Association of polymorphisms in one-carbon metabolizing genes with breast cancer risk in Syrian women

Dietary folate status as well as polymorphisms in one-carbon metabolism genes may affect the risk of breast cancer through aberrant DNA methylation and altered nucleotide synthesis and DNA repair. A large number of studies investigated the role of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) polymorphisms in breast cancer with inconsistent results. Association between multiple polymorphisms in one-carbon metabolism genes and breast cancer was not studied before in an Arab population. The purpose of the present study is to test the hypothesis that polymorphisms in one-carbon metabolism genes are associated with breast cancer susceptibility in Syrian breast cancer women patients. A total of 245 subjects (119 breast cancer women patients and 126 healthy controls) were genotyped for MTHFR C677T and A1298C and MTRR A66G polymorphisms. Association was tested for under numerous genetic models. A statistically significant association was found for MTHFR A1298C polymorphism especially under the allele contrast model (odds ratio (OR) = 1.68, 95% confidence interval (CI) (1.16-2.45), P = 0.006). On the other hand, no significant association was found for MTHFR C677T or MTRR A66G under any of the genetic models tested. The effects of the compound genotypes were also examined. The 66GG genotype was found to be protective against breast cancer when combined with the 677CT or 1298AC genotype (OR = 0.18, 95% CI (0.04-0.82), P = 0.014; OR = 0.3, 95% CI (0.08-1.11), P = 0.058). In conclusion, our study supports the hypothesis that polymorphisms in one-carbon gene metabolisms modulate the risk for breast cancer, particularly the A1298C polymorphism of the MTHFR gene.     

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.     

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.     

One-carbon metabolism related gene polymorphisms interact with alcohol drinking to influence the risk of colorectal cancer in Japan

One-carbon metabolism, in which folate plays an essential role, is involved in DNA methylation and synthesis, and is suspected of impacting on colorectal carcinogenesis. Alcohol is well recognized as a risk factor for colorectal cancer (CRC) and interactions with one-carbon metabolism have also been suggested. Therefore, functional polymorphisms in genes encoding members of this pathway, MTHFR C677T and A1298C (genes for methylenetetrahydrofolate reductase), MTR A2756G (gene for methionine synthase) and TS (gene for thymidylate synthase) tandem repeats polymorphisms, have attracted attention. We conducted a matched case-control study with 257 incident CRC cases and 771 non-cancer controls at the Aichi Cancer Center to clarify associations among folate intake and four polymorphisms with reference to CRC risk. Gene-environment interaction between polymorphisms, drinking and folate consumption was also evaluated. None of the polymorphisms showed any significant impact on CRC risk by genotype alone, but when combined with alcohol consumption the MTHFR 677CC type showed a significantly reduced risk (odds ratio (OR) = 0.45, 95% confidence interval (CI): 0.23-0.86) (P = 0.01). MTR GG showed increased risk only among drinkers (OR = 3.35, 1.40-8.05) (P = 0.047). TS polymorphism did not show statistical significance by genotype alone, while interaction with drinking was significant (P = 0.028). The association was not changed even after stratification by daily folate consumption and drinking habit. In conclusion, we found consistently significant interactions between one-carbon metabolism-related polymorphisms and alcohol drinking.     

Genetic polymorphisms of the methylenetetrahydrofolate reductase gene, plasma folate levels and breast cancer susceptibility: a case-control study in Taiwan

Methylenetetrahydrofolate reductase (MTHFR) balances the pool of folate coenzymes in one-carbon metabolism for DNA synthesis and methylation, both are implicated in carcinogenesis. Two common variants in the MTHFR gene (C677T and A1298C) have been associated with reduced enzyme activity, thereby making MTHFR polymorphisms a potential candidate cancer-predisposing factor. To evaluate the C677T and A1298C functional polymorphisms in the MTHFR gene and their associations with breast cancer risk, as well as the potential modifying effect by plasma folate status on the MTHFR-associated risk, a hospital-based case-control study was conducted on a Taiwanese population consisting of 146 histologically confirmed incident breast cancer cases and their 285 age-matched controls without a history of cancer. A PCR-RFLP method was used for MTHFR polymorphism genotyping and RIA was used to measure the plasma folate. Statistical evaluations were performed using logistic regression analysis. The plasma folate level was inversely associated with breast cancer risk with an adjusted odds ratio (OR) of 0.52 [95% confidence interval (CI): 0.26-1.05] observed among women who were in the highest plasma folate tertile. The MTHFR 677T and 1298C variant alleles were associated with decreased risk for breast cancer [adjusted ORs were 0.81 (95% CI: 0.54-1.21) and 0.57 (95% CI: 0.36-0.89) for 677CT + TT genotypes and 1298AC + CC genotypes, respectively]. Furthermore, compound heterozygote and homozygote variants (677CT + TT and 1298AC + CC) had greater reduced risk (adjusted OR: 0.11, 95% CI: 0.03-0.43) among women with lower plasma folate levels. These results provide support for the important role of folate metabolism in breast tumorigenesis. Further mechanistic studies are warranted to investigate how MTHFR combined genotypes exert their effect on cancer susceptibility.     

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.     

Polymorphisms in one-carbon metabolism and trans-sulfuration pathway genes and susceptibility to bladder cancer

We have previously reported significant inverse associations between bladder cancer risk and dietary intake of vitamins B2, B6, B12, folate and protein in a hospital-based bladder cancer case-control study conducted in Spain (1,150 cases;1,149 controls). Because these dietary factors are involved in the one-carbon metabolism pathway, we evaluated associations between bladder cancer risk and 33 single nucleotide polymorphisms (SNPs) in 8 genes (CBS, CTH, MTHFR, MTR, MTRR, SHMT1, SLC19A1 and TYMS) and interactions with dietary variables involved in this pathway. Two SNPs in the CTH gene were significantly associated with bladder cancer risk. OR (95% CI) for heterozygous and the homozygous variants compared to homozygous wild-type individuals were: 1.37 (1.04-1.80) IVS3-66 A > C and 1.22 (1.02-1.45) IVS10-430 C > T. Because the CTH gene is important for glutathione synthesis, we examined interactions with the GSTM1 gene, which codes for glutathione S-transferase muu. Increased risk for individuals with the IVS10-430 CT or TT genotype was limited to those with the GSTM1 null genotype (p-interaction = 0.02). No other SNPs were associated with risk of bladder cancer. These findings suggest that common genetic variants in the one-carbon pathway may not play an important role in the etiology of bladder cancer. However, our results provide some evidence that variation in glutathione synthesis may contribute to risk, particularly among individuals who carry a deletion in GSTM1. Additional work is needed to comprehensively evaluate genomic variation in CTH and related genes in the trans-sulfuration pathway and bladder cancer risk.     

C677T and A1298C MTHFR polymorphisms,a challenge for antifolate and fluoropyrimidine-based therapy personalisation

Pharmacogenetics represents an exciting, new promising tool for the individualisation of therapy. Several genetic polymorphisms and haplotypes have been considered in an attempt to optimise therapy with specific drugs but, up to now, their clinical applications remain limited.5,10-Methylenetetrahydrofolate reductase (MTHFR), a key enzyme of one-carbon metabolism, catalyses the irreversible conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. Two common non-synonymous variants, the C677T (Ala222Val) and A1298C (Glu429Ala), were described for the MTHFR gene and associated with a decreased enzymatic activity and an alteration of intracellular folate distribution. Other MTHFR polymorphisms with marginal impact on enzymatic activity were also reported.Several published clinical studies have investigated the potential predictive role of C677T and A1298C genetic variants on toxicity and efficacy of antifolate and fluoropyrimidine agents, such as methotrexate (MTX), 5-fluorouracil (5-FU) and raltitrexed. Many of these studies show significant associations with MTHFR variants, but others report neither association nor opposite results. A significant interaction between MTHFR polymorphisms and nutrient/environmental factors (i.e. folate status) as well as the ethnicity was reported. Finally, a haplotype approach and the combined analysis of multiple folate pathway gene variants seem to provide a more comprehensive strategy compared to single-locus investigations.The aim of this review is to critically analyse the available data on the importance of MTHFR polymorphisms in modulating the clinical outcome of antifolate and fluoropyrimidine therapies.     

The methionine synthase polymorphism c.2756A>G alters susceptibility to glioblastoma multiforme.

Genetic polymorphisms of methionine metabolism, in particular methionine synthase (MTR) c.2756A>G (D919G) and methylenetetrahydrofolate reductase (MTHFR) c.677C>T (A222V), have been associated with various human cancers. We investigated MTR c.2756A>G, MTHFR c.677C>T, and a third polymorphism, transcobalamin 2 c.776C>G (P259R), for a potential association with the formation of glioblastoma multiforme. The MTR c.2756G allele was significantly underrepresented among 328 glioblastoma multiforme patients of Caucasian origin when compared with 400 population controls [patients AA/AG/GG: 0.72/0.26/0.02 and controls AA/AG/GG: 0.57/0.38/0.05, degrees of freedom = 2; chi(2) = 17.86 (Pearson); P < 0.001]. No association between glioblastoma multiforme and the two other polymorphisms was observed.     

Impact of one-carbon metabolism-related gene polymorphisms on risk of lung cancer in Japan: a case control study

There is substantial evidence that the decreased risk of lung cancer with high intake of vegetables and fruits is linked to folate as a specific nutrient. Functional polymorphisms in genes encoding one-carbon metabolism enzymes, methylenetetrahydrofolate reductase (MTHFR C677T and A1,298C), methionine synthase (MTR A2,756G), methionine synthase reductase (MTRR A66G) and thymidylate synthase, influence folate metabolism and thus might be suspected of impacting on lung cancer risk. We therefore conducted a case-control study with 515 lung cancer cases newly and histologically diagnosed and 1,030 age- and sex-matched non-cancer controls to clarify associations with these five polymorphisms according to lung cancer subtype. Gene-environment interactions with smoking and drinking habit and folate consumption were also evaluated by logistic regression analysis. None of the polymorphisms showed any significant impact on lung cancer overall risk by genotype alone, but on histology-based analysis increase in MTHFR 677T and 1,298C alleles was associated with reduced risk of squamous/small cell carcinoma (P = 0.029), especially among heavy smokers (P = 0.035), whereas the MTHFR 677TT genotype was linked to decreased risk for these subtypes among heavy drinkers (odds ratio = 0.17, 95% confidence interval: 0.03-0.98). In addition, we found interactions between the MTRR A66G polymorphism and smoking (P = 0.015) and the MTHFR A1,298C polymorphism and alcohol consumption (P = 0.025) for risk of lung cancer overall. In conclusion, the results suggest that MTHFR polymorphisms contribute to risk of squamous/small cell carcinomas of the lung, along with possible interactions among folate metabolism-related polymorphisms and smoking/drinking habits. Further evaluation is warranted.     

Polymorphisms in folate metabolic genes and lung cancer risk in Xuan Wei, China

The aim of this study is to investigate the role of genetic polymorphisms in twelve folate metabolism genes on the risk of lung cancer in Xuan Wei, China, where the lung cancer mortality rate is among the highest and is mainly caused by indoor smoky coal emissions. A total of 122 incident primary lung cancer cases and 122 matched controls were enrolled. Three single nucleotide polymorphisms were associated with increased risk of lung cancer including homozygotes of the C allele of CBS Ala360Ala (OR: 4.02; 95% CI: 1.64-9.87), the 222Val allele of MTHFR (OR: 2.32; 95% CI: 1.34-4.03), and the C allele of SLC19A1 Pro232Pro (OR: 1.83; 95% CI: 1.02-3.28). The distribution of CBS and MTHFR haplotypes differed between cases and controls (P=0.002 and P=0.07, respectively). In summary, three genetic variants in folate metabolism genes are associated with an increased risk of lung cancer in Xuan Wei, China.     

Folate metabolism-related gene polymorphisms and susceptibility to primary liver cancer in North China

Genetic factors may contribute to individual differences in cancer susceptibility. This study was designed to investigate the effects of the polymorphisms of methylenetetrahydrofolate reductase 677 C → T (MTHFR 677 C → T), methylenetetrahydrofolate reductase 1298 A → C (MTHFR 1298A → C), thymidylate synthase (TYMS 3R → 2R), and methionine synthase 2756 A → G (MTR 2756 A → G) on the risk of primary liver cancer (PLC). We conducted a case-control study involving 356 PLC cases and 641 healthy controls in North China. Compared with the MTHFR 677CC genotype, the MTHFR 677TT genotype showed an increased risk for PLC (TT vs. CC: adjusted odds ratio (OR) = 1.56; 95% confidence interval (CI): 1.02-2.40; P = 0.043) after adjusting for gender and age, whereas the MTHFR 1298CC genotype showed a significantly decreased risk for PLC (CC vs. AA: adjusted OR = 0.23; 95% CI: 0.08-0.70; P = 0.010). However, no significant association was found between the TYMS 3R → 2R or the MTR 2756 A → G polymorphism and the risk of PLC. Our results suggest that the MTHFR 677 C → T and the MTHFR 1298A → C genetic polymorphisms might play important role in hepatic carcinogenesis. Further studies with larger sample sizes are required to validate this association.     

亚甲基四氢叶酸还原酶基因单核苷酸多态与乳腺癌风险

目的 内研究亚甲基四氢叶酸还原酶(MTHFR)基因单核苷酸多态与女性乳腺癌风险的关系。方法 以聚合酶链反应(PCR)和限制性片段长度多态性(RFLF)分析方法,检测了217例乳腺癌患者和218例配对的正常对照者MTHFR因C677T和A1298C基因型,并比较不同基因型与乳腺癌风险的关系。结果 677TT基因型频率在乳腺癌患者和正常对照中的分布差异有显著性(32．7％比24．8％,P=0．02)。携带MTHFR 677TT基因犁者与携带MTHFR 677CC基因型者比较,前者罹患乳腺癌的风险增加1,84倍(95％ C：1．09～3．14)。MTHFR 677CT基因型以及MTHFR A1298C多态与乳腺癌风险不相关。结论 MTHFR基因677C→T突变是女性乳腺癌的遗传易感因素。     

Germline polymorphisms in the one-carbon metabolism pathway and DNA methylation in colorectal cancer

Dietary intake of one-carbon nutrients (methyl donors) and germline variants in the one-carbon metabolism genes may influence global DNA methylation level and methylation in promoter CpG islands. In this study, we evaluated the relationship between single nucleotide polymorphisms (SNPs) in the one-carbon metabolism pathway and DNA methylation status in colorectal cancer. Utilizing 182 colorectal cancers cases in two prospective cohort studies, we determined the CpG island methylator phenotype (CIMP) status on eight CIMP-specific promoters and measured LINE-1 methylation level that correlates well with genome-wide DNA methylation level. We genotyped 23 nonsynonymous SNPs in the one-carbon metabolism genes using buffy coat DNA. Most of the 23 SNPs in the one-carbon metabolism pathway were not significantly associated with CIMP-high status (≥6/8 methylated promoters). However, the MTHFR 429 Ala/Ala variant (rs1801131) and the TCN2 259 Arg/Arg variant (rs1801198) were associated with CIMP-high status (MTHFR 429 multivariate odds ratio (MV OR) = 7.56; 95% confidence interval (CI), 1.32–43.3; p trend = 0.10; TCN2 259 Arg/Arg variant MV OR = 3.82; 95% CI, 1.02–14.4; p trend = 0.06). The one-carbon metabolism genotypes were not significantly associated with LINE-1 methylation, although there were modest differences in mean LINE-1 methylation levels between certain genotypes. Collectively, these exploratory data provide suggestive evidence for the association of MTHFR 429 Ala/Ala and TCN2 259 Arg/Arg and CIMP status in colorectal cancer.     

Functional polymorphisms in folate metabolism genes influence the risk of meningioma and glioma.

Folate metabolism plays an important role in carcinogenesis. To test the hypothesis that polymorphic variation in the folate metabolism genes 5,10-methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTRR), and methionine synthase reductase (MTR) influences the risk of primary brain tumors, we genotyped 1,005 glioma cases, 631 meningioma cases, and 1,101 controls for the MTHFR C677A and A1298C, MTRR A66G, and MTR A2756G variants. MTHFR C677T-A1298C diplotypes were associated with risk of meningioma (P = 0.002) and glioma (P = 0.02); risks were increased with genotypes associated with reduced MTHFR activity. The highest risk of meningioma was associated with heterozygosity for both MTHFR variants [odds ratio (OR), 2.11; 95% confidence interval (95% CI), 1.42-3.12]. The corresponding OR for glioma was 1.23 (95% CI, 0.91-1.66). A significant association between risk of meningioma and homozygosity for MTRR 66G was also observed (OR, 1.41; 95% CI, 1.02-1.94). Our findings provide support for the role of folate metabolism in the development of primary brain tumors. In particular, genotypes associated with increased 5,10-methylenetetrahydrofolate levels are associated with elevated risk.     

Association of aberrations in one-carbon metabolism with molecular phenotype and grade of breast cancer

We have earlier demonstrated the role of aberrant one-carbon metabolism in the etiology of breast cancer. In the current study, we examine the clinical utility of these factors in predicting the subtype of breast cancer and as indicators of disease progression. Polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) and PCR-amplified fragment length polymorphism (AFLP) approaches were used for genetic analysis. Plasma folate and homocysteine were measured using Axsym folate kit and reverse phase HPLC, respectively. Multiple linear regression models were used to test the predictability of disease progression. Luminal A subtype was associated with late age of onset, higher body mass index and lack of family history of breast cancer. Thymidylate synthase (TYMS) 5'-UTR 28?bp tandem repeat (OR: 2.09, 95% CI: 1.05-4.16) and methylene tetrahydrofolate reductase (MTHFR) C677T (OR: 4.10, 95% CI: 1.40-11.95) were strongly associated with Luminal B. Reduced folate carrier (RFC1) G80A (OR: 2.92, 95% CI: 1.22-6.97) and methionine synthase (MTR) A2756G (OR: 4.71, 95% CI: 1.66-13.31) polymorphisms were associated with LuminA-HH subtype while MTHFR C677T showed association with HER-enriched (OR: 30.41, 95% CI: 6.47-142.91). Cytosolic serine hydroxymethyltransferase (cSHMT) conferred protection against basal-like breast cancer (OR: 0.47, 95% CI: 0.22-0.98). HER-enriched and basal-like subtypes showed positive association with familial breast cancer and inverse association with plasma folate. Hyperhomocysteinemia was observed in Luminal B and basal-like subtypes. Multiple linear regression models of aberrant one-carbon metabolism were found to be moderate predictors of breast cancer grade (area under the receiver operating characteristic curve, C?=?0.72, 95% CI: 0.58-0.87, P?=?0.008). To conclude, aberrations in one-carbon metabolism predict the subtype of breast cancer and disease progression. ? 2011 Wiley Periodicals, Inc.     

Genetic polymorphisms in folate metabolism and the risk of stomach cancer.

Folate deficiency has been implicated in the etiology of stomach cancer through abnormal DNA methylation and disrupted DNA synthesis and repair. Enzyme-coding genes involved in folate metabolism are often polymorphic. In a population-based study of 305 cases and 427 controls in Warsaw, Poland, we evaluated the risk of stomach cancer in relation to polymorphisms in folate-metabolizing genes, including MTHFR (Ex5+79C>T and Ex8-62A>C), MTR (Ex26-20A>G), and MTRR (Ex2-64A>G, Ex5+123C>T, Ex15+572C>T, Ex15-405A>T, Ex9-85C>T, Ex15-526G>A, and Ex14+14C>T). Polymorphisms in the MTHFR gene were not associated with stomach cancer risk. No notable effect was found for polymorphisms in MTR or MTRR either, although MTR Ex26-20 A>G and MTRR Ex5+123C>T polymorphisms were associated with a borderline increased risk of stomach cancer (MTR Ex26-20A>G, AG/GG versus AA: odds ratio, 1.35; 95% confidence interval, 0.96-1.90; MTRR Ex5+123C>T, CT/TT versus CC: odds ratio, 1.30; 95% confidence interval, 0.93-1.82). We did not find significant interactions between polymorphisms in MTHFR, MTR, and MTRR genes and dietary folate and alcohol consumption. Our study did not identify strong genetic determinants in the folate metabolism pathway for stomach cancer risk.     

Polymorphisms of one-carbon-metabolizing genes and risk of breast cancer in a population-based study

One-carbon metabolism facilitates the crosstalk between genetic and epigenetic processes and plays critical roles in both DNA methylation and DNA synthesis, making it a good candidate for studying the risk of breast cancer. We previously reported that polymorphisms in methylenetetrahydrofolate reductase (MTHFR) in one-carbon pathway were associated with breast cancer risk in the population-based Long Island Breast Cancer Study Project. Herein, we systematically investigated putatively functional polymorphisms of seven other one-carbon-metabolizing genes in relation to the breast cancer risk in the same population. Except for a slight indication of increased risk of breast cancer associated with the double repeat (2R) allele in the thymidylate synthase (TYMS) 5'-untranslated region (UTR) (P, trend = 0.07), polymorphisms in the other six genes did not substantially modify the risk of breast cancer, or did they modify the risk associated with dietary intakes of folate and related B vitamins. However, we observed a significant multiplicative interaction between the MTHFR 677C>T and the TYMS 5'-UTR polymorphisms (P = 0.02). We used a recursive partitioning method, RTREE, in an attempt to tease out important or rate-limiting genes encoding these intricately related enzymes. Results from RTREE analyses indicate that MTHFR and TYMS are the two leading rate-limiting enzymes in the pathway, consistent with our epidemiological findings. Our findings underscore the importance of one-carbon metabolism in breast cancer etiology. Although the pathway is a network of interrelated enzymes, redundancy exists; evaluating the rate-limiting enzyme and its interaction with environment and other genes within the same pathway is critical in assessing breast cancer risk.     

B-vitamin intake, one-carbon metabolism, and survival in a population-based study of women with breast cancer

Breast cancer is the second leading cause of cancer mortality among women. Given its important role in DNA methylation and synthesis, one-carbon metabolism may affect breast cancer mortality. We used a population-based cohort of 1,508 women with breast cancer to investigate possible associations of dietary intake of B vitamins before diagnosis as well as nine polymorphisms of one-carbon metabolizing genes and subsequent survival. Women newly diagnosed with a first primary breast cancer in 1996 to 1997 were followed for vital status for an average of 5.6 years. Kaplan-Meier survival and Cox proportional hazard regression analyses were used to evaluate the association between dietary intakes of B vitamins (1,479 cases), genotypes ( approximately 1,065 cases), and all-cause as well as breast cancer-specific mortality. We found that higher dietary intake of vitamin B(1) and B(3) was associated with improved survival during the follow-up period (P(trend) = 0.01 and 0.04, respectively). Compared with the major genotype, the MTHFR 677 T allele carriers have reduced all-cause mortality and breast cancer-specific mortality in a dominant model [hazard ratio (95% confidence interval): 0.69 (0.49-0.98) and 0.58 (0.38-0.89), respectively]. The BHMT 742 A allele was also associated with reduced all-cause mortality [hazard ratio, 0.70 (0.50-1.00)]. Estrogen receptor/progesterone receptor status modified the association between the MTHFR C677T polymorphism and survival (P = 0.05). The survival associations with one-carbon polymorphisms did not differ with the use of chemotherapy, although study power was limited for examining such effect modification. Our results indicate that one-carbon metabolism may be an important pathway that could be targeted to improve breast cancer survival.     

Colorectal cancer and the methylenetetrahydrofolate reductase 677C -> T and methionine synthase 2756A -> G polymorphisms: a study of 2,168 case-control pairs from the JANUS cohort.

Polymorphisms in genes involved in the metabolism of folate and methyl groups have been implicated with risk of colorectal cancer. We evaluated the relation between the polymorphisms 677C --> T of the methylenetetrahydrofolate reductase (MTHFR) and 2756A --> G of the methionine synthase (MTR) genes and risk of colorectal cancer. From the Norwegian JANUS cohort of 309,000 subjects, 2,179 cases were identified and a similar number of controls were selected. The controls were matched for age, gender, time, and place of serum donation. Genotypes were obtained from 2,168 case-control pairs by real-time PCR of serum samples. Risk of colorectal cancer was estimated with conditional and unconditional logistic regression. Median age at diagnosis was 60 years and mean follow-up 13 years. The odds ratio for MTHFR TT versus CC was 0.73 [95% confidence interval (95% CI), 0.58-0.92] and for MTR GG versus AA was 0.65 (95% CI, 0.47-0.90). No interaction between the polymorphisms was found. Relative risk estimates were similar for men and women, and for young and old age at diagnosis. For the MTR GG genotype, risk reduction was observed at the two most distal sites (sigmoideum and rectum) only (P = 0.003). The folate marker, serum total homocysteine (tHcy), was measured in 1,837 subjects. Odds ratio for the upper versus the lower tertile of tHcy was 1.32 (95% CI, 1.04-1.68). No significant effect modification by tHcy levels was detected for either polymorphism. In summary, we found significantly reduced risk of colorectal cancer in subjects with the MTHFR 677 TT and MTR 2756 GG genotypes. No interaction between the polymorphisms, or of either polymorphism with tHcy, was detected.