Kazuo Tajima

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.

Reproducibility of a short food frequency questionnaire for japanese general population

BACKGROUND In epidemiologic field studies, a food frequency questionnaire (FFQ) is one of the most feasible tools to assess usual dietary habits. The purpose of this study is to evaluate the reproducibility of consumption of foods and nutrients assessed with a self-administered short FFQ in a Japanese general population. METHODS We have investigated 1-year interval reproducibility of a self-administered short FFQ, comprising 47 food items, and 8 frequency categories, among 1,918 subjects (844 males and 1,074 females) who participated in health check-up programs in Central Japan. RESULTS Intakes of energy and 24 nutrients along with 15 food groups estimated using the first questionnaire (FFQ1) were approximately equal to those using the second (FFQ2). Spearman’s rank correlation coefficients (CCs) between intakes of nutrients quantified with FFQ1 and FFQ2 in males were distributed as 0.74 - 0.66- 0.55 (maximum - median - minimum), and intraclass CCs (ICCs) as 0.85 - 0.78 - 0.67. Among females, Spearman’s rank CCs were distributed as 0.73 - 0.62 - 0.54, and ICCs as 0.84 - 0.77 - 0.69. Percentages of exact agreement, exact agreement plus agreement within adjacent categories and disagreement according to quintile categorization were 43%, 80%, and 1%, for males, and 42%, 79%, and 1% for females. Reproducibility figures were higher for the elderly than for young people in both sexes. CONCLUSIONS Our FFQ yielded substantially high reproducibility and it may be applicable for assessing consumption of foods/food groups and energy and selected nutrients for the middle-aged and elderly population in Japan.

Alcohol Dehydrogenase 2 His47Arg Polymorphism Influences Drinking Habit Independently of Aldehyde Dehydrogenase 2 Glu487Lys Polymorphism: Analysis of 2,299 Japanese Subjects

Although the functional effect of alcohol dehydrogenase 2 (ADH2) His47Arg polymorphism has been elucidated, its effect on habitual drinking remains unknown. Here, we conducted a cross-sectional study in 2,299 nonalcoholic Japanese subjects (989 men and 1,310 women). Drinking status, ethanol consumption, and physical reaction to one glass of beer were examined with regard to ADH2 and aldehyde dehydrogenase 2 (ALDH2) polymorphism. Strength of associations were assessed by age-, sex-, smoking status-, and genotype-adjusted odds ratios and their 95% confidence intervals. ADH2 His/Arg and Arg/Arg genotypes showed higher risk for habitual drinking. Among men, ALDH2 genotype- and confounder-adjusted odds ratios (95% confidence intervals) were 1.30 (0.89-1.89) and 3.16 (1.03-9.70), and this trend was significant (P = 0.024). A similar trend was observed among women. The combination genotypes of two polymorphisms revealed the clear effect of the ADH2 Arg allele among those with ALDH2 Glu/Lys in both sexes (Ptrend = 0.007 for men and 0.024 for women). Physical reactions, such as flushing and palpitation, were significantly less common in those with Arg/Arg compared with other ADH2 genotypes, and this was marked when combined with ALDH2 Glu/Lys. Heavy drinker status was also strongly associated with ADH2 Arg alleles. In conclusion, this study showed the strong effect of ADH2 His47Arg polymorphism on habitual drinking regardless of ALDH2 genotype. (Cancer Epidemiol Biomarkers Prev 2006;15(5):1009–13)

Dietary risk factors for colon and rectal cancers: a comparative case-control study.

BACKGROUND In Japan, the incidence rate of colon cancer has more rapidly increased than that of rectal cancer. The differential secular trends may be due to different dietary factors in the development of colon and rectal cancers. METHODS To compare dietary risk factors between colon and rectal cancers, we undertook a case-control study at Aichi Cancer Center Hospital, Japan. Subjects were 507 patients with newly diagnosed colon (n = 265) and rectal (n = 242) cancers, and 2,535 cancer-free outpatients (controls). Intakes of nutrients and food groups were assessed with a food frequency questionnaire, and multivariate-adjusted odds ratios (ORs) were estimated using unconditional logistic models. RESULTS We found a decreasing risk of colon cancer with increasing intakes of calcium and insoluble dietary fiber; the multivariate ORs across quartiles of intake were 1.00, 0.90, 0.80, and 0.67 (trend p = 0.040), and 1.00, 0.69, 0.64, and 0.65 (trend p = 0.027), respectively. For rectal cancer, a higher consumption of carotene and meat was associated with a reduced risk; the corresponding ORs were 1.00, 1.10, 0.71, and 0.70 for carotene (trend p = 0.028), and 1.00, 0.99, 0.68, and 0.72 for meat (trend p = 0.036). Carbohydrate intake was positively correlated with the risk of rectal cancer (ORs over quartiles: 1.00, 1.14, 1.42, and 1.54; trend p = 0.048). This association was stronger in women, while fat consumption was inversely correlated with the risk of female colon and rectal cancers. CONCLUSIONS Dietary risk factors appear to considerably differ between colon and rectal cancers.

Risk factors differ for non‐small‐cell lung cancers with and without EGFR mutation: assessment of smoking and sex by a case‐control study in Japanese

The present study aimed to assess the impact of smoking and sex for the risk of non‐small‐cell lung cancer (NSCLC) with or without epidermal growth factor receptor (EGFR) mutation. We conducted a case‐control study using 152 patients with EGFR‐mutated (EGFRmut) NSCLC, 283 with EGFR‐wild‐type (EGFRwt) NSCLC and 2175 age‐ and sex‐frequency‐matched controls. Smoking was a significant risk factor for EGFRwt NSCLC (odds ratio [OR] for ever‐smokers, 4.05; 95% confidence interval [CI], 2.79–5.88) but not for EGFRmut NSCLC (OR, 0.73; CI, 0.46–1.14). Sex did not affect this association. The association was observed consistently with other smoking‐related parameters including pack‐years. Sex was the sole risk factor for EGFRmut NSCLC (OR for women relative to men, 2.19; CI, 1.41–3.39) and there was no significant interaction between women and smoking. In contrast, sex, smoking and their interaction were significant in EGFRwt NSCLC. The impact of sex on EGFR mutation status was assessed by several indicators of reproductive history among women. Total fertile years showed a significant positive association with EGFRmut NSCLC but not with EGFRwt NSCLC. Other indicators showed similar trends and this result may partly explain the sexual difference in the acquisition of EGFR mutation. In conclusion, our case‐control study clearly demonstrated that the impacts of smoking and sex on the risk of EGFRmut NSCLC are different from those for EGFRwt NSCLC. Further epidemiological evaluation is warranted. (Cancer Sci 2007; 98: 96–101)

Breast cancer risk and erythrocyte compositions of n‐3 highly unsaturated fatty acids in Japanese

Dietary intake of fish rich in n‐3 highly unsaturated fatty acids (HUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), has been proposed to decrease cancer risk. In contrast to results from laboratory studies, however, protective effects for breast cancer have proved equivocal in epidemiological studies. In the present case‐control study, we examined associations between breast cancer risk and fatty acid compositions in erythrocyte membranes as biomarkers for those intakes. Dietary information and blood samples were collected from 103 incident breast cancer cases and 309 non‐cancer controls (matched by age and season) and erythrocyte fatty acids were measured using accelerated solvent extraction and gas‐liquid chromatography. Dietary intake of n‐3 HUFAs demonstrated a negative association with risk (the highest to the lowest tertile, odds ratio (OR), 0.51; 95% confidence interval (CI), 0.27–0.98; ptrend < 0.05), but there was no association with those of saturated fatty acids (SFAs) and meat. Moreover, risk was inversely associated with erythrocyte compositions of EPA (OR, 0.27; 95% CI, 0.14–0.53; ptrend < 0.0001), DHA (OR, 0.06; 95% CI, 0.02–0.16; ptrend < 0.0001) and n‐3 HUFAs (OR, 0.11; 95% CI, 0.05–0.24; ptrend < 0.0001), and positively with that of SFAs (OR, 12.29; 95% CI, 4.94–30.57; ptrend < 0.0001) and the ratio of SFAs/n‐3 HUFAs (OR, 14.65; 95% CI, 5.67–37.82; ptrend < 0.0001). In conclusion, we showed that erythrocyte compositions of specific fatty acids derived from fish intake, as biomarkers, are associated with lower risk of breast cancer, but further studies are needed to investigate mechanisms linked to the etiology.

Dietary patterns and the risk of breast cancer in Japanese women

Components of the Japanese diet that might contribute to the relatively low breast cancer incidence in Japanese women have not been clarified in detail. To evaluate associations between broad dietary patterns and breast cancer risk in a Japanese population, the authors conducted a case–control study using data from the hospital‐based epidemiologic research program at Aichi Cancer Center (HERPACC). Factor analysis (principal components) was used to derive food patterns based on the 31 food variables and allowed designation of four major dietary patterns: prudent, fatty, Japanese and salty. In total, 1885 breast cancer cases were included and 22 333 female non‐cancer patients were recruited as the control group. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were determined using multiple logistic regression analysis. After adjusting for potential confounders, there were no clear associations between the fatty, Japanese or salty dietary patterns and overall breast cancer risk. In contrast, an inverse association was evident for the prudent dietary. Women in the highest quartile of the prudent dietary pattern scores, had a 27% decreased risk of breast cancer compared with those in the lowest (95% CI: 0.63–0.84, p for trend < 0.0001). In addition, for women with a body mass index ≥25, the highest quartile of the fatty factor score was associated with a 58% increment in breast cancer risk compared to the lowest quartile, with a significant linear trend (P = 0.027). The authors found the prudent dietary pattern to be negatively associated with breast cancer risk. In addition, the fatty and Japanese patterns may increase breast cancer risk among obese women. (Cancer Sci 2007; 98: 1431–1438)

Risk of Colorectal Cancer Is Linked to Erythrocyte Compositions of Fatty Acids as Biomarkers for Dietary Intakes of Fish, Fat, and Fatty Acids

Consumption of fish rich in n-3 polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid, is suggested to reduce colorectal cancer risk through inhibition of the arachidonic acid (AA) cascade related to tumorigenesis and cell proliferation. High intake of saturated fatty acids (SFAs) may increase the risk. To examine associations between colorectal cancer risk and fatty acid compositions in erythrocyte membranes, as biomarkers for dietary intakes of fish, fat, and fatty acids, we conducted a case-control study with 74 incident cases and 221 noncancer controls (matched by age, sex, and season of sample collection). Erythrocyte fatty acids were measured using an accelerated solvent extraction and a gas-liquid chromatography. Colorectal cancer had no association with dietary intakes of meat, fish, fat, and fatty acids. However, the risk was inversely associated with erythrocyte compositions of docosahexaenoic acid, AA, and PUFAs [the highest to the lowest tertile, odds ratios, 0.36, 0.42, and 0.15; 95% confidence intervals, 0.14-0.93, 0.18-0.95, and 0.05-0.46; Ptrend < 0.05, respectively] and positively with those of palmitic acid, SFAs, and the ratio of SFAs/PUFAs (odds ratios, 6.46, 8.20, and 9.45; 95% confidence intervals, 2.41-17.26, 2.86-23.52, and 2.84-31.43; Ptrend < 0.005, respectively). In conclusion, we could clearly show decreased and increased risks for colorectal cancer related to PUFAs and SFAs compositions in erythrocyte membranes, respectively, but further research is needed to investigate the discrepancy between our findings and the generally accepted role of the AA cascade. (Cancer Epidemiol Biomarkers Prev 2006;15(10):1791–8)

Systematic review and meta-analysis: importance of CagA status for successful eradication of Helicobacter pylori infection

Some, but not all studies have provided evidence that the CagA status of Helicobacter pylori strains is a predictive factor for the outcome of eradication therapy.

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. (Cancer Sci 2007; 98: 1439–1446)