (adjusted OR=3.2, 95% CI, 2.10-4.74). Particularly, the synergistic effect between AhR haplotype and smoking was more apparent in squamous cell carcinoma (adjusted OR=6.1, 95% CI, 2.53-14.68). This result suggests that haplotypes of AhR gene play an important role in the development of lung cancer and there is a synergistic interaction between AhR gene and smoking for lung cancer risk.     

MDM2 gene promoter polymorphisms and risk of lung cancer: a case-control analysis

The MDM2 protein negatively regulates p53 expression level in modulating DNA repair, cell-cycle control, cell growth and apoptosis. Polymorphisms in the promoter region of the MDM2 gene have been shown to alter protein expression and may, thus, play a role in carcinogenesis. To test our hypothesis that the MDM2 promoter polymorphisms are associated with risk of lung cancer, we conducted a hospital-based, case-control study of 1026 non-Hispanic white patients newly diagnosed with lung cancer and 1145 cancer-free controls who were frequency-matched by age (+/-5 years), sex, ethnicity and smoking status. We genotyped for the MDM2 promoter G2580T (also called SNP309) and G2164A polymorphisms that have a minor allele frequency >0.05. The distributions of the MDM2-2580G variant allele and genotypes were significantly less common among the cases than among the controls (P = 0.038 and 0.045, respectively), but this was not evident for MDM2-2164G (P = 0.865 and 0.614, respectively). Compared with the MDM2-2580TT genotype, the MDM2-2580G variant genotypes were associated with a decreased risk of lung cancer [odds ratio = 0.81 and 95% confidence interval = 0.67-0.98 for GT, 0.83 (0.63-1.08) for GG, and 0.81 (0.68-0.97) for the combined GT/GG genotype]. However, no significant association was observed between the MDM2-2164G variant genotypes and lung cancer risk. Our results suggest that the MDM2-2580G allele may be a marker of reduced genetic susceptibility to lung cancer in the non-Hispanic white population, a finding that seems to contradict previous reports.     

细胞色素P450 1A1和谷胱苷肽硫转移酶基因多态性与肺癌关系的病例对照研究

目的　探讨细胞色素P4 5 0 1A1(CYP 1A1)和谷胱苷肽硫转移酶 (GST) M1基因多态性与肺癌易感性的关系。方法　选取新发肺癌患者 91例及同期非肺部疾患同性别患者 91例作匹配 ,另选取体检正常者 4 7例做频数对照 ,采用聚合酶链式反应 (PCR)和限制性片段长度多态性 (RFLP)技术检测CYP 1A1和GST M1的基因多态性。结果　单独分析CYP 1A1和GST M1基因多态性与肺癌的关系 ,其OR值分别为 1.5 3和 1.4 2 ,与对照组比较 ,差异均无显著性 (P >0 .0 5 ) ,表明与肺癌的发生无相关性。而将二者联合分析时 ,其OR值为 2 .4 7,95 %CI为 1.0 3～ 5 .90 ,与对照组比较 ,差异有显著性(P <0 .0 5 ) ,表明与肺癌的发生有一定相关性。结论　CYP 1A1和GST M1的单一基因多态性不增加患肺癌的危险 ,而两者联合作用时 ,则可增强患肺癌的风险。     

A case control study on the lung cancer risk factors in north of Iran

In this case control study, the risk factors of lung cancer was assessed in the north of Iran. Two groups were matched for gender and age (+/- 5 years). Data were collected from 40 cases and 40 controls attending to hospitals. A public information questionnaire was used for data collection. Incidence odds ratios (OR) and corresponding 95% confidence intervals calculated using logistic regression analyses. Results showed that in adjusted odd ratio positive family history of cancer (OR = 0/19, 95% CI: 0/04-0/8) was associated with a reduction, and consumption of baked bread in traditional oven (OR = 22/6, 95% CI: 1/9-270), was associated with increase in lung cancer risk. Based on the results, smoking was not correlated with lung cancer. In conclusion, the data offers consumption of traditional oven-baked bread may enhance the risk of lung cancer but positive family history of cancer may reduce it.     

XRCC3 Thr241Met gene polymorphisms and lung cancer risk: a meta-analysis

Many studies have examined the association between the XRCC3 Thr241Met gene polymorphism and lung cancer risk in various populations, but their results have been inconsistent. To assess this relationship more precisely, a meta-analysis was performed. The PubMed, Embase, Web of Science, and CNKI database was searched for case–control studies published up to July 2012. Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated.Ultimately, 17 studies, comprising 4123 lung cancer cases and 5597 controls were included. Overall, for T allele carriers (TC + TT) versus the wild-type homozygotes (CC), the pooled OR was 0.95 (95% CI = 0.87-1.04 P = 0.228 for heterogeneity), for TT versus CC the pooled OR was 0.99 (95% CI = 0.86-1.15 P = 0.315 for heterogeneity). In the stratified analysis by ethnicity, histological types of lung cancer and smoking status, no any significantly risks were found for (C/T + T/T) vs C/C or T/T vs C/C. No publication bias was found by using the funnel plot and Egger''s test.Overall, there is no evidence showing a significant correlation between XRCC3 Thr241Met polymorphism and lung cancer risk stratified analysis by ethnicity, histology and smoking status.     

西安地区肺癌危险因素的病例对照分析

目的分析西安地区肺癌危险因素，为进一步的肺癌危险因素监测提供依据。方法对西安地区1999年至2002年12月肺癌病例248例及对照263例按1：1配对进行病例对照分析，估计各危险因素与肺癌的联系强度。结果单因素分析的危险因素有吸烟(OR=1．66)、油烟污染暴露(OR=1．68)、精神创伤史(OR=1．80)、家族肿瘤史(OR=2．08)、呼吸道疾病史(OR=1．46)，其中具有COPD病史的患者，肺癌发生的危险性明显增高(OR=2．25)，肺功能的损伤增加了肺癌发生的危险性，(OR=2．28)。结论吸烟、油烟污染暴露、精神创伤史、家族肿瘤史、家族肺癌史、呼吸道疾病史是西安地区肺癌的危险因素。具有COPD病史的患者，肺癌发生的危险性明显增高。肺功能的损伤增加了肺癌发生的危险性。     

ERCC6/CSB gene polymorphisms and lung cancer risk

Nucleotide excision repair (NER) enzymes are critical for the removal of bulky DNA adducts caused by environmental carcinogens such as smoking. Of them, Cockayne syndrome complementation group B (CSB), coded by ERCC6, recruits NER repair factors to the DNA damage site and plays an important role in the repair process. Genetic variants of ERCC6 may alter the regulation of DNA repair and therefore were hypothesized to be associated with altered risk of smoking-related lung cancer. To test this hypothesis, we genotyped eight tagging single nucleotide polymorphisms (tSNPs) and three potentially functional SNPs of ERCC6 in 500 incident lung cancer cases and 517 controls in a Chinese population. Single locus analyses showed that none of the single SNP alone had the significant main affect on the risk of lung cancer. However, the combined variant genotypes of the four loci with P(trend) approaching to 0.10 (rs2228526, rs4253160, rs12571445 and rs3793784) were associated with a significantly increased lung cancer risk (adjusted OR 1.35, 95% CI, 1.04-1.75 among subjects carrying three or more variant alleles), indicating that multiple loci in ERCC6 may jointly contribute to the susceptibility of lung cancer. These findings, if validated, may contribute to identify at-risk subjects in the general population for smoking-related lung cancer.     

CHRNA3基因多态性与肺癌易感相关性分析

目的：探讨尼古丁乙酰胆碱受体基因CHRNA3多态性与肺癌易感性的关系。方法：采用以医院患者为基础的病例一对照研究方法,对2008-01-01-2011-06-30在江苏省肿瘤医院就诊原发性肺癌患者600例（病例组）和健康体检人员600名（正常对照组）,以TaqMan-MGB探针技术检测CHRNA3上的SNPs位点rs3743073（T〉G）基因型,比较组间基因型分布频率的差异。结果：肺癌患者CHRNA3rs3743073（T〉G）的TT、TG和GG基因型频率分别为20．7％、43．0％和36．3％,正常对照人群分别为31．0％、48．5％和20．5％,差异均有统计学意义,P〈0．05。肺癌患者CHRNA3rs3743073（T〉G）的A、G等位基因频率分别为42．2％和57．8％,正常对照人群分别为53．3％和44．8％,差异均有统计学意义,P〈0．05。与TT基因型患者相比,TG和GG基因型患者发生肺癌的风险分别增加1．132倍（95％CI：1．004～1．277,P=0．048）和1．663倍（95％CI：1．406～1．968,P=0．001）;rs3743073G（TG和GG）患者发生肺癌的风险增加1．290倍（95％CI：1．150～1．447,P=0．001）。年龄〉60岁、男性、吸烟的患者中,rs3743073G变异基因型的患者发生肺癌的危险性显著增加,P=0．05。结论：CHRNA3基因rs3743073G变异基因型发生肺癌的危险明显增加,尤其在年龄〉60岁、男性和吸烟患者中更为显著。     

细胞色素CYP2E1和GST M1与肺癌易感性的病例对照研究

目的探讨谷胱甘肽转硫酶(GST)和细胞色素CYP2E1多态性与肺癌易感性的关系.方法选取广州市广东籍新发肺癌病人91例及同期非肺部疾患及相同性别的病人91例作匹配,调查他们的吸烟、饮酒等因素的暴露情况.用聚合酶链式反应(PCR)和限制性片段长度多态性(RFLP)技术检测CYP2E1和GST的基因多态性.结果CYP2E1 C1C1基因型与C1C2基因型比较,其OR为1.82(95%CI=0.95～3.40),GSTM1基因缺失型的OR值为1.26(0.69～2.30),而两者联合分析时,则可增加患肺癌的危险,其OR值为2.13(0.82～5.56),但无统计学意义(P＞0.05).吸烟与肺癌关系密切,其OR值为2.82(1.56～5.12),当吸烟与这两种基因型协同作用时,可明显提高患肺癌的危险性,携带CYP2E1 C1C1基因型的吸烟者的OR值为5.42(2.05～14.32),GSTM1基因缺失型的吸烟者的OR值为4.38(1.81～10.61).多因素logistic回归分析结果表明:文化程度(OR为0.63,0.45～0.86)、吸烟量(OR为1.56,1.14～2.14)、元抽油烟机(OR为3.77,1.48～9.56)、食用动物油(OR为1.67,1.25～2.24)、胡萝卜(OR为0.47,0.22～0.98)、饮酒(OR为6.58,1.53～28.3)、直系亲属肺癌史(OR为3.75,1.64～8.58)等因素与肺癌有关,而上述两种基因均未进入模型.结论CYP2E1和GSTM1在单因素分析中未显示出与肺癌风险的联系.这两种基因分别与吸烟协同作用时明显提高肺癌的危险性.然而在多因素分析中均未进入logistic模型,说明它们均不是肺癌个体易感性的主效基因,而是次效基因.     

Association between polymorphisms in the GSTA4 gene and risk of lung cancer: a case-control study in a Southeastern Chinese population

GST Alpha 4 (GSTA4) has an important role in the protection against oxidative stress induced by carcinogens such as tobacco smoke. However, few studies investigated the association between GSTA4 polymorphisms and lung cancer risk. We genotyped three selected GSTA4 SNPs (rs182623 - 1718:T > A, rs3798804 + 5034:G > A and rs316141 + 13984:C > T) in a case-control study of 500 lung cancer patients and 517 cancer-free controls and evaluated the association between these SNPs and risk of lung cancer in this Han Chinese population. We found that there was a significant difference in genotype and allele frequency distributions of GSTA4 -1718 between the cases and the controls (P = 0.006 and P = 0.003, respectively). Compared with the GSTA4 -1718TT genotype, individuals with the TA + AA genotypes had a significantly decreased risk of lung cancer (adjusted OR, 0.63; 95% CI, 0.47-0.84; P = 0.006). Although there were no such statistical differences between the cases and controls at the loci +5034 and +13984, nor for histological types, individuals carrying the genotypes of -1718TA, +5034GG and +13984CT had a significantly decreased lung cancer risk (OR, 0.37; 95% CI, 0.23-0.61; P < 0.0001), especially for those smokers who smoked 相似文献