[Show abstract][Hide abstract] ABSTRACT: In a three-stage genome-wide association study among East Asian women including 22,780 cases and 24,8 controls, we identified 3 genetic loci newly associated with breast cancer risk, including rs4950 at q32. (in intron 2 of the ZC3H11A gene; P = 8.82 × 0 −9), rs0474352 at 5q4.3 (near the ARRDC3 gene; P = .67 × 0 −9) and rs2290203 at 5q26. (in intron 4 of the PRC1 gene; P = 4.25 × 0 −8). We replicated these associations in 6,003 cases and 4,335 controls of European ancestry (P = 0.030, 0.004 and 0.00, respectively). Data from the ENCODE Project suggest that variants rs4950 and rs0474352 might be located in an enhancer region and transcription factor binding sites, respectively. This study provides additional insights into the genetics and biology of breast cancer. Breast cancer is one of the most common malignancies among women worldwide. Genetic factors have a substantial role in breast cancer etiology 1,2 . Thus far, genome-wide association studies (GWAS) have identified approximately 75 genetic loci associated with breast cancer risk 2–5 . With the exception of the studies we have conducted among East Asian women 6–9 and one study conducted among women of African ancestry 10 , all other published GWAS have been conducted among women of European ancestry. Genetic risk variants identified thus far from GWAS explain only about 10% of familial risk for breast cancer in East Asian women 3 . Given the dif-ferences in genetic architecture and environmental exposures for women of European and East Asian ancestry, additional GWAS need to be conducted among East Asian women to study the genetic basis of breast cancer risk. The current study was conducted as part of the Asia Breast Cancer Consortium (ABCC) to search for additional susceptibility loci for breast cancer. Included in this study are data obtained from 22,780 breast cancer cases and 24,181 controls who were recruited in 14 studies conducted in multiple Asian countries (Supplementary Table 1). The discovery stage (stage 1) included 2 GWAS in which 5,285 Chinese women (SBCGS-1) and 4,777 Korean women (SeBCS1) were scanned primarily using Affymetrix Genome-Wide Human SNP Array 6.0, which consists of 906,602 SNPs. After applying quality control filters described previously 6,9,11 , 5,152 Chinese women (2,867 cases and 2,285 controls; 677,157 SNPs) and 4,298 Korean women (2,246 cases and 2,052 controls; 555,117 SNPs) remained in the cur-rent analysis. Imputation was conducted for each study following the MACH algorithm 12 using HapMap 2 release 22 CHB (Han Chinese in Beijing, China) and JPT (Japanese in Tokyo, Japan) data (2,416,663 SNPs) as the reference. Only SNPs with a high imputation quality score (RSQR ≥ 0.50) were analyzed for associations with breast can-cer risk. In the analyses of data from Chinese and Korean women, a total of 1,930,412 and 1,907,146 SNPs, respectively, were included. A meta-analysis of these GWAS data was conducted using a fixed-effects, inverse variance meta-analysis with the METAL program 13 . There was little evidence of inflation in the association test statis-tics for the studies included in stage 1 (genomic inflation factors (λ): λ = 1.0426 for SBCGS-1, λ = 1.0431 for SeBCS1 and λ = 1.0499 for both studies combined; Supplementary Fig. 1). When scaled to a study of 1,000 cases and 1,000 controls, λ 1,000 values were 1.02, 1.02 and 1.01, respectively. To select SNPs for stage 2 replication, we used the following criteria: (i) association P < 0.05 in the stage 1 meta-analysis results; (ii) the
[Show abstract][Hide abstract] ABSTRACT: No large population-based prospective study has investigated the risks of suicide and death by other externally caused injuries (ECIs) among stroke patients. The purpose of this study was to examine whether stroke increases the risks of suicide and ECI deaths.
[Show abstract][Hide abstract] ABSTRACT: Compared with western populations, the consumption of soy foods among Japanese is very high and the incidence of endometrial cancer very low. We evaluated the association of soy food and isoflavone intake with endometrial cancer risk in Japanese women.
BJOG An International Journal of Obstetrics & Gynaecology 06/2014; · 3.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Clarification of the putative etiologic role of heterocyclic aromatic amines (HAAs) in the development of cancer requires a validated assessment tool for dietary HAAs. This study primarily aimed to evaluate the validity of a food frequency questionnaire (FFQ) in estimating HAA intake, using 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) level in human hair as the reference method.
We first updated analytical methods of PhIP using liquid chromatography-electrospray ionization/tandem mass spectrometry (LC-ESI/MS/MS) and measured 44 fur samples from nine rats from a feeding study as part-verification of the quantitative performance of LC-ESI/MS/MS. We next measured PhIP level in human hair samples from a validation study of the FFQ (n = 65). HAA intake from the FFQ was estimated using information on intake from six fish items and seven meat items and data on HAA content in each food item. Correlation coefficients between PhIP level in human hair and HAA intake from the FFQ were calculated.
The animal feeding study of PhIP found a significant dose–response relationship between dosage and PhIP in rat fur. Mean level was 53.8 pg/g hair among subjects with values over the limit of detection (LOD) (n = 57). We found significant positive correlation coefficients between PhIP in human hair and HAA intake from the FFQ, with Spearman rank correlation coefficients of 0.35 for all subjects, 0.21 for subjects with over LOD values, and 0.34 for subjects with over limit of quantification.
Findings from the validation study suggest that the FFQ is reasonably valid for the assessment of HAA intake.
Cancer Causes and Control 06/2014; · 3.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: While the global methylation level of leukocyte DNA may be a suitable biomarker for cancer risk, the level may be influenced by multiple factors, both environmental and host-related, one of which is exposure to environmental pollutants. To date, three epidemiologic studies have examined associations between serum organochlorine levels and global DNA methylation level, but their findings are not fully consistent, and the associations thus require confirmation in other well-characterized populations. We tested the association between organochlorine exposure and the global DNA methylation level of leukocytes in Japanese women. We conducted a cross-sectional study using the control group of a breast cancer case-control study in Japan. Subjects were 403 Japanese women who provided blood samples. Serum polychlorinated biphenyls (PCBs) and nine pesticide-related organochlorines were measured by gas chromatography isotope-dilution high-resolution mass spectrometry. Further, global methylation level of peripheral leukocyte DNA among 399 women was measured by luminometric methylation assay. Linear trends in the association between methylation and quartile levels of organochlorines were evaluated by regression coefficients in a multivariable linear regression model. We found significant inverse associations between the global methylation level in leukocyte DNA and many of the organochlorine levels measured. Global methylation level was significantly decreased by 0.33-0.83% per quartile category for serum o,p'-dichlorodiphenyltrichloroethane (o,p'-DDT), p,p'-DDT, p,p'-dichlorodiphenyldichloroethylene, trans-nonachlor, oxychlordane, hexachlorobenzene, β-hexachlorocyclohexane, PCB17, PCB52/69, PCB74, PCB114, and PCB183. Serum organochlorine levels were inversely associated with the global methylation level of leukocyte DNA in a relatively large sample of Japanese women.
Science of The Total Environment 05/2014; 490C:603-609. · 3.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cyclin B1 is a checkpoint protein that regulates cell division from G2 to the M phase. Studies in mice have shown that cyclin B1 vaccine-induced immunity significantly delayed or prevented the spontaneous cancer development later in life. We hypothesized that if these results showing a protective effect of anti-cyclin B1 antibodies could be extrapolated to the human condition, cancer-free individuals should have higher levels of endogenous antibodies than patients with cancers characterized by the overexpression of this tumor-associated antigen. To test this hypothesis, we characterized a large (1739 subjects) number of multiethnic patients with breast cancer (which overexpresses cyclin B1) and matched controls for anti-cyclin B1 IgG antibodies. Multivariate analyses, after adjusting for the covariates, showed that cancer-free individuals had significantly higher levels of naturally occurring IgG antibodies to cyclin B1 than patients with breast cancer (mean ± SD: 148.0 ± 73.6 vs. 126.1 ± 67.8 arbitrary units per mL; p < 0.0001). These findings may have important implications for cyclin B1-based immunotherapy against breast cancer and many other cyclin B1-overexpressing malignancies.
[Show abstract][Hide abstract] ABSTRACT: Background:Global hypomethylation has been suggested to cause genomic instability and lead to an increased risk of cancer. We examined the association between the global methylation level of peripheral blood leukocyte DNA and breast cancer among Japanese women.Methods:We conducted a hospital-based case-control study of 384 patients aged 20-74 years with newly diagnosed, histologically confirmed invasive breast cancer, and 384 matched controls from medical checkup examinees in Nagano, Japan. Global methylation levels in leukocyte DNA were measured by LUminometric Methylation Assay. Odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between global hypomethylation and breast cancer were estimated using a logistic regression model.Results:Compared with women in the highest tertile of global methylation level, ORs for the second and lowest tertiles were 1.87 (95% CI=1.20-2.91) and 2.86 (95% CI=1.85-4.44), respectively. Global methylation levels were significantly lower in cases than controls, regardless of the hormone receptor status of the cancer (all P values for trend <0.05).Interpretation:These findings suggest that the global methylation level of peripheral blood leukocyte DNA is low in patients with breast cancer and may be a potential biomarker for breast cancer risk.British Journal of Cancer Advance online publication, 1 May 2014 1; doi:10.1038/bjc.2014.223 www.bjcancer.com.
British Journal of Cancer 05/2014; · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A positive association between body mass index (BMI) and breast cancer risk among postmenopausal women has been reported, and a weak inverse association has been suggested among premenopausal women from studies in the Western population. The effects of BMI on breast cancer have remained unclear among the Asian population, especially in premenopausal women.
We assessed the associations between BMI and breast cancer incidence by a pooled analysis from eight representative large-scale cohort studies in Japan. Cancer incidence was mainly confirmed through regional population-based cancer registries and/or through active patient notification from major local hospitals. Breast cancer was defined as code C50 according to ICD10. Pooled estimates of the hazard ratios (HRs) and 95% confidence interval (CIs) for breast cancer were calculated using random-effects models.
Analytic subjects were 183 940 women, 1783 of whom had breast cancer during 2 194 211 person-years of follow-up. A positive association between BMI and the risk of postmenopausal breast cancer was observed (trend P < 0.001). The HRs for premenopausal breast cancer were 1.05 (95% CI 0.56-1.99), 1.07 (95% CI 0.76-1.52), 0.91 (95% CI 0.64-1.30), 1.15 (95% CI 0.76-1.73), 1.45 (95% CI 0.71-2.94), and 2.25 (95% CI 1.10-4.60), respectively, in BMIs of <19, 19 to <21, 21 to <23, 25 to <27, 27 to <30, and ≥30 kg/m(2). These results were not substantially altered after excluding the patients who were diagnosed with breast cancer in the first 2 years of follow-up.
The increased risk of postmenopausal breast cancer among women with higher BMIs was confirmed in Japanese. A borderline-significant positive association between BMI and premenopausal breast cancer was observed, suggesting that body mass in Asian women might have opposite effects on breast cancer compared with Western women.
Annals of Oncology 02/2014; 25(2):519-24. · 7.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:Colorectal cancer (CRC) incidence rate increased rapidly in Japan between the 1950s and 1990s. We examined the association between rice intake and CRC risk in comparison with bread, noodles and cereal among Japanese adults enrolled in the Japan Public Health Center-based prospective Study.Methods:A total of 73 501 Japanese men and women were followed-up from 1995 to 1999 until the end of 2008 for an average of 11 years. During 801 937 person-years of follow-up, we identified 1276 incident cases of CRC. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) of CRC for rice, noodle, bread and cereal intake were calculated by Cox proportional hazards model.Results:Overall, no significant association was observed for the highest quartile of rice intake compared with the lowest and the risk of CRC and its subsites in men (HR, 0.77; 95% CI, 0.56-1.07) and women (HR, 1.10; 95% CI, 0.71-1.68). However, a non-significant inverse trend was observed between rice intake and rectal cancer in men. No clear patterns of association were observed in bread, noodle and cereal intake.Conclusion:Our findings suggest that the consumption of rice does not have a substantial impact on the risk of CRC in the Japanese population.British Journal of Cancer advance online publication, 2 January 2014; doi:10.1038/bjc.2013.799 www.bjcancer.com.
British Journal of Cancer 01/2014; · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose
Cross-sectional studies have shown an association between different coping styles and suicidal behavior. It is unknown whether there is any prospective association between coping behaviors and suicide in the general population.
The study population consisted of participants of the Japanese Public Health Center-based prospective study (JPHC Study). In the 10-year follow-up questionnaire, subjects aged 50-79 were asked how they handle daily problems. Coping behaviors were used to determine two coping strategies (approach coping and avoidance coping). Out of 99 439 subjects that returned the 10-year follow-up questionnaire, 70 213 subjects provided complete answers on coping and were included in our analyses. Cox regression models, adjusted for confounders, were used to determine the risk of committing suicide according to coping style. Mean follow-up time was 8.8 years.
Two coping behaviors were significantly associated with suicide over time: planning (HR=0.64, 95% CI, 0.42, 0.98), and self-blame (HR=2.15, 95% CI, 1.26, 3.68). Of the coping strategies, only the avoidance coping strategy was significantly associated with suicide (HR=2.51, 95% CI, 1.27, 4.95).
For the first time two coping behaviors and one coping strategy have been shown to have a significant prospective association with suicide in a general population.
Annals of epidemiology 01/2014; · 2.95 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In many developed countries, socioeconomic status is associated with cancer incidence and survival. However, research in Japan is sparse. We examined the association between neighborhood deprivation based on the Japanese Deprivation Index and the risk of incidence, mortality and survival from total and major cancers in the Japan Public Health Center-based Prospective Study.
PLoS ONE 01/2014; 9(9):e106729. · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although many in vitro and animal studies have suggested a protective effect of green tea against breast cancer, only a few epidemiological studies have examined this association, and findings have been inconsistent. We examined the association between green tea consumption and breast cancer risk in consideration of the hormone receptor status of tumors and investigated whether the association was modified by dietary and genetic factors based on a hospital-based case-control study in Nagano, Japan. A total of 369 pairs completed a validated food frequency questionnaire and provided blood samples. Four single nucleotide polymorphisms (SNPs) were genotyped: CYP19A1 (rs10046), COMT (rs4680), MTHFR C677T (rs1801133), and MTHFR A1298C (rs1801131). We found no inverse association between green tea consumption and breast cancer risk. Compared with women who drank less than 120 ml of green tea per day, the adjusted odds ratio for women who drank more than 600 ml was 1.27 (95% confidence interval = 0.75-2.14; P for trend = 0.20). We also found no inverse association for either tumor subtype. No substantial effect modification was observed for menopausal status, 4 SNPs, or dietary intake of folate or isoflavone. This study provides additional evidence that green tea consumption is not associated with a decreased risk.
Nutrition and Cancer 11/2013; · 2.70 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Reducing dietary salt intake remains a challenging issue in the management of chronic disease. Taste preference is suspected to be an important proxy index of daily sodium consumption. This study examined the difference in daily sodium intake according to self-reported taste preference for miso soup as representative of homemade cooking in middle-aged urban Japanese adults. Among 896 candidates randomly selected from examinees of cancer screening provided by the National Cancer Center, Japan, 143 men and women participated in this cross-sectional study. During the period from May 2007 through April 2008, participants provided a food frequency questionnaire, which included information on taste preference and dietary behaviors, a weighed food record over 4 consecutive days, a simultaneous 24-hour urine collection, and a sample of miso soup as it is usually prepared in the home. Mean 24-hour urinary sodium excretion and daily sodium intake were compared according to the self-reported taste preference for miso soup. Taste preference was significantly associated with both 24-hour urinary sodium excretion (trend P<0.01) and daily sodium intake (trend P=0.01), with a corresponding regression coefficient per 1 rank preference increment of 403 mg and 315 mg/day, respectively. The observed association between preference and urinary excretion was attenuated by further adjustment for discretionary salt-related behaviors. These findings suggest that self-reported taste preference for homemade cooking is a defining feature of daily sodium intake through discretionary salt-related dietary behaviors. A reduction in daily sodium consumption per 1 rank light preference was estimated to equate to approximately 1 g salt/day.
Journal of the American Academy of Nutrition and Dietetics 10/2013; · 3.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Epidemiological evidence for the impact of fruit and vegetable intake on breast cancer risk among the Japanese populations is scarce.
The purpose of this study was to evaluate the association between fruit and vegetable intake and breast cancer risk among 47,289 Japanese women.
The study was conducted under a population-based prospective cohort design. Dietary assessment was performed using a validated food frequency questionnaire. A Cox proportional hazards regression model was used to calculate relative risks (RRs) and their corresponding 95 % confidence intervals (CIs).
During an average of 10.2 years of follow-up, 452 cases of breast cancer were newly diagnosed. No association with breast cancer risk was seen for intake of total fruits and vegetables, cruciferous vegetables, green-leaf vegetables, yellow vegetables, or tomato products in overall or postmenopausal women. Cruciferous vegetable intake was associated with a statistically significant decrease in risk of premenopausal breast cancer [multivariable-RRQ4 vs. Q1 = 0.64 (95 % CI = 0.38-1.10; p trend = .046)] and showed a marginally inverse association with ER+ PR+ tumors [RRper 100 g increment = 0.64 (95 % CI = 0.41-1.00)]. In contrast, positive associations were seen between intake of total fruits and citrus fruits and breast cancer risk in overall and premenopausal women. However, these associations for fruit were all attenuated with additional adjustment for vitamin C intake.
Our results suggest an overall null association between total fruit and vegetable intake and breast cancer risk. Intake of cruciferous vegetable showed a statistically significant association with a decreased risk of breast cancer among premenopausal women.
Cancer Causes and Control 10/2013; · 3.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Excess body weight is an independent risk factor for primary liver cancer, and the role of adiponectin in the pathogenesis of obesity-related malignancies is a focus of research interest. Few prospective studies have examined the association between circulating adiponectin and liver cancer risk, so we investigated this association in a nested case-control study of a population-based prospective cohort in Japan. Methods: From 18,628 target participants aged 40 to 69 years who returned the baseline questionnaire and provided blood samples, we selected those with either hepatitis B virus or hepatitis C virus infection at baseline (n=1,544). Among these, 90 were newly diagnosed with primary liver cancer from 1993 through 2006, and matched to 177 controls. The odds ratios of liver cancer development based on plasma levels of adiponectin were estimated with a conditional logistic regression model. Results: From 18,628 target participants aged 40 to 69 years who returned the baseline questionnaire and provided blood samples, we selected those with either hepatitis B virus or hepatitis C virus infection at baseline (n=1,544). Among these, 90 were newly diagnosed with primary liver cancer from 1993 through 2006, and matched to 177 controls. The odds ratios of liver cancer development based on plasma levels of adiponectin were estimated with a conditional logistic regression model. Conclusions: Higher plasma adiponectin levels were associated with an increased risk of primary liver cancer in middle-aged Japanese adults with hepatitis virus infection. Impact: Circulating adiponectin levels may be a risk marker for primary liver cancer.
Cancer Epidemiology Biomarkers & Prevention 09/2013; · 4.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The present work aims to provide 10-year estimates of the probability of cancer occurrence in the Japanese population based on age, sex, and the pattern of adherence to five healthy lifestyle habits.
The study population consisted of 74,935 participants in the Japan Public Health Center-Based Prospective Study (aged 45 to 74years) who answered a 5-year follow-up questionnaire about various lifestyle habits between 1995 and 1999. The relationship between five previously identified healthy lifestyle habits (never smoking, moderate or no alcohol consumption, adequate physical activity, moderate salt intake, and appropriate body mass index) and cancer occurrence was assessed using a sex-specific parametric survival model.
Compared to individuals not adhering to any of the five habits, never-smoking men had a nearly 30% reduction in the 10-year probability of cancer occurrence (e.g., 20.5% vs. 28.7% at age 70), and never-smoking women had a 16% reduction (e.g., 10.5% vs. 12.5% at age 70). Adherence to all five habits was estimated to reduce the 10-year probability of cancer occurrence by 1/2 in men and 1/3 in women.
By quantifying the impact of lifestyle habits on the probability of cancer occurrence, this study emphasizes the importance of lifestyle improvement.
[Show abstract][Hide abstract] ABSTRACT: Immunoglobulin κ constant (IGKC) gene has recently been identified as a strong prognostic marker in several human solid tumors, including breast cancer. Although the mechanisms underlying the IGKC signature are not yet known, identification of tumor-infiltrating plasma cells as the source of IGKC expression strongly suggests a role for humoral immunity in breast cancer progression. The primary aim of the present investigation was to determine whether the genetic variants of IGKC, KM (κ marker) allotypes, are risk factors for breast cancer, and whether they influence the magnitude of humoral immunity to epidermal growth factor receptor 2 (HER2), which is overexpressed in 25-30% of breast cancer patients and is associated with poor prognosis. Using a matched case-control design, we genotyped a large (1719 subjects) study population from Japan and Brazil for KM alleles. Both cases and controls in this study population had been previously characterized for GM (γ marker) and Fcγ receptor (FcγR) alleles, and the cases had also been characterized for anti-HER2 antibodies. Conditional logistic regression analysis of the data showed that KM1 allele additively contributed to the risk of breast cancer in the Japanese subjects from Nagano: Compared to KM3 homozygotes, KM1 homozygotes were almost twice as likely to develop breast cancer (OR=1.77, CI 1.06-2.95). Additionally, KM genotypes-individually and in particular epistatic combinations with FcγRIIa genotypes-contributed to the magnitude of anti-HER2 antibody responsiveness in the Japanese patients. This is the first report implicating KM alleles in the immunobiology of breast cancer.