MTHFR polymorphisms, dietary folate intake and risks to breast cancer / 中华预防医学杂志

<p><b>OBJECTIVE</b>To evaluate the relationship between dietary folate intake and genetic polymorphisms of 5, 10-methylenetetrahydrofolate reductase (MTHFR) with reference to breast cancer risk.</p><p><b>METHODS</b>A case-control study was conducted with 669 cases and 682 population-based controls in Jiangsu province of China. MTHFR C677T and A1298C genotypes were identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Dietary folate intake was assessed by using an 83-item food frequency questionnaire. Odds ratios (OR) were estimated with an unconditional logistic model.</p><p><b>RESULTS</b>The frequencies of MTHFR C677T C/C, C/T and T/T genotypes were 32.37% (202/624), 48.88% (305/624) and 18.75% (117/624) in cases and 37.66% (235/624), 48.24% (301/624) and 14. 10% (88/624) in controls, respectively. The difference in distribution was significant (chi2 = 6.616, P = 0.037), the T/T genotype being associated with an elevated OR for breast cancer (1.62, 95% CI: 1.14 -2.30). The frequencies of MTHFR A1298C A/A, A/C and C/C were 71.47% (446/624), 27.08% (169/624) and 1.44% (9/624) in cases and 68.11%(425/624), 30.13% (188/624) and 1.76% (11/624)in controls,with no significant differences found (chi2 = 1.716, P= 0.424). Folate intake of cases [(263.00 +/- 137.38) microg/d] was significantly lower than that of controls [(285.12 +/- 149.61) microg/d] (t = -2. 830, P =0.005). Compared with the lowest tertile (< or = 199.08 microg/d) of folate intake, the adjusted OR for breast cancer in the top tertile (> or = 315.11 microg/d) was 0.70 (95% CI: 0.53 -0.92). Among individuals with the MTHFR A1298C A/A genotype,adjusted OR for breast cancer were 0.89 (95% CI: 0.62 - 1.27) and 1.69 (95% CI: 1.20 - 2.36) for the second to the third tertile of folate intake compared with the highest folate intake group (X2trend = 11.372, P = 0.001).</p><p><b>CONCLUSION</b>The findings of the present study suggest that MTHFR genetic polymorphisms,and dietary intake of folate may modify susceptibility to breast cancer.</p>

Aberrant promoter methylation profile in pleural fluid DNA and clinicopathological factors in patients with non-small cell lung cancer.

The aim of this study was to investigate the prognostic value of hypermethylation of tumor suppressor genes in patients with non-small cell lung cancer (NSCLC). In samples from 34 lung patients with malignant pleural effusions, we used a methylation-specific polymerase chain reaction to detect aberrant hypermethylation of the promoters of the DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT), p16INK4a, ras association domain family 1A (RASSF1A), apoptosis-related genes, death-associated protein kinase (DAPK), and retinoic acid receptor beta(RARbeta).There is no association between methylation status of five tumor suppressor genes including MGMT, p16INK4a, RASSF1A, DAPK and RARbeta in pleural fluid DNA and clinicopathological parameters including clinical outcome. Aberrant promoter methylation of tumor suppressor genes in pleural fluid DNA could not be a valuable prognostic marker of NSCLC patients with malignant pleural effusion.

The JICA training course, community-based cancer prevention for the Asian and Pan-Pacific countries, fiscal year 2006 (epidemiological approach).

Communicable diseases are still major causes of deaths in developing countries. Cancer incidence, however, increased 19% between 1990 and 2000, mainly in this same developing world (Stewart and Kleihaus, 2003), and malignant neoplasms are now the second leading cause of mortality in these countries (WHO, 2003). Limitations of medical facilities and equipment mean that prevention is indispensable for cancer control (Mikheev et al., 1994). However, human resources concerning cancer prevention are also limited, and encouragement of their development should be taken as a first priority. To assist in this aim, the present training course was designed by the Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Japan, and has been annually conducted since 1999, supported by the Japan International Cooperation Agency (JICA) (Takezaki, 2001; 2002; 2003; Wakai, 2004; 2006). The course targets doctors and public health workers who are responsible for community-based cancer prevention in developing countries to promote the introduction of comprehensive procedures, focusing mainly on primary prevention but also including screening for secondary prevention of cancer.

Risk factors for multiple myeloma: evidence from the Japan Collaborative Cohort (JACC) study.

This study assessed the association of multiple myeloma (MM) with age, body mass index (BMI, kg/m(2)), physical activity, occupational history, and medical history for a Japanese cohort of 46,157 men and 63,541 women aged 40-79 years followed during 1988-2003 years. Cox proportional hazard model was mainly used to estimate the age and sex adjusted hazard ratio (HR) of MM including 95% confidence interval (CI) for both sexes. Same model, adjusted for age, was also used for each sex. In total, 98 MM deaths (men=49 and women=49) was observed for both sexes. Higher age groups (60-69 and 70-79 years) experienced significantly higher unadjusted HR of MM than the age group of 40-49 years. Men revealed significantly higher age-adjusted MM than women (HR=1.5; 95% CI=1.0-2.2). For both sexes, higher BMI of >or=30 kg/m(2)) (HR=2.8; 95% CI=1.0-7.7), walking <or=30 minutes/day (HR=2.0; 95% CI=1.2-3.4), worried about personal relationship in working place (HR=2.3; 95% CI=1.3-4.2), restricted own pace in working place (HR=1.9; 95% CI=1.0-3.4), and history of peptic ulcer (HR=1.7; 95% CI=1.0-2.7) significantly increased age and sex adjusted MM risk. Some of the above-mentioned significant associations became insignificant for age adjusted sex specific analyses. However, these findings should be validated by further epidemiologic studies in Japan before generalization.

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.

Risk factors for esophageal cancer: a case-control study in South-western China.

Esophageal cancer is a crucial cancer in China. Yanting in Sichuan Province was a key area with highest esophageal cancer mortality in China, but little evidence on esophageal cancer risk factors has been reported for this area and the etiology remains unclear. To clarify risk factors, a 1:1 matched case-control study was conducted. Totals of 185 eligible esophageal cancer patients and 185 healthy residents matched for sex and age were recruited. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for possible risk/protective factors. All ORs were adjusted by family history of esophageal cancer and occupation, and then further adjusted by other possible confounding factors. Our results showed that smoking and alcohol drinking were risk factors for esophageal cancer with dose-response. The ORs (95% CI) compared with never smokers and drinkers were 4.06 (1.55-10.6) and 2.49 (1.06-5.85), respectively. The OR was further increased to 8.86 (95% CI, 3.82-20.5) for both smoking and drinking in combination. Eating food rapidly (OR=5.84, 95% CI, 2.05-16.7), drinking shallow ground water (OR=4.18, 95% CI, 1.30-13.4) and frequent intake of picked vegetables (OR=2.12, 95% CI, 1.00-4.49) appeared to increase the risk, while frequent intake of fresh fruit (OR=0.42, 95% CI, 0.19-0.89), fresh vegetables (OR= 0.62, 95% CI, 0.32-1.17) and eggs (OR=0.59, 95% CI, 0.25-1.39) decreased the risk. In conclusion, smoking and alcohol drinking are common in Yanting and main contributors to esophageal cancer. Consumption of fresh fruit and eggs are not common and high consumption of these two foods as well as fresh vegetables may decrease the risk of esophageal cancer in this area. In addition, drinking shallow ground water and eating food rapidly, as well as frequent intake of pickled vegetables, are also factors increasing the risk.

Relation of the CD36 gene A52C polymorphism to the risk of colorectal cancer among Japanese, with reference to with the aldehyde dehydrogenase 2 gene Glu487Lys polymorphism and drinking habit.

High consumption of white meat (or saturated fatty acids) and alcohol has been demonstrated to have a tendency to increase the risk of colorectal cancer, according to the level of malondialdehyde-deoxyguanosine adducts derived from lipid per-oxidation in the colorectal mucosa. CD36 plays important roles as a long-chain fatty acid translocase and oxidized low-density lipoprotein (LDL) scavenger, while alcohol is metabolized by aldehyde dehydrogenase 2 (ALDH2) and decreases transiently metabolism of dietary fat and serum lipids. To examine associations between the risk of colorectal cancer and the CD36 gene A52C polymorphism according to the ALDH2 gene Glu487Lys polymorphism and drinking habit, a hospital-based case-control study was conducted with 128 colorectal cancer cases and 238 cancer-free controls. Odds ratios (ORs) for the C/C genotype relative to the A/A genotype were 1.70 [95% confidence interval (CI), 0.76-4.11] and 4.24 (95% CI, 1.42-22.66) for men and women, respectively, with the low-activity (Glu/Lys + Lys/Lys) ALDH2 genotype. The high-activity (Glu/Glu) genotype for men and women had no associations. On the other hand, the OR for the C/C genotype with high frequency of drinking habit relative to the A/A genotype with low frequency of drinking habit among men was 3.63 (95% CI, 1.29-13.15). The number of women with a high frequency drinking habit was too small for any corresponding analyses. Our findings suggest a significant interaction between alcohol consumption and the CD36 gene A52C polymorphism related to the metabolism of long-chain fatty acids and oxidized LDL in the etiology of colorectal cancer.

Comparison of lifestyle risk factors by family history for gastric, breast, lung and colorectal cancer.

To assess the theoretical impact of lifestyle of a cancer family history in first-degree relatives (CFH) and clarify interactions between CFH and lifestyle factors, hospital-based comparison and case-reference studies were conducted in Nagoya, Japan. Totals of 1988 gastric, 2455 breast, 1398 lung and 1352 colorectal cancer patients, as well as 50,706 non-cancer outpatients collected from 1988 to 1998, were checked for lifestyle factors, which included dietary and physical exercise habits, as well as smoking/drinking status. General lifestyle factors with non-cancer outpatients did not differ by the CFH status. Case-reference analyses showed that frequent intake of fruits, raw vegetables, carrots, pumpkin, cabbage and lettuce, as well as frequent physical exercise, were associated with decreased risk for all four sites of cancer, while habitual smoking increasing the risk of gastric, and more particularly, lung cancer. Interestingly, the study revealed the magnitude of odds ratios for the above lifestyle factors obtained from CFH positives to be similar to those from CFH negatives for these four sites of cancer. There were no significant interactions between CFH and any particular lifestyle factor. In conclusion, our results suggest no appreciable influence of CFH on lifestyle related risk factors for gastric, breast, lung, and colorectal cancer. Habitual smoking increased, while frequent physical exercise and raw vegetables intake decreased cancer risk, regardless of the CFH status.

Polymorphisms in thymidylate synthase and methylenetetrahydrofolate reductase genes and the susceptibility to esophageal and stomach cancer with smoking.

Thymidylate synthetase (TS) and methylenetetrahydrofolate reductase (MTHFR) are major enzymes in the metabolism of folates, involved in DNA 'breaks', instability and hypomethylation. To investigate the possible relations between the TS 3'-UTR and MTHFR C677T polymorphisms and environmental factors impacting on risk of esophageal and stomach cancers, we conducted a case-control study in a high incidence region of China for these cancers. We recruited 138 esophageal and 155 stomach cancer cases, and 223 controls. The TS 3' -UTR and MTHFR C677T genotypes were detected by RFLP assay, using PCR products. The frequency of the -6 bp homozygous TS 3' -UTR genotype was 37.7 % in controls, higher than in Caucasians, although the present distribution was not in Hardy-Weinberg equilibrium. Ever-smoking with the -6 bp/-6 bp TS genotype elevated the ORs (2.61, 1.24-5.49; 3.54, 1.60-7.82) for cases of esophageal and stomach cancers, respectively, when compared with never-smoking with the +6 bp/+6 bp and +6 bp/-6 bp genotypes. No combination between the TS and MTHFR genotypes gave increased ORs. The present results suggest that TS polymorphism may modify the risk of esophageal and stomach cancer with smoking, pointing to the necessity for further investigations with information on folate and methionine intake with a larger population.