Rare TCF3 variants associated with pediatric B cell acute lymphoblastic leukemia.

Germline genetic variants influence development of pediatric B cell acute lymphoblastic leukemia (B-ALL). Genome-wide association studies (GWAS) have identified several pediatric B-ALL susceptibility loci. IKZF1 and PAX5, transcription factors involved in B cell development, have been reported as susceptibility genes for B-ALL development. Therefore, we hypothesized that rare variants of genes involved in B cell development would be candidate susceptibility loci for pediatric B-ALL. Thus, we sequenced TCF3, a key transcription factor gene involving in B cell development. Saliva DNA from 527 pediatric patients with pediatric B-ALL in remission who were registered with the Tokyo Children's Cancer Study Group (TCCSG) were examined. As a TCF3 gene-based evaluation, the numbers of rare deleterious germline TCF3 sequence variants in patients with pediatric B-ALL were compared with those in cancer-free individuals using data in public databases. As a TCF3 single-variant evaluation, the frequencies of rare deleterious germline TCF3 sequence variants in patients with pediatric B-ALL were also compared with those in control data. TCF3 gene-based analysis revealed significant associations between rare deleterious variants and pediatric B-ALL development. In addition, TCF3 variant-based analysis showed particularly strong association between variant rs372168347 (three in 521 TCCSG and three in the 15780 gnomAD whole genome analysis cohort, p = 0.0006) and pediatric B-ALL development. TCF3 variants are known to influence B cell maturation and may increase the risk of preleukemic clone emergence.

Increase in Bifidobacterium is a characteristic of the difference in the salivary microbiota of pregnant and non-pregnant women.

BACKGROUND: The establishment of symbiotic microbiota in pregnant women is important for both the mother and her offspring. Little is known about the salivary symbiotic bacteria in pregnancy, and analysis of composition of microbiome (ANCOM) is useful to detect small differences in the number of bacteria. The aim of this study was to investigate the differences in the salivary bacteria between healthy pregnant and non-pregnant women using ANCOM. METHODS: Unstimulated saliva samples were collected from 35 healthy pregnant women at 35 weeks gestation and 30 healthy non-pregnant women during menstruation. All participants underwent a periodontal examination. Estradiol and progesterone levels were examined by enzyme-linked immunosorbent assay. DNA extracted from the saliva was assessed by 16S ribosomal RNA amplicon sequencing and real-time PCR. RESULTS: Salivary estradiol and progesterone levels were significantly increased in pregnant women. The alpha and beta diversities were higher in pregnant women than in non-pregnant women. The largest effect size difference noted when the microbiota of the pregnant and non-pregnant women were analyzed was that for Bifidobacteriales. Levels of Bifidobacterium dentium, but not of Bifidobacterium adolescentis, were significantly increased in pregnant women, and the levels were significantly correlated with progesterone concentration. CONCLUSION: The results suggest that Bifidobacterium and progesterone levels are elevated in the saliva of healthy pregnant women compared with non-pregnant women.

Effect of Dietary Nori (Dried Laver) on Blood Pressure in Young Japanese Children: An Intervention Study.

BACKGROUND: Few studies have examined the association between seaweed intake and blood pressure in children. We conducted an intervention study to investigate whether seaweed intake affects blood pressure. METHODS: Subjects were children aged 4 to 5 years attending a preschool in Aichi Prefecture, Japan, in 2010. Among 99 students, 89 (89.9%) were enrolled in our study. Nori (dried laver), an edible seaweed widely consumed in Japan, was used as a dietary intervention. Children in the intervention group were asked to consume 1.76 grams per day of roasted nori in addition to standard meals for 10 weeks. Children in the control group consumed their usual diet. Before the intervention and at the 10th week of the intervention, children's blood pressure was measured three times successively using an automated sphygmomanometer with subjects in a sitting position. Changes in systolic (SBP) and diastolic blood pressure (DBP) were compared between 55 children in the intervention group and 26 in the control group after adjustment for SBP and DBP before the intervention. RESULTS: Changes in SBP were -8.29 mm Hg in the intervention group and +0.50 mm Hg in the control group (P for difference in change = 0.051). Changes in DBP were -6.77 mm Hg in the intervention group and -0.05 mm Hg in the control group (P = 0.031). In girls, no difference in blood pressure changes was found between the intervention and control groups. CONCLUSION: Nori intake lowered DBP level in boys. Seaweed intake might have preventive effects on elevated blood pressure in childhood.

Effect of interleukin-1ß on bone morphogenetic protein-9-induced osteoblastic differentiation of human periodontal ligament fibroblasts.

Bone morphogenetic protein-9 (BMP-9) has been shown to potently induce osteoblastic differentiation of periodontal ligament fibroblasts (PDLFs) and may be a candidate therapeutic agent for periodontal tissue healing/regeneration, but the effect of the inflammatory environment of periodontitis on such approaches is unclear. We investigated whether interleukin-1ß (IL-1ß) affected BMP-9-mediated osteoblastic differentiation of human (h) PDLFs. IL-1ß suppressed BMP-9-induced osteogenic differentiation of hPDLFs, as evidenced by reduced alkaline phosphatase (ALP) activity and mineralization, and the downregulated expression of BMP-9-mediated bone-related genes, RUNX2, SP7, IBSP, and SPP1. In hPDLFs, with or without BMP-9, IL-1ß increased the protein expression of activin A, a BMP-9 antagonist, and decreased follistatin protein, an antagonist of activin A. Similarly, IL-1ß upregulated the expression of the activin A gene and downregulated that of the follistatin gene. Notably, follistatin re-established BMP-9-induced ALP activity suppressed by IL-1ß. Activin A inhibited the expression of BMP-9-responsive genes and BMP-9-induced ALP activity, while follistatin re-established them. Finally, extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and nuclear factor-kappa B (NF-κB) inhibition significantly blocked IL-1ß-induced activin A gene expression. Our data indicate that IL-1ß inhibits BMP-9-induced osteoblastic differentiation of hPDLFs, possibly by promoting activin A production via the ERK1/2, p38, and NF-κB pathways.

The Hekinan Children's Study: Design and Profile of Participants at Baseline.

BACKGROUND: The early life environment is now recognized as a key factor contributing to susceptibility to certain diseases in later life. METHODS: We initiated a cohort study among school children in 2011 to primarily investigate the associations between lifestyle and environmental factors and some surrogate markers of chronic diseases, such as cardiometabolic risk factors (ie, obesity, high blood pressure, high blood glucose, insulin, or lipids) and cancer risk factors (ie, height and age at menarche). A baseline questionnaire asked for information, including demographic variables, medical history and use of medication, dietary habits, physical activity, sleep habits, and behavioral and emotional problems of children. Follow-up surveys are planned for the fourth grade of elementary school and the first grade of junior high school. At these follow-up surveys, fasting blood samples will be obtained to measure cardiometabolic markers. We also checked the validity of a food frequency questionnaire, which was originally created for 6-year-olds but was modified for use in older children. RESULTS: A total of 3,141 first-year students at elementary schools in Hekinan City, Aichi Prefecture, participated in the study. The response rate was 87.4%. The means of age and body mass index were 6.99 (standard deviation, 0.28) years and 15.3 (standard deviation, 1.7) kg/m2, respectively, in the 3,067 Japanese children (1,639 boys and 1,428 girls). CONCLUSIONS: This cohort will reveal determinants of cardiometabolic risk factors and cancer risk factors during childhood.

ZNF384-related fusion genes define a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with a characteristic immunotype.

Fusion genes involving ZNF384 have recently been identified in B-cell precursor acute lymphoblastic leukemia, and 7 fusion partners have been reported. We further characterized this type of fusion gene by whole transcriptome sequencing and/or polymerase chain reaction. In addition to previously reported genes, we identified BMP2K as a novel fusion partner for ZNF384 Including the EP300-ZNF384 that we reported recently, the total frequency of ZNF384-related fusion genes was 4.1% in 291 B-cell precursor acute lymphoblastic leukemia patients enrolled in a single clinical trial, and TCF3-ZNF384 was the most recurrent, with a frequency of 2.4%. The characteristic immunophenotype of weak CD10 and aberrant CD13 and/or CD33 expression was revealed to be a common feature of the leukemic cells harboring ZNF384-related fusion genes. The signature gene expression profile in TCF3-ZNF384-positive patients was enriched in hematopoietic stem cell features and related to that of EP300-ZNF384-positive patients, but was significantly distinct from that of TCF3-PBX1-positive and ZNF384-fusion-negative patients. However, clinical features of TCF3-ZNF384-positive patients are markedly different from those of EP300-ZNF384-positive patients, exhibiting higher cell counts and a younger age at presentation. TCF3-ZNF384-positive patients revealed a significantly poorer steroid response and a higher frequency of relapse, and the additional activating mutations in RAS signaling pathway genes were detected by whole exome analysis in some of the cases. Our observations indicate that ZNF384-related fusion genes consist of a distinct subgroup of B-cell precursor acute lymphoblastic leukemia with a characteristic immunophenotype, while the clinical features depend on the functional properties of individual fusion partners.

Comparison of the effects of recombinant human bone morphogenetic protein-2 and -9 on bone formation in rat calvarial critical-size defects.

OBJECTIVES: Among bone morphogenetic protein (BMP) family members, BMP-2 and BMP-9 have demonstrated potent osteoinductive potential. However, in vivo differences in their potential for bone regeneration remain unclear. The present study aimed to compare the effects of recombinant human (rh) BMP-2 and rhBMP-9 on bone formation in rat calvarial critical-size defects (CSD). MATERIALS AND METHODS: Twenty-eight Wistar rats surgically received two calvarial defects bilaterally in each parietal bone. Defects (n = 56) were allocated into four groups: absorbable collagen sponge (ACS) alone, rhBMP-2 with ACS (rhBMP-2/ACS), rhBMP-9/ACS, or sham surgery (control), on the condition that the treatments of rhBMP-2/ACS and rhBMP-9/ACS, or the same treatments were not included in the same animal. Animals were sacrificed at 2 and 8 weeks post-surgery. The calvarial defects were analyzed for bone volume (BV) by micro-computed tomography and for percentages of defect closure (DC/DL), newly formed bone area (NBA/TA), bone marrow area (BMA/NBA), adipose tissue area (ATA/NBA), central bone height (CBH), and marginal bone height (MBH) by histomorphometric analysis. RESULTS: The BV in the rhBMP-2/ACS group (5.44 ± 3.65 mm3, n = 7) was greater than the other groups at 2 weeks post-surgery, and the rhBMP-2/ACS and rhBMP-9/ACS groups (18.17 ± 2.51 and 16.30 ± 2.46 mm3, n = 7, respectively) demonstrated significantly greater amounts of BV compared with the control and ACS groups (6.02 ± 2.90 and 9.30 ± 2.75 mm3, n = 7, respectively) at 8 weeks post-surgery. The rhBMP-2/ACS and rhBMP-9/ACS groups significantly induced new bone formation compared to the control and ACS groups at 8 weeks post-surgery. However, there were no statistically significant differences found between the rhBMP-2/ACS and rhBMP-9/ACS groups in any of the histomorphometric parameters. The ATA/NBA in the rhBMP-2/ACS group (9.24 ± 3.72%, n = 7) was the highest among the treatment groups at 8 weeks post-surgery. CONCLUSIONS: Within the limits of this study, it can be concluded that rhBMP-2/ACS induced a slight early increase in new bone formation at 2 weeks and that rhBMP-9/ACS provided comparable new bone formation to rhBMP-2/ACS with less adipose tissues after a healing period of 8 weeks in rat CSD. CLINICAL RELEVANCE: RhBMP-9/ACS treatment provided new bone formation with less adipose tissues compared with rhBMP-2/ACS.

Level of perception of technical terms regarding the effect of radiation on the human body by residents of Japan.

BACKGROUND: This study aimed to examine the level of perception of the technical terms related to the effect of radiation on the human body among residents of the six prefectures of Miyagi, Fukushima, Tokyo, Aichi, Hiroshima, and Nagasaki in Japan. Miyagi and Fukushima were selected as devastated area by Great East Japan Earthquake. Tokyo and Aichi were selected as control. Hiroshima and Nagasaki were selected as the A-bombed area. METHODS: A total of 1030 respondents, 172, 173, 171, 173, 171, and 170, respectively, were surveyed. Differences in the recognition level of technical terms related to the effect of radiation on the human body among residents of the six prefectures were assessed. RESULTS: The highest recognition levels were reported by the respondents from Fukushima (17 items). Those from Miyagi scored the second highest recognition levels (10 out of the 17 terms); the second highest recognition levels for the remaining seven terms were marked by the respondents of Tokyo. Respondents in the Tohoku region had a better recognition for the technical terminology relevant to the effect of radiation on the human body. CONCLUSIONS: Our findings indicate a need for continued, comprehensive risk communication pertaining to health hazards of radiation exposure in Tohoku region. Concerted efforts by central/local governments and other stakeholders are required to allay the anxiety/stress related to radiation exposure among the residents.

Associations between polymorphisms in folate-metabolizing genes and pancreatic cancer risk in Japanese subjects.

BACKGROUND: Evidence supporting the associations between folate metabolizing gene polymorphisms and pancreatic cancer has been inconclusive. We examined their associations in a case-control study of Japanese subjects. METHODS: Our case-control study involved 360 newly diagnosed pancreatic cancer cases and 400 frequency-matched, non-cancer control subjects. We genotyped four folate metabolizing gene polymorphisms, including two polymorphisms (rs1801133 and rs1801131) in the methylenetetrahydrofolate (MTHFR) gene, one polymorphism (rs1801394) in the 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) gene and one polymorphism (rs1805087) in the 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) gene. Genotyping was performed using Fluidigm SNPtype assays. Unconditional logistic regression methods were used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) for the associations between folate metabolizing gene variants and pancreatic cancer risk. RESULTS: Overall we did not observe a significant association between these four genotypes and pancreatic cancer risk. For rs1801133, compared with individuals with the CC genotype of MTHFR C677T, the OR for those with the CT genotype and TT genotype was 0.87 (0.62-1.22) and 0.99 (0.65-1.51), respectively. For rs1801131, individuals with the CC genotype had approximately 1.2-fold increased risk compared with those with the AA genotype, but the association was not statistically significant. In analyses stratified by smoking and drinking status, no significant associations were noted for C677T genotypes. No significant interactions were observed with smoking and drinking with respect to pancreatic cancer risk. CONCLUSIONS: Our data did not support the hypothesis that MTHFR polymorphisms or other polymorphisms in the folate metabolizing pathway are associated with pancreatic cancer risk.

Sleep Duration and the Risk of Mortality From Stroke in Japan: The Takayama Cohort Study.

BACKGROUND: Few studies have assessed the associations between sleep duration and stroke subtypes. We examined whether sleep duration is associated with mortality from total stroke, ischemic stroke, and hemorrhagic stroke in a population-based cohort of Japanese men and women. METHODS: Subjects included 12 875 men and 15 021 women aged 35 years or older in 1992, who were followed until 2008. The outcome variable was stroke death (ischemic stroke, hemorrhagic stroke, and total stroke). RESULTS: During follow-up, 611 stroke deaths (354 from ischemic stroke, 217 from hemorrhagic stroke, and 40 from undetermined stroke) were identified. Compared with 7 h of sleep, ≥9 h of sleep was significantly associated with an increased risk of total stroke and ischemic stroke mortality after controlling for covariates. Hazard ratios (HRs) and 95% confidence intervals (CIs) were 1.51 (95% CI, 1.16-1.97) and 1.65 (95% CI, 1.16-2.35) for total stroke mortality and ischemic stroke mortality, respectively. Short sleep duration (≤6 h of sleep) was associated with a decreased risk of mortality from total stroke (HR 0.77; 95% CI, 0.59-1.01), although this association was of borderline significance (P = 0.06). The trends for total stroke and ischemic stroke mortality were also significant (P < 0.0001 and P = 0.0002, respectively). There was a significant risk reduction of hemorrhagic stroke mortality for ≤6 h of sleep as compared with 7 h of sleep (HR 0.64; 95% CI, 0.42-0.98; P for trend = 0.08). The risk reduction was pronounced for men (HR 0.31; 95% CI, 0.16-0.64). CONCLUSIONS: Data suggest that longer sleep duration is associated with increased mortality from total and ischemic stroke. Short sleep duration may be associated with a decreased risk of mortality from hemorrhagic stroke in men.

Susceptibility to 6-MP toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukaemia.

Genotyping of TPMT prior to 6-mercaptopurine (6-MP) administration in acute lymphoblastic leukaemia (ALL) patients has been integrated into clinical practice in some populations of European ancestry. However, the comparable rates of 6-MP myelotoxicity, but rarity of TPMT variants, in Asians suggest that major determinants have yet to be discovered in this population. We genotyped 92 Japanese paediatric ALL patients for NUDT15 rs116855232, a 6-MP toxicity-related locus discovered in Asians. Logistic regression and survival analysis were used to evaluate its association with leucopenia, hepatotoxicity, 6-MP dose reduction, therapy interruption and event-free survival. The allele frequency of rs116855232 was 0·16, and leucopenia was more common in carriers of the T allele (odds ratio, 7·20; 95% confidence interval, 2·49-20·80; P = 2·7 × 10(-4) ). As leucopenia results in 6-MP dose reduction, we observed average doses during maintenance therapy of 40·7, 29·3 and 8·8 mg/m(2) for patients with CC, CT and TT genotypes, respectively (P < 0·001). Hepatotoxicity was observed only in CC genotype patients. Event-free survival did not significantly differ by NUDT15 genotype. rs116855232 is an important determinant of 6-MP myelotoxicity in Japanese children with ALL and may represent the most robust toxicity-related locus in Asians to date. Considerations for clinical application may be warranted.

Choline and Betaine Intakes Are Not Associated with Cardiovascular Disease Mortality Risk in Japanese Men and Women.

BACKGROUND: Dietary intakes of betaine and choline may reduce the risk of cardiovascular disease; however, epidemiologic evidence is limited. Seafood is a rich source of betaine and is a popular traditional food in Japan. OBJECTIVE: We examined the associations of betaine and choline intakes with cardiovascular disease mortality in a population-based cohort study in Japan. METHODS: Study subjects were 13,355 male and 15,724 female residents of Takayama City, Japan, who were aged ≥35 y and enrolled in 1992. Their diets were assessed by a validated food frequency questionnaire. Deaths from coronary heart disease and stroke were identified from death certificates over 16 y. Multivariable-adjusted HRs were computed by using Cox regression models. RESULTS: During follow-up, we documented 308 deaths from coronary heart disease and 676 deaths from stroke (393 from ischemic and 153 from hemorrhagic strokes). Compared with the lowest quartile, the second, third, and highest quartiles of betaine intake were significantly associated with a decreased risk of mortality from coronary heart disease in men after controlling for covariates. The HRs were 0.58 (95% CI: 0.36, 0.93), 0.62 (95% CI: 0.39, 0.998), and 0.60 (95% CI: 0.37, 0.97), respectively. The trend was not statistically significant (P = 0.08). There was no significant association between betaine intake and the risk of mortality from ischemic stroke. In women, betaine intake was unrelated risk of mortality from coronary heart disease and stroke (P = 0.32 and 0.73, respectively, for interaction by sex). There was no significant association between choline intake and cardiovascular disease mortality risk in men or women. CONCLUSION: Overall, we found no clear evidence of significant associations between choline and betaine intakes and cardiovascular disease mortality risk in Japanese men and women.

Dietary intakes of glutamic acid and glycine are associated with stroke mortality in Japanese adults.

BACKGROUND: Dietary intakes of glutamic acid and glycine have been reported to be associated with blood pressure. However, the link between intakes of these amino acids and stroke has not been studied. OBJECTIVE: We aimed to examine the association between glutamic acid and glycine intakes and the risk of mortality from stroke in a population-based cohort study in Japan. METHODS: The analyses included 29,079 residents (13,355 men and 15,724 women) of Takayama City, Japan, who were aged 35-101 y and enrolled in 1992. Their body mass index ranged from 9.9 to 57.4 kg/m(2). Their diets were assessed by a validated food frequency questionnaire. Deaths from stroke were ascertained over 16 y. RESULTS: During follow-up, 677 deaths from stroke (328 men and 349 women) were identified. A high intake of glutamic acid in terms of a percentage of total protein was significantly associated with a decreased risk of mortality from total stroke in women after controlling for covariates; the HR (95% CI) for the highest vs. lowest quartile was 0.72 (0.53, 0.98; P-trend: 0.03). Glycine intake was significantly associated with an increased risk of mortality from total and ischemic stroke in men without history of hypertension at baseline; the HRs (95% CIs) for the highest vs. lowest tertile were 1.60 (0.97, 2.51; P-trend: 0.03) and 1.88 (1.01, 3.52; P-trend: 0.02), respectively. There was no association between animal or vegetable protein intake and mortality from total and any subtype of stroke. CONCLUSION: The data suggest that glutamic acid and glycine intakes may be associated with risk of stroke mortality. Given that this is an initial observation, our results need to be confirmed.

Dietary glycaemic index and glycaemic load in relation to all-cause and cause-specific mortality in a Japanese community: the Takayama study.

Diets with a high glycaemic index (GI) or glycaemic load (GL) have been hypothesised to increase the risk of diabetes, CVD and some cancers. In the present study, the associations of dietary GI and GL with the risk of all-cause and cause-specific mortality were prospectively examined in a general population in Japan, where white rice is the main contributor of dietary GI and GL. A total of 28,356 residents of Takayama City, Japan, who responded to a self-administered questionnaire in 1992 were included in the present analyses. Dietary intake was assessed using a validated FFQ. Mortality was ascertained over 16 years. In men, dietary GI was found to be significantly inversely associated with the risk of all-cause and non-cancer, non-cardiovascular mortality; the hazard ratios (HR) for the highest v. lowest quartile were 0.80 (95% CI 0.68, 0.95) and 0·64 (95% CI 0.49, 0.84), respectively. Dietary GL was found to be significantly inversely associated with the risk of all-cause, cancer, and non-cancer, non-cardiovascular mortality; the HR for the highest v. lowest quartile were 0.71 (95% CI 0.59, 0.86), 0.71 (95% CI 0.52, 0.99) nd 0.64 (95% CI 0.48, 0.87), respectively. The results obtained for the GL derived from white rice, but not from other foods, closely mirrored those obtained for overall GL. In women, dietary GI was found to be significantly positively associated with the risk of cardiovascular mortality; the HR for the highest v. lowest quartile was 1.56 (95% CI 1.15, 2.13). The results of the present study suggest potential favourable effects of dietary GI and GL on mortality in men, but an association between high GI and an increased risk of cardiovascular mortality in women.

Association of cigarette smoking with skin colour in Japanese women.

OBJECTIVES: Having a lighter skin tone is highly valued among many Asian women. If skin colour is affected by smoking, women may be motivated to avoid tobacco or quit smoking. The present study examined the association of tobacco smoking with skin colour in Japanese women. METHOD: Information on smoking habits was obtained through a self-administered questionnaire completed by 939 Japanese women aged 20-74 in Gifu, Japan, during 2003-2006. Skin colour was examined on the inner side of the upper and lower arm and on the forehead using a Mexameter device (a narrow-band reflective spectrophotometer), which expressed results as a melanin index and erythema index. RESULTS: Current smokers had higher melanin indices than never-smokers and former smokers for all measured sites. The number of cigarettes smoked per day, the years of smoking and pack-years were significantly positively associated with melanin indices for all measured sites after adjustments for age, body mass index, lifetime sun exposure, and room temperature and humidity. Smoking was also significantly associated with erythema indices on the inner upper and lower arms. CONCLUSIONS: These data suggest that smoking is associated with a darker skin colour. If our findings are confirmed by further studies, they could be used in antismoking campaigns or by smoking cessation services.

Soy isoflavone intake and breast cancer risk in Japan: from the Takayama study.

The effects of soy or isoflavone intake on breast cancer need to be examined further in epidemiologic studies. We assessed the associations of soy and isoflavone intake with breast cancer incidence in a population-based prospective cohort study in Japan. Participants were members from the Takayama study, aged 35 years or older in 1992. The follow-up was conducted from the time of the baseline study (September 1, 1992) to the end of March 2008. Cancer incidence was mainly confirmed through regional population-based cancer registries. Breast cancer was defined as code C50 according to ICD-10. Soy and isoflavone intakes were assessed with a validated food frequency questionnaire. Using the Cox proportional hazard models, the association of soy and isoflavone intake with breast cancer was assessed after adjustments for age, body mass index, physical activity, smoking, alcohol consumption, education, age at menarche, age at first delivery, menopausal status, number of children and history of hormone replacement therapy. Among the 15,607 women analyzed, 172 had developed breast cancer. The relative risks of postmenopausal breast cancer were lower among women with higher intakes of soy (trend p = 0.023) and isoflavone (trend p = 0.046), although the relative risks of premenopausal breast cancer were not associated with intakes of soy and isoflavone. Decreased risks of breast cancer were found even among women with a moderate intake of soy and isoflavone. These results suggested that soy and isoflavone intakes have a protective effect on postmenopausal breast cancer.

Diabetes mellitus and risk of cancer in Takayama: a population-based prospective cohort study in Japan.

Diabetes mellitus (DM) has been reported to be associated with an increased risk of site-specific cancers; however, few studies have assessed associations of DM with both total and site-specific cancers in Japan. We examined the association of a history of DM with cancer incidence in a population-based prospective cohort study in Japan. A total of 14 173 men and 16 547 women over 35 years old, who completed a self-administered baseline questionnaire in 1992, were followed up for cancer incidence from September 1992 to March 2008. At baseline, 6.3% men and 2.9% women had a history of diabetes. A total of 1974 men and 1514 women were identified as newly diagnosed with cancer. Hazard ratios (HR) and 95% confidence intervals (CI) were determined using Cox proportional hazards models. After controlling for potential confounders, men with DM had a modest risk increase of total cancer occurrence compared with those without DM (HR, 1.09; 95% CI, 0.93-1.29). Increased risk of cancer of the liver (HR, 2.18; 95% CI, 1.27-3.74), bile duct (HR, 2.17; 95% CI, 1.01-4.66), and larynx (HR, 3.61; 95% CI, 1.16-11.2) in diabetic men were observed. In women, significant increased risk of total cancer (HR, 1.35; 95% CI, 1.06-1.73) and stomach cancer (HR, 2.15; 95% CI, 1.30-3.54) were observed among diabetic subjects. These data suggest that people with DM may be at increased risk of both total and some site-specific cancers.