Hepatocyte Growth Factor in Blood and Gastric Cancer Risk: A Nested Case-Control Study.

BACKGROUND: Potential of hepatocyte growth factor (HGF)-stimulating signaling pathways related to cytotoxin-associated gene A (CagA) to predict gastric cancer development has not been fully investigated. METHODS: We conducted a nested case-control study consisting of 238 gastric cancer cases and 238 matched controls within the Korean Multicenter Cancer Cohort. Plasma HGF concentrations were measured with a human HGF ELISA. Odds ratios (OR) and 95% confidence intervals (CI) for gastric cancer development according to HGF level were calculated using conditional logistic regression model. RESULTS: Sequential elevation of gastric cancer risk according to HGF level increase was observed (OR, 10.99; 95% CI, 4.91-24.62) for highest quartile HGF (≥364 pg/mL) versus lowest quartile HGF (<167 pg/mL). A significantly increased gastric cancer risk associated with high HGF level measured even 6 or more years prior to cancer diagnosis was also found. The group with both high risk of HGF and CagA-related genetic variants was associated with highest gastric cancer risk compared with the group with both low risk of HGF and genetic variants (P interaction = 0.05). Model performance using HGF and CagA-related genetic variants to discriminate gastric cancer was fair [area under the curve of receiver operating characteristic (AUC-ROC), 0.71; 95% CI, 0.64-0.78] and significantly higher than that of model not including those biomarkers. CONCLUSIONS: Our results suggest HGF as a potential biomarker to predict gastric cancer development. IMPACT: These findings suggest HGF as a useful biomarker to predict gastric cancer risk. Further research to assess gastric cancer risk based on useful biomarkers, including HGF, may contribute to primary prevention of gastric cancer.

The Effect of Breastfeeding Duration and Parity on the Risk of Epithelial Ovarian Cancer: A Systematic Review and Meta-analysis.

OBJECTIVES: We conducted a systematic review and meta-analysis to summarize current evidence regarding the association of parity and duration of breastfeeding with the risk of epithelial ovarian cancer (EOC). METHODS: A systematic search of relevant studies published by December 31, 2015 was performed in PubMed and EMBASE. A random-effect model was used to obtain the summary relative risks (RRs) and 95% confidence intervals (CIs). RESULTS: Thirty-two studies had parity categories of 1, 2, and ≥3. The summary RRs for EOC were 0.72 (95% CI, 0.65 to 0.79), 0.57 (95% CI, 0.49 to 0.65), and 0.46 (95% CI, 0.41 to 0.52), respectively. Small to moderate heterogeneity was observed for one birth (p<0.01; Q=59.46; I2=47.9%). Fifteen studies had breastfeeding categories of <6 months, 6-12 months, and >13 months. The summary RRs were 0.79 (95% CI, 0.72 to 0.87), 0.72 (95% CI, 0.64 to 0.81), and 0.67 (95% CI, 0.56 to 0.79), respectively. Only small heterogeneity was observed for <6 months of breastfeeding (p=0.17; Q=18.79, I2=25.5%). Compared to nulliparous women with no history of breastfeeding, the joint effects of two births and <6 months of breastfeeding resulted in a 0.5-fold reduced risk for EOC. CONCLUSIONS: The first birth and breastfeeding for <6 months were associated with significant reductions in EOC risk.

Impact of alcohol drinking on gastric cancer development according to Helicobacter pylori infection status.

BACKGROUND: Helicobacter pylori are major carcinogen of gastric cancer, but the associations among gastric cancer, H. pylori infection status, and alcohol consumption are not fully described. This study aimed to clarify how H. pylori infection status affects the association between alcohol consumption and gastric cancer risk. METHODS: We selected 949 case-cohort participants from the 18,863 Korean Multi-center Cancer Cohort (KMCC) populations. Gastric cancer incidence inside and outside of the subcohort were 12 and 254 cases, respectively. Seropositivities for CagA, VacA, and H. pylori infection were determined by performing immunoblot assays. Weighted Cox regression models were used to calculate hazard ratios and 95% confidence intervals (CIs). RESULTS: Relative to non-drinking, heavy drinking (⩾7 times a week), and binge drinking (⩾55 g alcohol intake per occasion) showed a 3.48-fold (95% CI, 1.13-10.73) and 3.27-fold (95% CI, 1.01-10.56) higher risk in subjects not previously infected by H. pylori. There was no significant association between drinking pattern and gastric cancer risk in H. pylori IgG seropositive subjects. An increased risk for gastric cancer in heavy- and binge-drinking subjects were also present in subjects not infected by CagA- or VacA-secreting H. pylori. CONCLUSIONS: Heavy and binge alcohol consumption is an important risk factor related to an increasing incidence of gastric cancer in a population not infected by H. pylori.

Metformin intervention in obese non-diabetic patients with breast cancer: phase II randomized, double-blind, placebo-controlled trial.

Previous observational studies have suggested that metformin in diabetes patients may reduce breast cancer risk more than the reductions from other anti-diabetes medications. This randomized, double-blind, placebo-controlled trial was performed to evaluate the efficacy of metformin for controlling physical and metabolic profiles related to prognosis and adverse events in non-diabetic breast cancer patients. Female breast cancer patients (N = 105), at least 6 months post-mastectomy, with obesity (≥25 kg/m(2)) and/or pre-diabetes (fasting blood sugar levels ≥100 mg/dL), were randomly assigned to three groups (placebo, metformin 500 mg, and metformin 1000 mg) stratified by tamoxifen use. A linear mixed model for repeated measurements among three groups and ANOVA for profile differences during 6 months of treatment were used for the intention-to-treat analysis. The metformin 1000 mg group had a significantly greater decline in glucose and HbA1c levels between treatment weeks 0 and 6 month (p = 0.008 and 0.009, respectively), and the declines increased with an increase in body mass index (BMI) level (p interaction with BMI = 0.007 and 0.067, respectively). A marginally significant different effect from the metformin 1000 mg treatment was detected for glucose and HbA1c levels (p interaction = 0.084 and 0.063, respectively) in the intention-to-treat analysis. Metformin 1000 mg treatment had a favorable effect on controlling glucose and HbA1C levels in obese non-diabetic breast cancer patients, indicating prognostic importance. Further trials are needed to elucidate the risk-benefit ratio of long-term use of metformin.

Radioactive Iodine Therapy Did Not Significantly Increase the Incidence and Recurrence of Subsequent Breast Cancer.

CONTEXT: Previous studies on the extent to which radioactive iodine (RAI) therapy for thyroid cancer increases the risk of subsequently developing breast cancer have given conflicting results. OBJECTIVE: This study aimed to evaluate the effect of RAI treatment on breast cancer development and recurrence among female patients with primary thyroid cancer. DESIGN: This was a retrospective cohort study. The risk of subsequent breast cancer associated with RAI and its dose in hazard ratios (HRs) with 95% confidential intervals (CIs) were calculated using time-dependent Cox proportional hazard models. PATIENTS: A total of 6150 patients with thyroid cancer enrolled between 1973 and 2009 were followed until December 2012. Of these, 3631 (59.0%) received RAI therapy. During the follow-up period, 99 primary breast cancers were diagnosed. MAIN OUTCOME MEASURE: Risk of breast cancer development according to RAI therapy and RAI dose during treatment for primary thyroid cancer. RESULTS: RAI therapy did not significantly increase the incidence of subsequent breast cancer among female patients (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.22-1.06) when a 2-year latency period was accounted for. High-dose RAI (≥120 mCi) was associated with a reduced incidence of subsequent breast cancer (HR, 0.17; 95% CI, 0.05-0.62) in the cohort with a 2-year latency period. CONCLUSIONS: The long-term follow-up results of this study suggest that RAI treatment for patients with thyroid cancer may not increase the risk or recurrence of breast cancer.

Gene polymorphisms in the ornithine decarboxylase-polyamine pathway modify gastric cancer risk by interaction with isoflavone concentrations.

BACKGROUND: The study aimed to examine the association between genes encoding molecules in the ornithine decarboxylase (ODC)-polyamine pathway (ODC1, AMD1, NQO1, NOS2A, and OAZ2) and gastric cancer risk and whether the gene-phytoestrogen interaction modifies gastric cancer risk. METHODS: Among 76 gastric cancer cases and their 1:4 matched controls within the Korean Multi-center Cancer Cohort, a total of 30 SNPs in five genes involved in the ODC pathway were primarily analyzed. The second-stage genotyping in 388 matched case-control sets was conducted to reevaluate the significant SNPs interacting with phytoestrogens during the primary analysis. The summary odds ratios (ORs) [95 % confidence intervals (CIs)] for gastric cancer were estimated. Interaction effects between the SNPs and plasma concentrations of phytoestrogens (genistein, daidzein, equol, and enterolactone) were evaluated. RESULTS: In the pooled analysis, NQO1 rs1800566 showed significant genetic effects on gastric cancer without heterogeneity [OR 0.83 (95 % CI 0.70-0.995)] and a greater decreased risk at high genistein/daidzein levels [OR 0.36 (95 % CI 0.15-0.90) and OR 0.26 (95 % CI 0.10-0.64), respectively; p interaction < 0.05]. Risk alleles of AMD1 rs1279599, AMD1 rs7768897, and OAZ2 rs7403751 had a significant gene-phytoestrogen (genistein and daidzein) interaction effect to modify the development of gastric cancer. They had an increased gastric cancer risk at low isoflavone levels, but a decreased risk at high isoflavone levels (p interaction < 0.01). CONCLUSIONS: Our findings suggest that common variants in the genes involved in the ODC pathway may contribute to the risk of gastric cancer possibly by modulating ODC polyamine biosynthesis or by interaction between isoflavones and NQO1, OAZ2, and AMD1.

Diabetes mellitus and risk of thyroid cancer: a meta-analysis.

INTRODUCTION: Diabetes mellitus (DM) is an important risk factor for endocrine cancers; however, the association with thyroid cancer is not clear. We performed a systematic review and meta-analysis to clarify the association between thyroid cancer and DM. METHODS: We searched MEDLINE, PUBMED and EMBASE databases through July 2012, using search terms related to diabetes mellitus, cancer, and thyroid cancer. We conducted a meta-analysis of the risk of incidence of thyroid cancer from pre-existing diabetes. Of 2,123 titles initially identified, sixteen articles met our inclusion criteria. An additional article was identified from a bibliography. Totally, 14 cohort and 3 case-control studies were selected for the meta-analysis. The risks were estimated using random-effects model and sensitivity test for the studies which reported risk estimates and used different definition of DM. RESULTS: Compared with individuals without DM, the patients with DM were at 1.34-fold higher risk for thyroid cancer (95% CI 1.11-1.63). However, there was heterogeneity in the results (p<0.0001). Sensitivity tests and studies judged to be high quality did not show heterogeneity and DM was associated with higher risk for thyroid cancer in these sub-analyses (both of RRs = 1.18, 95% CIs 1.08-1.28). DM was associated with a 1.38-fold increased risk of thyroid cancer in women (95% CI 1.13-1.67) after sensitivity test. Risk of thyroid cancer in men did not remain significant (RR 1.11, 95% CI 0.80-1.53). CONCLUSIONS: Compared with their non-diabetic counterparts, women with pre-existing DM have an increased risk of thyroid cancer.

Korean risk assessment model for breast cancer risk prediction.

PURPOSE: We evaluated the performance of the Gail model for a Korean population and developed a Korean breast cancer risk assessment tool (KoBCRAT) based upon equations developed for the Gail model for predicting breast cancer risk. METHODS: Using 3,789 sets of cases and controls, risk factors for breast cancer among Koreans were identified. Individual probabilities were projected using Gail's equations and Korean hazard data. We compared the 5-year and lifetime risk produced using the modified Gail model which applied Korean incidence and mortality data and the parameter estimators from the original Gail model with those produced using the KoBCRAT. We validated the KoBCRAT based on the expected/observed breast cancer incidence and area under the curve (AUC) using two Korean cohorts: the Korean Multicenter Cancer Cohort (KMCC) and National Cancer Center (NCC) cohort. RESULTS: The major risk factors under the age of 50 were family history, age at menarche, age at first full-term pregnancy, menopausal status, breastfeeding duration, oral contraceptive usage, and exercise, while those at and over the age of 50 were family history, age at menarche, age at menopause, pregnancy experience, body mass index, oral contraceptive usage, and exercise. The modified Gail model produced lower 5-year risk for the cases than for the controls (p = 0.017), while the KoBCRAT produced higher 5-year and lifetime risk for the cases than for the controls (p<0.001 and <0.001, respectively). The observed incidence of breast cancer in the two cohorts was similar to the expected incidence from the KoBCRAT (KMCC, p = 0.880; NCC, p = 0.878). The AUC using the KoBCRAT was 0.61 for the KMCC and 0.89 for the NCC cohort. CONCLUSIONS: Our findings suggest that the KoBCRAT is a better tool for predicting the risk of breast cancer in Korean women, especially urban women.

A prospective cohort study on the relationship of sleep duration with all-cause and disease-specific mortality in the Korean Multi-center Cancer Cohort study.

OBJECTIVES: Emerging evidence indicates that sleep duration is associated with health outcomes. However, the relationship of sleep duration with long-term health is unclear. This study was designed to determine the relationship of sleep duration with mortality as a parameter for long-term health in a large prospective cohort study in Korea. METHODS: The study population included 13 164 participants aged over 20 years from the Korean Multi-center Cancer Cohort study. Information on sleep duration was obtained through a structured questionnaire interview. The hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality were estimated using a Cox regression model. The non-linear relationship between sleep duration and mortality was examined non-parametrically using restricted cubic splines. RESULTS: The HRs for all-cause mortality showed a U-shape, with the lowest point at sleep duration of 7 to 8 hours. There was an increased risk of death among persons with sleep duration of ≤5 hours (HR, 1.21; 95% CI, 1.03 to 1.41) and of ≥10 hours (HR, 1.36; 95% CI, 1.07 to 1.72). In stratified analysis, this relationship of HR was seen in women and in participants aged ≥60 years. Risk of cardiovascular disease-specific mortality was associated with a sleep duration of ≤5 hours (HR, 1.40; 95% CI, 1.02 to 1.93). Risk of death from respiratory disease was associated with sleep duration at both extremes (≤5 and ≥10 hours). CONCLUSIONS: Sleep durations of 7 to 8 hours may be recommended to the public for a general healthy lifestyle in Korea.

Intake of soy products and other foods and gastric cancer risk: a prospective study.

BACKGROUND: Gastric cancer, the most common cancer in the world, is affected by some foods or food groups. We examined the relationship between dietary intake and stomach cancer risk in the Korean Multi-Center Cancer Cohort (KMCC). METHODS: The KMCC included 19 688 Korean men and women who were enrolled from 1993 to 2004. Of those subjects, 9724 completed a brief 14-food frequency questionnaire at baseline. Through record linkage with the Korean Central Cancer Registry and National Death Certificate databases, we documented 166 gastric cancer cases as of December 31, 2008. Cox proportional hazard models were used to estimate relative risks (RRs) and 95% CIs. RESULTS: Frequent intake of soybean/tofu was significantly associated with reduced risk of gastric cancer, after adjustment for age, sex, cigarette smoking, body mass index, alcohol consumption, and area of residence (P for trend = 0.036). We found a significant inverse association between soybean/tofu intake and gastric cancer risk among women (RR = 0.41, 95% CI: 0.22-0.78). Men with a high soybean/tofu intake had a lower risk of gastric cancer, but the reduction was not statistically significant (RR = 0.77, 95% CI: 0.52-1.13). There was no interaction between soybean/tofu intake and cigarette smoking in relation to gastric cancer risk (P for interaction = 0.268). CONCLUSIONS: Frequent soybean/tofu intake was associated with lower risk of gastric cancer.

Screening for diabetic retinopathy and nephropathy in patients with diabetes: a nationwide survey in Korea.

This study was performed to identify factors associated with screening for diabetic retinopathy and nephropathy. Data from the Korean National Health and Nutrition Examination Survey between 2007 and 2009 were analyzed. Of 24,871 participants, 1,288 patients diagnosed with diabetes at ≥30 years of age were included. 36.3% received screening for diabetic retinopathy, and 40.5% received screening for diabetic nephropathy during the previous year. Patients living in rural areas, those with less education, those who had not received education about diabetes care, and those who did not receive medical care for diabetes were screened less often for retinopathy or nephropathy. Patients with poorer self-reported health status were screened more often. Occupation, smoking status, and diabetes duration were associated with retinopathy screening. Lower family income was associated with decreased nephropathy screening. Receiving education about diabetes care and receiving medical care for diabetes were significant factors in patients with a shorter duration of diabetes (the significant odds ratio [OR] of not receiving education varied between 0.27 and 0.51, and that of not receiving medical care varied between 0.34 and 0.42). Sociodemographic factors and health-related factors as well as education and medical care influenced screening for diabetic complications among those with a longer duration of diabetes (for retinopathy and nephropathy, the significant OR of living in a rural area varied between 0.56 and 0.61; for retinopathy, the significant OR of current smokers was 0.55, and the p-trend of subjective health status was <0.001; for nephropathy, the significant OR of a monthly household income of <3000 dollars was 0.61 and the p-trends of education and subjective health status were 0.030 and 0.007, respectively). Efforts to decrease sociodemographic disparities should be combined with education about diabetes care to increase the screening, especially for those with a longer duration of diabetes.

Soluble c-Met protein as a susceptible biomarker for gastric cancer risk: A nested case-control study within the Korean Multicenter Cancer Cohort.

This study was conducted to evaluate the relevance of the soluble form of c-Met protein, a truncated form of the c-Met membrane receptor involved in the CagA pathway, as a potential biomarker for gastric cancer. Among 290 gastric cancer case-control sets selected from the Korean Multicenter Cancer Cohort, the plasma concentrations of soluble c-Met protein were measured with enzyme-linked immunosorbent assays. Using analysis of variance and covariance models with age, sex, smoking, Helicobacter pylori infection, and CagA seropositivity, the mean concentrations of soluble c-Met protein between cases and controls were compared. To evaluate the association between gastric cancer and a c-Met protein level, odds ratios and 95% confidence intervals were estimated using conditional logistic regression models. Interactions between CagA-related genes and the soluble c-Met protein concentration were also investigated. The overall median plasma concentration of soluble c-Met among cases was significantly lower than those of controls (1.390 vs. 1.610 ng/mL, p < 0.0001). Closer to the onset of gastric cancer, the soluble c-Met protein level decreased linearly in a time-dependent manner (p for trend = 0.0002). The combined effects between the CagA-related genes and the soluble c-Met protein concentration significantly intensified risks for gastric cancer. Restricted analyses including cases that had been diagnosed within 1 year after entering the cohort had a fair degree of ability (area under the receiver operating characteristic curve of 0.73-0.77) to discriminate gastric cancer cases from normal controls. Our findings demonstrate the potential of the soluble form of c-Met protein as a novel biomarker for gastric cancer. The beneficial effects of a high soluble c-Met concentration in human plasma are strongly supported.

Interaction of body mass index and diabetes as modifiers of cardiovascular mortality in a cohort study.

OBJECTIVES: Diabetes and obesity each increases mortality, but recent papers have shown that lean Asian persons were at greater risk for mortality than were obese persons. The objective of this study is to determine whether an interaction exists between body mass index (BMI) and diabetes, which can modify the risk of death by cardiovascular disease (CVD). METHODS: Subjects who were over 20 years of age, and who had information regarding BMI, past history of diabetes, and fasting blood glucose levels (n=16 048), were selected from the Korea Multi-center Cancer Cohort study participants. By 2008, a total of 1290 participants had died; 251 and 155 had died of CVD and stroke, respectively. The hazard for deaths was calculated with hazard ratio (HR) and 95% confidence interval (95% CI) by Cox proportional hazard model. RESULTS: Compared with the normal population, patients with diabetes were at higher risk for CVD and stroke deaths (HR, 1.84; 95% CI, 1.33 to 2.56; HR, 1.82; 95% CI, 1.20 to 2.76; respectively). Relative to subjects with no diabetes and normal BMI (21 to 22.9 kg/m(2)), lean subjects with diabetes (BMI <21 kg/m(2)) had a greater risk for CVD and stroke deaths (HR, 2.83; 95% CI, 1.57 to 5.09; HR, 3.27; 95% CI, 1.58 to 6.76; respectively), while obese subjects with diabetes (BMI ≥25 kg/m(2)) had no increased death risk (p-interaction <0.05). This pattern was consistent in sub-populations with no incidence of hypertension. CONCLUSIONS: This study suggests that diabetes in lean people is more critical to CVD deaths than it is in obese people.

Genetic susceptibility factors on genes involved in the steroid hormone biosynthesis pathway and progesterone receptor for gastric cancer risk.

BACKGROUND: The objective of the study was to investigate the role of genes (HSD3B1, CYP17A1, CYP19A1, HSD17B2, HSD17B1) involved in the steroid hormone biosynthesis pathway and progesterone receptor (PGR) in the etiology of gastric cancer in a population-based two-phase genetic association study. METHODS: In the discovery phase, 108 candidate SNPs in the steroid hormone biosynthesis pathway related genes and PGR were analyzed in 76 gastric cancer cases and 322 controls in the Korean Multi-Center Cancer Cohort. Statistically significant SNPs identified in the discovery phase were re-evaluated in an extended set of 386 cases and 348 controls. Pooled- and meta-analyses were conducted to summarize the results. RESULTS: Of the 108 SNPs in steroid hormone biosynthesis pathway related genes and PGR analyzed in the discovery phase, 23 SNPs in PGR in the recessive model and 10 SNPs in CYP19A1 in the recessive or additive models were significantly associated with increased gastric cancer risk (p<0.05). The minor allele frequencies of the SNPs in both the discovery and extension phases were not statistically different. Pooled- and meta-analyses showed CYP19A1 rs1004982, rs16964228, and rs1902580 had an increased risk for gastric cancer (pooled OR [95% CI] = 1.22 [1.01-1.48], 1.31 [1.03-1.66], 3.03 [1.12-8.18], respectively). In contrast, all PGR SNPs were not statistically significantly associated with gastric cancer risk. CONCLUSIONS: Our findings suggest CYP19A1 that codes aromatase may play an important role in the association of gastric cancer risk and be a genetic marker for gastric cancer susceptibility.

Korean epithelial ovarian cancer study (Ko-EVE): protocols and interim report.

BACKGROUND: There have been few studies of Asian ovarian cancer and benign tumors. The primary aim of this paper was to report the protocol of the Ko-EVE study to examine epidemiological and molecular factors for ovarian cancer and benign neoplasms and to ascertain the major risk factors for ovarian cancer control in Korea. METHODS: This case-control study covers incident epithelial ovarian cancers and benign neoplasms, four major centers participating in enrolling incident cases and 3 hospitals enrolling healthy controls among health examinees. Standardized questionnaires were administered by trained interviewers, including sections on socio-demographics characteristics, past medical history, medication usage, family history, lifetime consumption of alcohol and tobacco, diet, physical activity, and reproductive factors for women. Various biological specimens were collected in the biorepository according to the standardized protocol. Annual follow-up for cancer cases and follow-up at the 1st year for benign tumor cases are performing to evaluate treatment effect and progression. Passive follow to see long-term survival will be conducting using record linkage with national data. RESULTS: The total number recruited in 2010-2011 was 246 epithelial ovarian cancer cases, 362 benign epithelial tumors and 345 controls. We are planning to collect subjects for at least 1,500 sets of ovarian cancer, 2,000 benign tumors and 1,500 controls till 2018. CONCLUSION: The Ko-EVE will provide unique and important data to probe the etiology and natural history of Korean epithelial ovarian cancer. It will be continued by genomic and proteomic epidemiological analyses and future intervention studies for the prevention of ovarian cancer among Koreans.

Innate immunity and non-Hodgkin's lymphoma (NHL) related genes in a nested case-control study for gastric cancer risk.

OBJECTIVE: Genetic variants regulating the host immune system may contribute to the susceptibility for the development of gastric cancer. Little is known about the role of the innate immunity- and non-Hodgkin's lymphoma (NHL)-related genes for gastric cancer risk. This nested case-control study was conducted to identify candidate genes for gastric cancer risk for future studies. METHODS: In the Discovery phase, 3,072 SNPs in 203 innate immunity- and 264 NHL-related genes using the Illumine GoldenGateTM OPA Panel were analyzed in 42 matched case-control sets selected from the Korean Multi-center Cancer Cohort (KMCC). Six significant SNPs in four innate immunity (DEFA6, DEFB1, JAK3, and ACAA1) and 11 SNPs in nine NHL-related genes (INSL3, CHMP7, BCL2L11, TNFRSF8, RAD50, CASP7, CHUK, CD79B, and CLDN9) with a permutated p-value <0.01 were re-genotyped in the Replication phase among 386 cases and 348 controls. Odds ratios (ORs) for gastric cancer risk were estimated adjusting for age, smoking status, and H. pylori and CagA sero-positivity. Summarized ORs in the total study population (428 cases and 390 controls) are presented using pooled- and meta-analyses. RESULTS: Four SNPS had no heterogeneity across the phases: in the meta-analysis, DEFA6 rs13275170 and DEFB1 rs2738169 had both a 1.3-fold increased odds ratio (OR) for gastric cancer (95% CIs = 1.1-1.6; and 1.1-1.5, respectively). INSL3 rs10421916 and rs11088680 had both a 0.8-fold decreased OR for gastric cancer (95% CIs = 0.7-0.97; and 0.7-0.9, respectively). CONCLUSIONS: Our findings suggest that certain variants in the innate immunity and NHL-related genes affect the gastric cancer risk, perhaps by modulating infection-inflammation-immunity mechanisms that remain to be defined.

Alcohol consumption and mortality in the Korean Multi-Center Cancer Cohort Study.

OBJECTIVES: To examine the association between alcohol consumption habit, types of beverages, alcohol consumption quantity, and overall and cancer-specific mortality among Korean adults. METHODS: The alcohol consumption information of a total of 16 320 participants who were 20 years or older from the Korean Multi-center Cancer Cohort were analyzed to examine the association between alcohol consumption habit and mortality (median follow-up of 9.3 years). The Cox proportional hazard model was used to estimate the hazard ratio (HR) of alcohol consumption to mortality adjusting for age, sex, geographic areas, education, smoking status, and body mass index. RESULTS: Alcohol drinkers showed an increased risk for total mortality compared with never drinkers (HR, 1.72; 95% confidence interval [CI], 1.38 to 2.14 for past drinkers; HR, 1.21; 95% CI, 1.06 to 1.39 for current drinkers), while past drinkers only were associated with higher risk for cancer deaths (HR, 1.84; 95% CI, 1.34 to 2.53). The quantity of alcohol consumed per week showed a J-shaped association with risk of mortality. Relative to light drinkers (0.01 to 90 g/wk), never drinkers and heavy drinkers (>504 g/wk) had an increased risk for all-cause and cancer deaths: (HR, 1.18; 95% CI, 0.96 to 1.45) and (HR, 1.39; 95% CI, 1.05 to 1.83) for all-cause mortality; and (HR, 1.55; 95% CI, 1.15 to 2.11) and (HR, 2.07; 95% CI, 1.39 to 3.09) for all cancer mortality, respectively. Heavy drinkers (>504 g/wk) showed an elevated risk for death from stomach and liver cancers. CONCLUSIONS: The present study supports the existence of a J-shaped association between alcohol consumption quantity and the risk of all-cause and cancer deaths. Heavy drinkers had an increased risk of death from cancer overall and liver and stomach cancer.

Interaction effects between genes involved in the AKT signaling pathway and phytoestrogens in gastric carcinogenesis: a nested case-control study from the Korean Multi-Center Cancer Cohort.

SCOPE: To investigate whether genes involved in AKT/nuclear factor kappa B signaling and/or gene-environment interactions between the genes and phytoestrogens may be susceptible factors for gastric cancer. METHODS AND RESULTS: The representative single nucleotide polymorphisms (SNPs) identified during the primary analysis (screening a total of 622 SNPs within ± 5 kbp of the 51 target gene locations) were further investigated in 317 matched case-control sets. The summary odds ratios (ORs) and 95% confidence intervals (CIs) for gastric cancer were calculated. Interaction effects between the SNPs and phytoestrogen biomarkers (genistein, daidzein, equol, and enterolactone) were computed. CDK1 rs4145643, FAS rs6586161, and FAS rs1468063 in the AKT signaling pathway presented significant genetic effects on gastric cancer (OR = 0.81 (95% CI: 0.66-0.99) for CDK1 rs4145643; OR = 1.27 (95% CI: 1.03-1.58) for FAS rs6586161; OR = 1.29 (95% CI: 1.03-1.56) for FAS rs1468063; Cochran Q statistics > 0.10). Risk alleles of FAS rs6586161, FAS rs1468063, MAP3K1 rs16886448, and MAP3K1 rs252902 showed significant interaction effects with enterolactone (p(interaction) < 0.05). CONCLUSION: CDK1 and FAS genes involved in AKT signaling and influenced by anti-carcinogenic property of phytoestrogens can play a role as susceptible genetic factors in gastric carcinogenesis. FAS and MAP3K1 genes significantly interact with enterolactone, thereby modifying the individual's risk for gastric cancer.

Genetic susceptibility on CagA-interacting molecules and gene-environment interaction with phytoestrogens: a putative risk factor for gastric cancer.

OBJECTIVES: To evaluate whether genes that encode CagA-interacting molecules (SRC, PTPN11, CRK, CRKL, CSK, c-MET and GRB2) are associated with gastric cancer risk and whether an interaction between these genes and phytoestrogens modify gastric cancer risk. METHODS: In the discovery phase, 137 candidate SNPs in seven genes were analyzed in 76 incident gastric cancer cases and 322 matched controls from the Korean Multi-Center Cancer Cohort. Five significant SNPs in three genes (SRC, c-MET and CRK) were re-evaluated in 386 cases and 348 controls in the extension phase. Odds ratios (ORs) for gastric cancer risk were estimated adjusted for age, smoking, H. pylori seropositivity and CagA strain positivity. Summarized ORs in the total study population (462 cases and 670 controls) were presented using pooled- and meta-analysis. Plasma concentrations of phytoestrogens (genistein, daidzein, equol and enterolactone) were measured using the time-resolved fluoroimmunoassay. RESULTS: SRC rs6122566, rs6124914, c-MET rs41739, and CRK rs7208768 showed significant genetic effects for gastric cancer in both the pooled and meta-analysis without heterogeneity (pooled OR = 3.96 [95% CI 2.05-7.65], 1.24 [95% CI = 1.01-1.53], 1.19 [95% CI = 1.01-1.41], and 1.37 [95% CI = 1.15-1.62], respectively; meta OR = 4.59 [95% CI 2.74-7.70], 1.36 [95% CI = 1.09-1.70], 1.20 [95% CI = 1.00-1.44], and 1.32 [95% CI = 1.10-1.57], respectively). Risk allele of CRK rs7208768 had a significantly increased risk for gastric cancer at low phytoestrogen levels (p interaction<0.05). CONCLUSIONS: Our findings suggest that SRC, c-MET and CRK play a key role in gastric carcinogenesis by modulating CagA signal transductions and interaction between CRK gene and phytoestrogens modify gastric cancer risk.

Ecological study for refrigerator use, salt, vegetable, and fruit intakes, and gastric cancer.

We used an ecological approach to determine the correlation between vegetable, fruit and salt intakes, refrigerator use, and gastric cancer mortality in Korean population. Information on fruit and vegetable intakes per capita from the National Health and Nutrition Survey, death certificate data from the National Statistical office, refrigerator per household data from Korean Statistical Information Service, and salt/sodium intake data from a cross-sectional survey were utilized. Correlation coefficients were calculated between vegetable and fruit intakes, refrigerator per household, and gastric cancer mortality and between salt and sodium intakes, and gastric cancer mortality and incidence in the four areas. With 5, 10, and 15 years lag time, refrigerator usage and fruit intake were negatively associated with gastric cancer mortality (p < 0.01), but vegetable intake was not associated with gastric cancer mortality. When estimates of salt/sodium intake evaluated by 24-h urine collection in four areas of Korea were compared to the gastric cancer mortality and incidence in these regions, positive correlation was shown between salt/sodium intake, and gastric cancer incidence and mortality. Negative associations between refrigerator use, fruit intake, and gastric cancer mortality and positive associations between salt/sodium intake and gastric cancer mortality and incidence were suggested.