Methionine Synthase Reductase A66G Polymorphism is not Associated with Breast Cancer Susceptibility - a Meta-analysis

Background: Several studies have investigated the association between methionine synthase reductase(MTRR) A66G polymorphism and breast cancer risk, but controversial results were yielded. Therefore, weperformed a meta-analysis to provide a more robust estimate of the effect of this polymorphism on susceptibilityto breast cancer. Materials and Methods:Case-control studies investigating the relationship between MTRRA66G polymorphism and breast cancer risk were included by searching PubMed, EMBASE, China NationalKnowledge Infrastructure and Wanfang Database. Either fixed-effects or random-effects models were appliedto calculate odds ratios(ORs) and 95% confidence intervals (CIs) by RevMan5.2 software. Results: A total of9 studies bearing 7,097 cases and 7,710 controls were included in the meta-analysis. The results were that thecombined ORs and 95%CIs of MTRR 66AG, GG, (AG+GG) genotypes were 0.98(0.91-1.05), 1.06(0.97-1.16)and 1.02(0.94-1.10), respectively with p=0.52, 0.19 and 0.65. We also performed subgroup analysis by specificethnicity. The results of the combined analysis of MTRR 66AG, GG, (AG+GG) genotypes and breast cancer inAsian descent were Z=0.50, 0.53 and 0.21, with p all>0.05; for breast cancer in Caucasian descent, the results wereZ=1.14, 1.65 and 0.43, with p all>0.05. Conclusions: Our findings suggested that MTRR A66G polymorphismwas not associated with breast cancer susceptibility.     

Genetic Polymorphisms of Gene Methionine Synthase Reductase (MTRR) and Risk of Urinary Bladder Cancer

Methionine synthase reductase (MTRR) gene involved in the signaling for production of enzyme called methionine synthase reductase that use for the synthesis of methionine, which further used in DNA replication and repair. Genetic variation in MTRR gene may alter the susceptibility of developing urinary bladder cancer. The present study undertaken to identify the contribution of genetic polymorphisms in the MTRR gene on the selected polymorphic sites including c.66A>G and c.524C>T towards urinary bladder cancer risk. Direct-DNA sequencing method was applied for the observation of genotyping distribution of MTRR c.66A>G and c.524C>T polymorphisms in 232 histopathological confirmed cases of transitional cell carcinoma (TCC) of urinary bladder cancer and 250 age-, sex- and ethnicity-matched cancer free controls. With significant difference (p = 0.05) of genotype analysis further corresponding Odds ratio (OR) and 95% confidence interval (CI) were calculated. Multivariable logistic regression analysis was applied for adjusting significant confounder variables. Haploview software (version 4.2) was used to perform pairwise Linkage Disequilibrium (LD) analysis. Age (p = 0.01), Habit of smoking (p = 0.05), tobacco consumption (p = 0.001) and diet (p = 0.02) were significantly differed between cases and controls. Both the MTRR substitution showed higher risk of developing urinary bladder cancer (p = <0.001), although this effect alters in multivariable logistic regression analysis in a protective association for both the substitution. No LD observed between the c.66A>G and c.524C>T substitutions. In conclusion, MTRR c.66A>G and c.524C>T substitutions showed a joint effect with the other associated risk factors. Further studies with a greater number of subjects of different ethnicity and polymorphisms are recommended for the better understanding urinary bladder cancer etiology and to screen the population who are at higher risk of developing urinary bladder cancer.     

The Common 677C>T Gene Polymorphism of Methylenetetrahydrofolate Reductase Gene is not Associated with Breast Cancer Risk

Methylenetetrahydrofolate reductase (MTHFR) is involved in folate metabolism and plays a role in DNA biosynthesis, methylation, and repair in actively dividing cells. A common 677C>T polymorphism in the gene for MTHFR, leading to a thermolabile enzyme with decreased activity, has been associated with reduced plasma folate levels and elevated homocysteine levels and could be a risk factor for breast cancer. In the present case-control study, MTHFR genotype was determined in 500 women with clinically verified breast cancer and 500 female age-matched healthy control subjects. The homozygous TT genotype was found in 13.0% patients and 13.1% controls (P = n.s.). The odds ratio of TT homozygotes for breast cancer was 0.99 (95% confidence interval 0.68–1.43). The MTHFR genotype was furthermore not associated with tumor size, histological grading, estrogen or progesterone receptor status and age at diagnosis. In a subgroup of 116 premenopausal patients, no increased frequency of the homozygous 677T genotype was found (13.8%). Therefore, we conclude that the MTHFR 677C>T polymorphism is not associated with individual susceptibility to breast cancer.     

Polymorphisms in the Thymidylate Synthase Gene and Risk of Colorectal Cancer

To evaluate the relationship between polymorphisms (28 bp repeated sequences in 5’-UTR and 6-bp ins/del in 3’-UTR) in then thymidylate synthetase gene (TS) and risk of colorectal, colon and rectal cancers, weconducted a case-control study with 315 cases of colorectal cancer and 439 population-based controls in Jiangsuprovince, China. TS genotypes were identified using PCR–RFLP (restriction fragment length polymorphism)methods. Odds ratios (ORs) were estimated with an unconditional logistic regression model. We found that thedistributions of 5’-UTR genotypes in TS were significantly different between controls and male colon cases (χ2=8.25, P = 0.016). Compared with 3R/3R genotype, individuals with the 2R allele were at an increased risk ofcolon cancer (age-, BMI-, smoking- and alcohol drinking-adjusted OR=1.98, 95%CI: 1.11-3.53) among men. Inccontrast, the 6-bp ins/del polymorphism at the TS 3’- UTR did not influence risk of the colorectal, colon andrectal cancers. When combined genotypes for both TS 5’-UTR and 3’-UTR polymorphisms were evaluated,individuals with the 5’-UTR 2R allele had a OR of 3.61 (95%CI: 1.38-9.49) for colon cancer among men withthe 3’-UTR –6bp/-6bp genotype. These results show that the polymorphism of the 28 bp repeated sequences inTS 5’-UTR could influence susceptibility to colon cancer and that there was a coordinated effect between TS3’-UTR and 5’-UTR polymorphisms in increasing risk of colon cancer among Chinese men.     

MTRR基因A66G多态性与儿童急性淋巴细胞白血病关系的Meta分析

目的 评估甲硫氨酸合成酶还原酶（MTRR）基因A66G多态性与儿童急性淋巴细胞白血病（ALL）发生风险的关系。方法 全面检索PubMed、Elsevier、Embase、中文期刊全文数据库（CNKI）和万方数据库,收集探索MTRR基因A66G多态性与儿童ALL发生关系的病例对照研究,纳入符合入选标准的文献并评估其质量。优势比（ORs）及95%可信区间（CIs）评估关联强度。应用RevMan 5.2软件对纳入研究进行异质性检验和效应值合并,漏斗图评估发表性偏倚,敏感性分析采用逐一排除的方法以评估结果的稳定性。结果 共纳入7篇文献,包括儿童ALL患者2 326例,对照3 090例。异质性检验结果表明纳入研究间无显著异质性,采用固定效应模型合并数据。Meta分析结果示,在整体人群纯合子模型和显性模型发现MTRR A66G多态性与儿童ALL风险有关联（GG vs. AA: OR=0.81, 95%CI: 0.69~0.95, P=0.009; AG+GG vs. AA: OR=0.87, 95%CI: 0.77~0.98, P=0.03）;根据种族 进行亚组分析时在白种人群中发现显著性关联（AG vs. AA: OR=0.84, 95%CI: 0.72~0.99, P=0.04; GG vs. AA: OR=0.79, 95%CI: 0.66~0.95, P=0.01; AG+GG vs. AA: OR=0.82, 95%CI: 0.71~0.96, P=0.01）。漏斗图未检测出显著性发表性偏倚,敏感性分析表明结果稳定可靠。结论 目前Meta分析表明MTRR基因A66G多态性与儿童ALL发生风险存在关联,尤其在白种人群。     

Association of a VDR Gene Polymorphism with Risk of Colorectal Cancer in Kashmir

Roles of the vitamin D receptor in etiology of cancers, including colorectal cancer, have been repeatedlystressed in different parts of the world. A case control study aimed to evaluate the relationship between thetwo was therefore initiated in Kashmir, known both for its increasing incidence of gastrointestinal cancers anddeficiency of micro-nutrients especially vitamin D. The study included a total of 617 subjects (312 colorectalcancer cases and 305 controls), with sampling carried out over a period of 5 years. DNA samples from the bloodof the subjects were analyzed for start codon Fok I VDR polymorphism. We obtained a 1.3 fold increased riskamong individuals homozygous for f variants as compared to subjects homozygous for F allele (odds ratioOR 1.3, 95%CI, 0.861-1.65). Our study also showed statistically significant results when dwelling and tumorlocation characteristics were stratified with Fok I polymorphism, all of which suggests a possible role of Fok Ipolymorphism in the etiology of CRC in Kashmir     

Folate-Related Nutrients,Genetic Polymorphisms,and Colorectal Cancer Risk: the Fukuoka Colorectal Cancer Study

One-carbon metabolism plays an important role in colorectal carcinogenesis. Meta-analyses have suggestedprotective associations of folate and vitamin B6 intakes with colorectal cancer primarily based on studies inCaucasians, and genetic polymorphisms pertaining to the folate metabolism have been a matter of interest.Less investigated are the roles of methionine synthase (MTR) and thymidylate synthetase (TS) polymorphismsin colorectal carcinogenesis. In a study of 816 cases and 815 community controls in Japan, we investigatedassociations of dietary intakes of folate, methionine, vitamin B2, vitamin B6, and vitamin B12 with colorectal cancerrisk. The associations with MTR 2756A>G, MTRR 66A>G, and TSER repeat polymorphism were examined in685 cases and 778 controls. Methionine and vitamin B12 intakes were inversely associated with colorectal cancerrisk, but the associations were totally confounded by dietary calcium and n-3 fatty acids. The other nutrientsshowed no association with the risk even without adjustment for calcium and n-3 fatty acids. The TSER 2R allelewas dose-dependently associated with an increased risk. The MTR and MTRR polymorphisms were unrelatedto colorectal cancer risk. There was no measurable gene-gene or gene-nutrient interaction, but increased riskassociated with the TSER 2R allele seemed to be confined to individuals with high folate status. This study doesnot support protective associations for folate and vitamin B6. The TSER 2R allele may confer an increased riskof colorectal cancer. The role of the TSER polymorphism in colorectal carcinogenesis may differ by ethnicity.     

XRCC1 Gene Polymorphism,Diet and Risk of Colorectal Cancer in Thailand

Background: Colorectal cancer (CRC) is one of the most common cancers worldwide. This study aimed to investigate the interaction between the presence of a polymorphism of the XRCC1 gene and known risk factors for colorectal cancer in Thailand. Materials and Methods: A hospital-based case-control study was conducted in Thailand. The participants were 230 histologically confirmed new cases and 230 controls matched by sex and age and recruited from the same hospital. Information about demographic characteristics, life style, anddietary habits was collected using structured interviews, and blood samples were taken which were used for the detection of a homozygous and heterozygous polymorphisms of XRCC1. Associations were assessed using multiple conditional logistic regression. Results: In the univariate analysis, factors found to be significantly associated with an increased risk for CRC were the presence of the XRCC1 AA homozygote (OR= 4.95; 95% CI: 1.99-12.3), a first degree family history of cancer (OR= 1.74; 95% CI: 1.18-2.58), and a high frequency ofpork consumption (OR= 1.49; 95% CI: 1.00-2.21). Intakes of fish fruit and vegetables appeared to be protective factors, but the associations were not statistically significant. In the multivariate analysis only the XRCC1 AAhomozygote polymorphism and a family history of cancer emerged as risk factors (OR= 4.96; 95% CI: 1.90-12.95 and OR=1.80; 95% CI: 1.18-2.72, respectively). Conclusions: While the XRCC1 AA homozygote and a family history of cancer were found to be associated with an increased risk of CRC, none of the dietary intake variables were clearly identified as risk or protective factors. There is a need for further research to determine the reasons for this.     

Association between Circulating Vitamin D,the Taq1 Vitamin D Receptor Gene Polymorphism and Colorectal Cancer Risk among Jordanians

Background: The physiological role of vitamin D extends beyond bone health and calcium-phosphate homeostasis to effects on cancer risk, mainly for colorectal cancer. Vitamin D may have an anticancer effect in colorectal cancer mediated by binding of the active form 1,25(OH)2D to the vitamin D receptor (VDR). The Taq1 VDR gene polymorphism, a C-to-T base substitution (rs731236) in exon 9 may influence its expression and function. The aim of this study wass to determine the 25(OH)D vitamin D level and to investigate the association between circulating vitamin D level and Taq1VDR gene polymorphism among Jordanian colorectal cancer patients. Materials and Methods: This case control study enrolled ninety-three patients and one hundred and two healthy Jordanian volunteers from AL-Basheer Hospital/Amman (2012-2013). Ethical approval and signed consent forms were obtained from all participants before sample collection. 25(OH)D levels were determined by competitive immunoassay Elecsys (Roche Diagnostic, France). DNA was extracted (Promega, USA) and amplified by PCR followed by VDR Taq1 restriction enzyme digestion. The genotype distribution was evaluated by pairedt-test and chi-square. Comparison between vitamin D levels among CRC and control were assessed by odds ratio with 95% confidence interval. Results: The vitamin D serum level was significantly lower among colorectal cancerpatients (8.34 ng/ml) compared to the healthy control group (21.02ng/ml). Patients deficient in vitamin D (less than 10.0 ng/ml) had increased colorectal cancer risk 19.2 fold compared to control. Only 2.2% of CRC patients had optimal vitamin D compared to 23.5% among healthy control. TT, Tt and tt Taq1 genotype frequencies among CRC cases was 35.5%, 50.5% and 14% compared to 43.1%, 41.2% and 15.7% among healthy control; respectively. CRC patients had lower mean vitamin D level among TT (8.91±4.31) and Tt (9.15±5.25) genotypescompared to control ((21.3±8.31) and (19.3±7.68); respectively. Conclusions: There is significant association between low 25(OH)D serum level and colorectal cancer risk. The VDRTaq1 polymorphism was associated with increased colorectal cancer risk among patient with VDRTaq1 TT and Tt genotypes. Understanding the functional mechanism of VDRTaq1 TT and Tt may provide a strategy for colorectal cancer prevention and treatment.     

Nitric Oxide Synthase 3 Gene Variants and Colorectal Cancer: a Meta-Analysis

Background: Colorectal cancer (CRC) is the worldwide disease which causes enormous losses every year.Recent studies suggested that environmental and gene factors might be the etiologies in increasing the risk ofmorbidity. Nitric oxide synthase 3 (NOS3) gene polymorphisms are said to be associated with CRC risk butthe conclusion is still controversial. Materials and Methods: Pubmed and HuGENet databases up to December2013 were used in this meta-analysis. Three different certain genotypic models were applied, namely dominant(AA+AC versus CC), recessive (AA versus AC+CC), per-allele analysis (A vs C). In addition, information ontumor sites and pathologic stages was collected. The strength of associations was assessed through combiningodds ratio (OR) and 95% confidence interval (CI). Results: Finally, five and three studies about the rs1799983and rs2070744 were covered in the analysis with 2,745 cases and 2,478 controls. Three models were applied, butno significant association was found for NOS3 G894T/rs1799983 (dominant: OR=0.999, 95%CI=0.797-1.253,I2=63.8%; recessive: OR=0.924, 95%CI=0.589-1.450, I2=59.3%; allele analysis: OR=0.979, 95%CI=0.788-1.216,I2=74.9%) and T-786C/rs2070744 (dominant: OR=1.138, 95%CI=0.846-1.530, I2=67.9%; recessive: OR=0.956,95%CI=0.708-1.291, I2=0.0%; allele analysis: OR=1.110, 95%CI=0.865-1.425, I2=69.4%). The same resultswere also obtained for tumor sites and pathologic stage subgroups. After further analyzing the NOS3 gene,rs1799983 as the tag- and functional SNP was presented. Conclusions: On the basis of this meta-analysis andthe characteristics of the NOS3 gene, we suggested rs1799983 might be a key locus associated with CRC risk.Further prospective studies were needed to make more comprehensive explanation of the associations.     

Methylenetetrahydrofolate Reductase Gene Germ-Line C677T and A1298C SNPs are Associated with Colorectal Cancer Risk in the Turkish Population

Colorectal cancer (CRC) is the third most common cause of death due to cancer in the worldwide and theincidence is also increasing in Turkey. Our present aim was to investigate any association between germ-linemethylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and CRC risk in Turkey.A total of 86 CRC cases and 212 control individuals of the same ethnicity were included in the current study.Peripheral blood-DNA samples were used for genotyping by StripAssay technique, based on the reversehybridizationprinciple and real-time PCR methods. Results were compared in Pearson Chi-square and multiplelogistic regression models. The MTHFR 677TT (homozygous) genotype was found in 20.9% and the T allelefrequency 4.2-fold increased in CRC when compared with the control group.The second SNP MTHFR 1298CC(homozygous) genotype was found in 14.0% and the C allele frequency 1.4-fold elevated in the CRC group.The current data suggest strong associations between both SNPs of germ-line MTHFR 677 C>T and 1298 A>Cgenotypes and CRC susceptibility in the Turkish population. Now the results need to be confirmed with a largersample size.     

XRCC1基因G28152A多态与肺癌风险的研究

背景与目的 :研究碱基切除修复基因XRCC1基因G28152A单核苷酸多态与肺癌风险的关系。材料与方法 :以病例_对照研究方法 ,采用聚合酶链反应一限制性片段长度多态性法检测肺癌病例(n=149)和按性别、年龄频数匹配的正常对照(n=157)XRCC1基因G28152A多态 ,分析各基因型与肺癌易感性的关系。 结果 :肺癌患者中 ,XRCC1基因28152AA突变基因型频率为15.4 % ,高于对照组7.6 % ;此基因型个体发生肺癌风险是其他基因型个体的2.2倍(95 %CI1.06～4.61)。 结论 :XRCC1基因G28152A多态可能在肺癌发生中起一定作用。     

Methionine Synthase Reductase-A66G and -C524T Single Nucleotide Polymorphisms and Prostate Cancer: A Case-Control Trial

Purpose: Some variations in the sequence of methionine synthase reductase (MTRR) gene can increase the risk ofvarious cancers such as prostate cancer. The aim of this study was to investigate the association between prostate cancerand the MTRR A66G and C524T gene single nucleotide polymorphisms (SNPs) using an in silico analysis. Methods:In this case-control study, 218 Iranian men, including 108 men with prostate cancer and 110 prostate cancer-free men,were enrolled. The MTRR A66G and C524T genotyping was performed by PCR-RFLP. Some of the bioinformaticstools were employed for the evaluation of polymorphism on the molecular aspects of the MTRR. Results: With regardto the MTRR A66G polymorphism, the genotype AG (OR: 0.85, 95% CI: 0.47-1.54, p= 0.6014), genotype GG (OR:0.89, 95% CI: 0.42-1.87, p= 0.7512), and allele G (OR: 0.92, 95% CI: 0.63-1.35, p= 0.6686) were not associated withprostate cancer risk. However, the data for C524T SNP showed that the genotype CT was associated with prostatecancer risk (OR: 1.92, 95% CI: 1.06-3.47, p= 0.0308). Further, carriers of the allele T (OR: 1.80, 95% CI: 1.04-3.13,p= 0.0358) were associated with high risk of prostate cancer. In addition, bioinformatics analysis revealed that C524TSNP could affect some molecular aspects of the protein structure, while having no effect on the mRNA structure.Conclusion: The MTRR C524T is a genetic risk factor for prostate cancer; however, the MTRR A66G is not suggestedas a suitable biomarker for prostate cancer. To obtain more reliable results, further studies are recommended to uselarger sample sizes and investigate the effects of environmental factors.     

The 870G>A Polymorphism of the Cyclin D1 Gene is not Associated with Breast Cancer

A common 870G > A polymorphism in the gene for cyclin D1, CCND1, has been linked to alternative splicing and cancer susceptibility. To analyze its role for breast cancer, we determined the CCND1 genotype in 500 breast cancer patients and 500 controls. CCND1 genotype frequencies were similar among patients and controls. The CCND1 genotype was furthermore not associated with tumor characteristics. We conclude that the CCND1 870G > A polymorphism is not associated with breast cancer.     

Functional Polymorphism of the Thymidylate Synthase Gene in Colorectal Cancer Accompanied by Frequent Loss of Heterozygosity

The thymidylate synthase ( TS ) gene has a polymorphic repeated sequence in its 5'-untranslated region. The repeat length is associated with TS protein expression, which suggests that we may be able to predict the efficacy of 5-fluorouracil (S-FU)-based chemotherapy from a patient's TS genotype determined through analysis of normal tissue obtained non-invasively. However, it is not yet elucidated whether the TS genotype is identical in tumor and normal tissue. In this study, we investigated the TS genotype in 151 matched tumor and normal DNA samples isolated from colorectal cancer and adjacent normal tissues by PCR analysis. The results showed that TS genotypes are identical in normal and tumor tissues of homozygous individuals, suggesting that the repeat sequence is stable through carcinogenesis. However, in heterozygous samples, an unbalance between the 2R and 3R alleles in the tumor DNA was frequently observed, suggesting loss of heterozygosity (LOH) at the TS locus. Detailed LOH analysis revealed that 62% (31 of 50) of 2R/3R-heterozygous samples had LOH. Frequent LOH at the TS locus was confirmed by RT-PCR of TS mRNA and microsatellite analysis using the marker D18S59, located on 18p11.3. There was no difference in the expressions of TS mRNA and TS protein between LOH and non-LOH samples. However, when the heterozygous genotype bearing LOH was subdivided according to the number of repeats, the cancer tissue with 2R/loss genotype expressed a significantly lower level of TS protein than did that with 3R/loss genotype. The results suggest that the difference in TS genotype between tumor and normal tissue due to LOH should be considered when the genotype is analyzed with normal tissue, such as peripheral blood cells, because it is important for TS protein expression.     

RPSA Gene Mutants Associated with Risk of Colorectal Cancer among the Chinese Population

The primary aim of this study was to evaluate the relationship of single nucleotide polymorphisms (SNPs) inribosomal protein SA (RPSA) gene with colorectal cancer (CRC). A case-control study including 388 controls and387 patients with CRC was conducted in a Chinese population. Information about socio-demography and livingbehavior factors was collected by a structured questionnaire. Three SNPs (rs2133579, rs2269349, rs7641291)in RPSA gene were genotyped by Illumina SnapShot method. Multiple logistic regression models were used forassessing the joint effects between tea consumption and SNPs on CRC. The subjects with rs2269349 CC genotypehad a decreased risk for CRC (OR=0.60; 95%CI = 0.37-0.99), compared with TT/CT genotype after adjustmentfor covariates. A similar association of rs2269349 with rectal cancer was observed (OR=0.49; 95%CI=0.24-1.00).Further analyses indicated that this SNP could modify the protective effect of tea drinking on CRC. Amongthe subjects with rs2269349 TT/CT or rs2133579 AA/GA, there was a marginal significantly lower risk of CRC(OR and 95%CI: 0.63 and 0.39-1.01 for rs2269349; 0.64 and 0.40-1.02 for rs2133579) in tea-drinking subjects incomparison to non-tea-drinking subjects. Mutants in the RPSA gene might be associated with genetic susceptibilityto CRC and influence the protective effect of tea consumption in the Chinese population.     

亚甲基四氢叶酸还原酶和胸苷酸合成酶基因多态预测氟尿嘧啶为基础化疗方案治疗晚期胃癌疗效关系的研究

目的观察亚甲基四氢叶酸还原酶（MTHFR）（C677T、A1298C）和胸苷酸合成酶（TS3’-UTR）多态与5-FU为基础化疗方案及晚期胃癌敏感性的关系。方法选取173例晚期胃癌患者,所有病例均接受5-FU为基础化疗方案（FOLFOX,FP和DCF方案）化疗。在化疗前获取外周血白细胞DNA。采用PCR—RELP检测基因型。在2个基因中共检测了9种遗传多态。173例中检测了MTHFR（C677T、A1298C）和TS（3＇-TUR）多态。结果所有患者化疗总有效率为35．8％。DCF方案的有效率显著高于FP和FOLFOX方案（55．8％ vs 27．1％,31．1％;P=0．006）。MTHFRC677TT／T基因型患者的有效率显著高于C／C和C／T基因型（73．3％vs28．0％;P=0．000）。在MTHFRA1298C中,A／A基因型患者的有效率显著高于C／C和A／C基因型（41．8％vs21．6％,P=0．011）。在TS 3＇-UTR中,-6／-6bp和-6/＋6bp基因型患者的有效率显著高于＋6／＋6bp基因型（40．3％vs17．6％,P=0．014）。FOLFOX和FP方案中,MTHFR C677T T／T基因型患者的有效率均显著高于C／C和C／T基因型（P=0．008;P=0．000）,但在DCF方案中没有发现差异。在MTHFRC／T和C／C基因型中,DCF方案的有效率显著高于FP和FOLFOX方案（P=0．000）。MTHFR C677T T／T基因型患者的Ⅲ～Ⅳ度呕吐（66．7％）和口腔炎（30．0％）发生率显著高于C／C和C／T基因型（41．3％,9．8％;P=0．011,0．003）。MTHFRA1298CA／A基因型患者的Ⅲ～Ⅳ°度口腔炎（17．2％）和腹泻（13．9％）发生率同样显著高于A／C和C／C基因（3．9％,2．0％;P=0．025,0．026）。TS 3^＋-UTR的不同多态之间没有发现毒性差异。结论检测外周血白细胞DNA中的MTHFR和TS基因多态能预测以5-FU为基础化疗方案治疗晚期胃癌的有效性和化疗相关的毒性反应。     

Lack of Influence of the SMAD7 Gene rs2337107 Polymorphism on Risk of Colorectal Cancer in an Iranian Population

SMAD7 has been identified as a functional candidate gene for colorectal cancer (CRC). SMAD7 protein isa known antagonist of the transforming growth factor beta (TGF-b) signaling pathway which is involved intumorigenesis. Polymorphisms in SMAD7 may thus alter cancer risk. The aim of this study was to investigatethe influence of a SMAD7 gene polymorphism (rs2337107) on risk of CRC and clinicopathological featuresin an Iranian population. In total, 210 subjects including 105 patients with colorectal cancer and 105 healthycontrols were recruited in our study. All samples were genotyped by TaqMan assay via an ABI 7500 Real TimePCR System (Applied Biosystems) with DNA from peripheral blood. The polymorphism was statisticallyanalyzed to investigate the relationship with the risk of colorectal cancer and clinicopathological properties.Logistic regression analysis revealed that there was no significant association between rs2337107and the risk ofcolorectal cancer. In addition, no significant association between genotypes and clinicopathological features wasobserved (p value>0.05). Although there was not any association between genotypes and disorder, CT was themost common genotype in this population. This genotype prevalence was also higher in the patients with wellgrade (54.9%) and colon (72.0%) tumors. Our results provide the first evidence that this polymorphism is not apotential contributor to the risk of colorectal cancer and clinicopathological features in an Iranian population,and suggests the need of a large-scale case-control study to validate our results.     

Evaluation of the MTHFR C677T Polymorphism as a Risk Factor for Colorectal Cancer in Asian Populations

Background: Genetic and environmental factors play important roles in pathogenesis of digestive tract cancers like those in the esophagus, stomach and colorectum. Folate deficiency and methylenetetrahydrofolate reductase (MTHFR) as an important enzyme of folate and methionine metabolism are considered crucial for DNA synthesis and methylation. MTHFR variants may cause genomic hypomethylation, which may lead to the development of cancer, and MTHFR gene polymorphisms (especially C677T and A1298C) are known to influence predispositions for cancer development. Several case control association studies of MTHFR C677T polymorphisms and colorectal cancer (CRC) have been reported in different populations with contrasting results, possibly reflecting inadequate statistical power. Aim: The present meta-analysis was conducted to investigate the association between the C677T polymorphism and the risk of colorectal cancer. Materials and Methods: A literature search of the PubMed, Google Scholar, Springer link and Elsevier databases was carried out for potential relevant articles. Pooled odds ratio (OR) with corresponding 95 % confidence interval (95 % CI) was calculated to assess the association of MTHFR C677T with the susceptibility to CRC. Cochran’s Q statistic and the inconsistency index (I2) were used to check study heterogeneity. Egger’s test and funnel plots were applied to assess publication bias. All statistical analyses were conducted by with MetaAnalyst and MIX version 1.7. Results: Thirty four case-control studies involving a total of 9,143 cases and 11,357 controls were retrieved according to the inclusion criteria. Overall, no significant association was found between the MTHFR C677T polymorphism and colorectal cancer in Asian populations (for T vs. C: OR=1.03; 95% CI= 0.92 1.5; p= 0.64; for TT vs CC: OR=0.88; 95%CI= 0.74-1.04; p= 0.04; for CT vs. CC: OR = 1.02; 95%CI= 0.93-1.12; p=0.59; for TT+ CT vs. CC: OR=1.07; 95%CI= 0.94-1.22; p=0.87). Conclusions: Evidence from the current meta-analysis indicated that the C677T polymorphism is not associated with CRC risk in Asian populations. Further investigations are needed to offer better insight into any role of this polymorphism in colorectal carcinogenesis.     

The Prostaglandin Synthase 2/cyclooxygenase 2 (PTGS2/COX2) rs5277 Polymorphism Does not Influence Risk of Colorectal Cancer in an Iranian Population

Background: The prostaglandin-endoperoxide synthase 2 [PTGS2, commonly known as cyclooxygenase-2(COX-2)] is an enzyme induced by proinflammatory stimuli that is often overexpressed in malignant tissue andinvolved in the synthesis of prostaglandins and thromboxanes, regulators of processes such as inflammation, cellproliferation, and angiogenesis, all relevant for cancer development. We investigated whether a functional geneticpolymorphism, rs5277, in COX-2 may have a risk-modifying effect on sporadic colorectal cancer in an Iranianpopulation. Materials and Methods: We conducted a case-control study on 167 patients with colorectal cancerand 197 cancer-free controls in Taleghani Hospital in Tehran, Iran, between 2007 and 2011. Peripheral bloodsamples of both groups were processed for DNA extraction and genotyping of the COX-2 gene polymorphism(rs5277) using PCR-RFLP. RFLP results were confirmed by direct sequencing. Logistic regression analysis wasperformed to calculate the adjusted odds ratio (OR) and 95% confidence interval (95% CI). Results: There wasno significant difference in the distribution of COX-2 gene rs5277 polymorphism genotype and the allelic form,among CRC patients compared with the healthy control group (p: 0.867). Conclusions: Our results suggest thatrs5277 polymorphism in COX2 could not be a good prognostic indicator for patients with CRC.