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1.  Association of body mass index and risk of death from pancreas cancer in Asians: findings from the Asia Cohort Consortium 
Objective
We aimed to examine the association between BMI and the risk of death from pancreas cancer in a pooled analysis of data from the Asia Cohort Consortium.
Methods
The data for this pooled-analysis included 883,529 men and women from 16 cohort studies in Asian countries. Cox proportional-hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for pancreas cancer mortality in relation to BMI. Seven predefined BMI categories (<18.5, 18.5–19.9, 20.0–22.4, 22.5–24.9, 25.0–27.4, 27.5–29.9, ≥30) were used in the analysis, with BMI of 22.5–24.9 serving as the reference group. The multivariable analyses were adjusted for known risk factors, including age, smoking, and history of diabetes.
Results
We found no statistically significant overall association between each BMI category and risk of death from pancreas cancer in all Asians, and obesity was unrelated to mortality risk in both East Asians and South Asians. Age, smoking, and history of diabetes did not modify the association between BMI and risk of death from pancreas cancer. In planned subgroup analyses among East Asians, an increased risk of death from pancreas cancer among those with a BMI<18.5 was observed for individuals with a history of diabetes; HR = 2.01(95%CI: 1.01–4.00) (p for interaction=0.07).
Conclusion
The data do not support an association between BMI and risk of death from pancreas cancer in these Asian populations.
doi:10.1097/CEJ.0b013e3283592cef
PMCID: PMC3838869  PMID: 23044748
body mass index; insulin resistance; obesity; overweight; pancreatic cancer
2.  Association of Selected Medical Conditions With Breast Cancer Risk in Korea 
Objectives
To estimate the effect of medical conditions in the population of Korea on breast cancer risk in a case-control study.
Methods
The cases were 3242 women with incident, histologically confirmed breast cancer in two major hospitals interviewed between 2001 and 2007. The controls were 1818 women each admitted to either of those two hospitals for a variety of non-neoplastic conditions. Information on each disease was obtained from a standardized questionnaire by trained personnel. Odds ratios (ORs) for each disease were derived from multiple logistic regression adjusted for age, age of menarche, pregnancy, age of first pregnancy, and family history of breast cancer.
Results
Among all of the incident breast cancer patients, pre-existing diabetes (OR, 1.33; 95% confidence interval [CI], 0.99 to 1.78), hypertension (OR, 1.46; 95% CI, 1.18 to 1.83), thyroid diseases (OR, 1.26; 95% CI, 1.00 to 1.58), and ovarian diseases (OR, 1.70; 95% CI, 1.23 to 2.35) were associated with an increased risk of breast cancer when other factors were adjusted for. In a stratified analysis by menopausal status, pre-existing hypertension (pre-menopause OR, 0.80; 95% CI, 0.48 to 1.34 vs. post-menopause OR, 1.87; 95% CI, 1.44 to 2.43; p-heterogeneity <0.01) and ovarian disease (pre-menopause OR, 4.20; 95% CI, 1.91 to 9.24 vs. post-menopause OR, 1.39; 95% CI, 1.02 to 1.91; p-heterogeneity 0.01) showed significantly different risks of breast cancer.
Conclusions
Our results suggest the possibility that medical conditions such as hypertension affect breast cancer development, and that this can differ by menopausal status. Our study also indicates a possible correlation between ovarian diseases and breast cancer risk.
doi:10.3961/jpmph.2013.46.6.346
PMCID: PMC3859856  PMID: 24349656
Breast neoplasms; Diabetes mellitus; Hypertension; Ovarian diseases; Menopause
3.  Korean Risk Assessment Model for Breast Cancer Risk Prediction 
PLoS ONE  2013;8(10):e76736.
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.
doi:10.1371/journal.pone.0076736
PMCID: PMC3808381  PMID: 24204664
4.  Intake of Soy Products and Other Foods and Gastric Cancer Risk: A Prospective Study 
Journal of Epidemiology  2013;23(5):337-343.
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.
doi:10.2188/jea.JE20120232
PMCID: PMC3775527  PMID: 23812102
soybean; dietary intake; gastric cancer
5.  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.
doi:10.3961/jpmph.2013.46.5.271
PMCID: PMC3796652  PMID: 24137529
Sleep duration; Mortality; Prospective cohort
6.  Genome-wide association study identifies breast cancer risk variant at 10q21.2: results from the Asia Breast Cancer Consortium 
Human Molecular Genetics  2011;20(24):4991-4999.
Although approximately 20 common genetic susceptibility loci have been identified for breast cancer risk through genome-wide association studies (GWASs), genetic risk variants reported to date explain only a small fraction of heritability for this common cancer. We conducted a four-stage GWAS including 17 153 cases and 16 943 controls among East-Asian women to search for new genetic risk factors for breast cancer. After analyzing 684 457 SNPs in 2062 cases and 2066 controls (Stage I), we selected for replication among 5969 Chinese women (4146 cases and 1823 controls) the top 49 SNPs that had neither been reported previously nor were in strong linkage disequilibrium with reported SNPs (Stage II). Three SNPs were further evaluated in up to 13 152 Chinese and Japanese women (6436 cases and 6716 controls) (Stage III). Finally, two SNPs were evaluated in 10 847 Korean women (4509 cases and 6338 controls) (Stage IV). SNP rs10822013 on chromosome 10q21.2, located in the zinc finger protein 365 (ZNF365) gene, showed a consistent association with breast cancer risk in all four stages with a combined per-risk allele odds ratio of 1.10 (95% CI: 1.07–1.14) (P-value for trend = 5.87 × 10−9). In vitro electrophoretic mobility shift assays demonstrated the potential functional significance of rs10822013. Our results strongly implicate rs10822013 at 10q21.2 as a genetic risk variant for breast cancer among East-Asian women.
doi:10.1093/hmg/ddr405
PMCID: PMC3221542  PMID: 21908515
7.  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/m2), lean subjects with diabetes (BMI <21 kg/m2) 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/m2) 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.
doi:10.3961/jpmph.2012.45.6.394
PMCID: PMC3514470  PMID: 23230470
Diabetes mellitus; Body mass index; Cardiovascular diseases; Mortality
8.  Genetic Susceptibility Factors on Genes Involved in the Steroid Hormone Biosynthesis Pathway and Progesterone Receptor for Gastric Cancer Risk 
PLoS ONE  2012;7(10):e47603.
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.
doi:10.1371/journal.pone.0047603
PMCID: PMC3479131  PMID: 23110082
9.  Innate Immunity and Non-Hodgkin’s Lymphoma (NHL) Related Genes in a Nested Case-Control Study for Gastric Cancer Risk 
PLoS ONE  2012;7(9):e45274.
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.
doi:10.1371/journal.pone.0045274
PMCID: PMC3448653  PMID: 23028900
10.  DNA Methylation in Peripheral Blood: A Potential Biomarker for Cancer Molecular Epidemiology 
Journal of Epidemiology  2012;22(5):384-394.
Aberrant DNA methylation is associated with cancer development and progression. There are several types of specimens from which DNA methylation pattern can be measured and evaluated as an indicator of disease status (from normal biological process to pathologic condition) and even of pharmacologic response to therapy. Blood-based specimens such as cell-free circulating nucleic acid and DNA extracted from leukocytes in peripheral blood may be a potential source of noninvasive cancer biomarkers. In this article, we describe the characteristics of blood-based DNA methylation from different biological sources, detection methods, and the factors affecting DNA methylation. We provide a comprehensive literature review of blood-based DNA methylation as a cancer biomarker and focus on the study of DNA methylation using peripheral blood leukocytes. Although DNA methylation patterns measured in peripheral blood have great potential to be useful and informative biomarkers of cancer risk and prognosis, large systematic and unbiased prospective studies that consider biological plausibility and data analysis issues will be needed in order to develop a clinically feasible blood-based assay.
doi:10.2188/jea.JE20120003
PMCID: PMC3798632  PMID: 22863985
DNA methylation; blood-based biomarker; serum; plasma; leukocyte; peripheral blood
11.  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.
doi:10.3961/jpmph.2012.45.5.301
PMCID: PMC3469812  PMID: 23091655
Alcohol drinking; Mortality; Korean Multi-center Cancer Cohort; Korea
12.  Prognosis of breast cancer is associated with one-carbon metabolism related nutrients among Korean women 
Nutrition Journal  2012;11:59.
Background
The 5-year survival rate for breast cancer among Korean women has increased steadily; however, breast cancer remains the leading cause of cancer mortality among women. One-carbon metabolism, which requires an adequate supply of methyl group donors and B vitamins, may affect the prognosis of breast cancer. This aim of this study was to investigate the associations of dietary intake of vitamin B2, vitamin B6 and folate before diagnosis on the prognosis of breast cancer.
Methods
We assessed the dietary intake using a food frequency questionnaire with 980 women who were newly diagnosed and histopathologically confirmed to have primary breast cancer from hospitals in Korea, and 141 disease progression events occurred. Cox’s proportional hazard regression models were used to estimate the hazard ratio (HR) and 95% confidence interval (95% CI) adjusting for age, education, recruitment sites, TNM stage, hormone status, nuclear grade and total calorie.
Results
There was no significant association between any one-carbon metabolism related nutrients (vitamin B2, B6 and folate) and the progression of breast cancer overall. However, one-carbon metabolism related nutrients were associated with disease progression in breast cancer patients stratified by subtypes. In ER + and/or PR + breast cancers, no association was observed; however, in ER–/PR– breast cancers, a high intake of vitamin B2 and folate statistically elevated the HR of breast cancer progression (HR = 2.28; 95% CI, 1.20-4.35, HR = 1.84; 95% CI, 1.02-3.32, respectively) compared to a low intake. This positive association between the ER/PR status and progression of the disease was profound when the nutrient intakes were categorized in a combined score (Pinteraction = 0.018). In ER–/PR– breast cancers, high combined scores were associated with a significantly poor DFS compared to those belonging to the low score group (HR = 3.84; 95% CI, 1.70-8.71).
Conclusions
In conclusion, our results suggest that one-carbon related nutrients have a role in the prognosis of breast cancer depending on the ER/PR status.
doi:10.1186/1475-2891-11-59
PMCID: PMC3478215  PMID: 22929014
Breast cancer prognosis; One-carbon metabolism; Vitamin B2; Vitamin B6; Folate
13.  Asia Cohort Consortium: Challenges for Collaborative Research 
Journal of Epidemiology  2012;22(4):287-290.
In this era of chronic diseases, large studies are essential in investigating genes, environment, and gene–environment interactions as disease causes, particularly when associations are important but not strong. Moreover, to allow expansion and generalization of the results, studies should be conducted in populations outside Western countries. Here, we briefly describe the Asia Cohort Consortium (ACC), a collaborative cancer cohort research project that was first proposed in 2004 and now involves more than 1 million healthy individuals across Asia. There are approximately 50 active members from Bangladesh, China, India, Japan, Korea, Malaysia, Singapore, Taiwan, Thailand, the United States, and elsewhere. To date, the work of the ACC includes 3 articles published in 2011 on the roles of body mass index, tobacco smoking, and alcohol consumption in mortality, diabetes, and cancer of the small intestine. Many challenges remain, including data harmonization, resolution of ethical and legal issues, establishment of protocols for biologic samples and transfer agreements, and funding procurement.
doi:10.2188/jea.JE20120024
PMCID: PMC3798645  PMID: 22672913
Asia; cohort; consortium
14.  Breast Cancer Risk and 6q22.33: Combined Results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2 
Kirchhoff, Tomas | Gaudet, Mia M. | Antoniou, Antonis C. | McGuffog, Lesley | Humphreys, Manjeet K. | Dunning, Alison M. | Bojesen, Stig E. | Nordestgaard, Børge G. | Flyger, Henrik | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Ahn, Sei-Hyun | Dork, Thilo | Schürmann, Peter | Karstens, Johann H. | Hillemanns, Peter | Couch, Fergus J. | Olson, Janet | Vachon, Celine | Wang, Xianshu | Cox, Angela | Brock, Ian | Elliott, Graeme | Reed, Malcolm W.R. | Burwinkel, Barbara | Meindl, Alfons | Brauch, Hiltrud | Hamann, Ute | Ko, Yon-Dschun | Broeks, Annegien | Schmidt, Marjanka K. | Van ‘t Veer, Laura J. | Braaf, Linde M. | Johnson, Nichola | Fletcher, Olivia | Gibson, Lorna | Peto, Julian | Turnbull, Clare | Seal, Sheila | Renwick, Anthony | Rahman, Nazneen | Wu, Pei-Ei | Yu, Jyh-Cherng | Hsiung, Chia-Ni | Shen, Chen-Yang | Southey, Melissa C. | Hopper, John L. | Hammet, Fleur | Van Dorpe, Thijs | Dieudonne, Anne-Sophie | Hatse, Sigrid | Lambrechts, Diether | Andrulis, Irene L. | Bogdanova, Natalia | Antonenkova, Natalia | Rogov, Juri I. | Prokofieva, Daria | Bermisheva, Marina | Khusnutdinova, Elza | van Asperen, Christi J. | Tollenaar, Robert A.E.M. | Hooning, Maartje J. | Devilee, Peter | Margolin, Sara | Lindblom, Annika | Milne, Roger L. | Arias, José Ignacio | Zamora, M. Pilar | Benítez, Javier | Severi, Gianluca | Baglietto, Laura | Giles, Graham G. | kConFab,  | Group, AOCS Study | Spurdle, Amanda B. | Beesley, Jonathan | Chen, Xiaoqing | Holland, Helene | Healey, Sue | Wang-Gohrke, Shan | Chang-Claude, Jenny | Mannermaa, Arto | Kosma, Veli-Matti | Kauppinen, Jaana | Kataja, Vesa | Agnarsson, Bjarni A. | Caligo, Maria A. | Godwin, Andrew K. | Nevanlinna, Heli | Heikkinen, Tuomas | Fredericksen, Zachary | Lindor, Noralane | Nathanson, Katherine L. | Domchek, Susan M. | SWE-BRCA,  | Loman, Niklas | Karlsson, Per | Askmalm, Marie Stenmark | Melin, Beatrice | von Wachenfeldt, Anna | HEBON,  | Hogervorst, Frans B. L. | Verheus, Martijn | Rookus, Matti A. | Seynaeve, Caroline | Oldenburg, Rogier A. | Ligtenberg, Marjolijn J. | Ausems, Margreet G.E.M. | Aalfs, Cora M. | Gille, Hans J.P. | Wijnen, Juul T. | Gómez García, Encarna B. | EMBRACE,  | Peock, Susan | Cook, Margaret | Oliver, Clare T. | Frost, Debra | Luccarini, Craig | Pichert, Gabriella | Davidson, Rosemarie | Chu, Carol | Eccles, Diana | Ong, Kai-Ren | Cook, Jackie | Douglas, Fiona | Hodgson, Shirley | Evans, D. Gareth | Eeles, Rosalind | Gold, Bert | Pharoah, Paul D.P. | Offit, Kenneth | Chenevix-Trench, Georgia | Easton, Douglas F. | Prokunina-Olsson, Ludmila
PLoS ONE  2012;7(6):e35706.
Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00–1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I2 = 49.3%; p = <0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95%CI 0.80–1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.
doi:10.1371/journal.pone.0035706
PMCID: PMC3387216  PMID: 22768030
15.  7q21-rs6964587 and breast cancer risk: an extended case–control study by the Breast Cancer Association Consortium 
Milne, Roger L | Lorenzo-Bermejo, Justo | Burwinkel, Barbara | Malats, Núria | Arias, Jose Ignacio | Zamora, M Pilar | Benítez, Javier | Humphreys, Manjeet K | García-Closas, Montserrat | Chanock, Stephen J | Lissowska, Jolanta | Sherman, Mark E | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Nevanlinna, Heli | Heikkinen, Tuomas | Aittomäki, Kristiina | Blomqvist, Carl | Anton-Culver, Hoda | Ziogas, Argyrios | Devilee, Peter | van Asperen, Christie J | Tollenaar, Rob A E M | Seynaeve, Caroline | Hall, Per | Czene, Kamila | Liu, Jianjun | Irwanto, Astrid K | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Couch, Fergus J | Olson, Janet E | Wang, Xianshu | Fredericksen, Zachary | Nordestgaard, Børge G | Bojesen, Stig E | Flyger, Henrik | Margolin, Sara | Lindblom, Annika | Fasching, Peter A | Schulz-Wendtland, Ruediger | Ekici, Arif B | Beckmann, Matthias W | Wang-Gohrke, Shan | Shen, Chen-Yang | Yu, Jyh-Cherng | Hsu, Huan-Ming | Wu, Pei-Ei | Giles, Graham G | Severi, Gianluca | Baglietto, Laura | English, Dallas R | Cox, Angela | Brock, Ian | Elliott, Graeme | Reed, Malcolm W R | Beesley, Jonathan | Chen, Xiaoqing | Fletcher, Olivia | Gibson, Lorna | Silva, Isabel dos Santos | Peto, Julian | Frank, Bernd | Heil, Joerg | Meindl, Alfons | Chang-Claude, Jenny | Hein, Rebecca | Vrieling, Alina | Flesch-Janys, Dieter | Southey, Melissa C | Smith, Letitia | Apicella, Carmel | Hopper, John L | Dunning, Alison M | Pooley, Karen A | Pharoah, Paul D P | Hamann, Ute | Pesch, Beate | Ko, Yon-Dschun | Easton, Douglas F | Chenevix-Trench, Georgia
Journal of Medical Genetics  2011;48(10):698-702.
Background
Using the Breast Cancer Association Consortium, the authors previously reported that the single nucleotide polymorphism 7q21-rs6964587 (AKAP9-M463I) is associated with breast cancer risk. The authors have now assessed this association more comprehensively using 16 independent case–control studies.
Methods
The authors genotyped 14 843 invasive case patients and 19 852 control subjects with white European ancestry and 2595 invasive case patients and 2192 control subjects with Asian ancestry. ORs were estimated by logistic regression, adjusted for study. Heterogeneity in ORs was assessed by fitting interaction terms or by subclassifying case patients and applying polytomous logistic regression.
Results
For white European women, the minor T allele of 7q21-rs6964587 was associated with breast cancer risk under a recessive model (OR 1.07, 95% CI 1.00 to 1.13, p = 0.04). Results were inconclusive for Asian women. From a combined analysis of 24 154 case patients and 33 376 control subjects of white European ancestry from the present and previous series, the best-fitting model was recessive, with an estimated OR of 1.08 (95% CI 1.03 to 1.13, p = 0.001). The OR was greater at younger ages (p trend = 0.01).
Conclusion
This may be the first common susceptibility allele for breast cancer to be identified with a recessive mode of inheritance.
doi:10.1136/jmedgenet-2011-100303
PMCID: PMC3371608  PMID: 21931171
16.  The association between the preoperative serum levels of lipocalin-2 and matrix metalloproteinase-9 (MMP-9) and prognosis of breast cancer 
BMC Cancer  2012;12:193.
Background
Although a number of experimental studies have suggested the role of lipocalin-2 (LCN2) and matrix metalloproteinase-9 (MMP-9) in breast cancer progression, limited numbers of epidemiological studies have examined the relationship between the levels of lipocalin-2 and MMP-9 and breast cancer survival.
Methods
Preoperative serum levels of lipocalin-2 and MMP-9 were measured in 303 breast cancer patients and 74 healthy controls recruited between 2004 and 2007. We examined the association between lipocalin-2 and MMP-9 levels and disease-free survival (DFS) using Cox proportional hazard regression model.
Results
The serum levels of lipocalin-2 and MMP-9 were not significantly different between patients and controls (P > 0.05). Elevated lipocalin-2 and MMP-9 levels were associated with reduced DFS of breast cancer ( Ptrend = 0.029 and Ptrend = 0.063, respectively). When lipocalin-2 and MMP-9 levels were categorized based on the combined risk score, patients with higher levels of both lipocalin-2 and MMP-9 exhibited poor DFS compared to patients with lower levels (Ptrend = 0.004). Furthermore, these effects were profound in patients with BMI less than 25 kg/m2 (adjusted hazard ratio (aHR), 3.17; 95% confidence intervals (CI), 1.66-6.06, Ptrend < 0.001) or lymph-node negative breast cancer (aHR, 5.36; 95% CI, 2.18-13.2, Ptrend < 0.001).
Conclusions
Our study suggests that the elevated levels of lipocalin-2 and MMP-9 are associated with reduced breast cancer survival, particularly in patients with lower BMI and lymph-node negative breast cancers.
doi:10.1186/1471-2407-12-193
PMCID: PMC3479006  PMID: 22640376
17.  Common genetic polymorphisms of microRNA biogenesis pathway genes and breast cancer survival 
BMC Cancer  2012;12:195.
Background
Although the role of microRNA’s (miRNA’s) biogenesis pathway genes in cancer development and progression has been well established, the association between genetic variants of this pathway genes and breast cancer survival is still unknown.
Methods
We used genotype data available from a previously conducted case–control study to investigate association between common genetic variations in miRNA biogenesis pathway genes and breast cancer survival. We investigated the possible associations between 41 germ-line single-nucleotide polymorphisms (SNPs) and both disease free survival (DFS) and overall survival (OS) among 488 breast cancer patients. During the median follow-up of 6.24 years, 90 cases developed disease progression and 48 cases died.
Results
Seven SNPs were significantly associated with breast cancer survival. Two SNPs in AGO2 (rs11786030 and rs2292779) and DICER1 rs1057035 were associated with both DFS and OS. Two SNPs in HIWI (rs4759659 and rs11060845) and DGCR8 rs9606250 were associated with DFS, while DROSHA rs874332 and GEMIN4 rs4968104 were associated with only OS. The most significant association was observed in variant allele of AGO2 rs11786030 with 2.62-fold increased risk of disease progression (95% confidence interval (CI), 1.41-4.88) and in minor allele homozygote of AGO2 rs2292779 with 2.94-fold increased risk of death (95% CI, 1.52-5.69). We also found cumulative effects of SNPs on DFS and OS. Compared to the subjects carrying 0 to 2 high-risk genotypes, those carrying 3 or 4–6 high-risk genotypes had an increased risk of disease progression with a hazard ratio of 2.16 (95% CI, 1.18- 3.93) and 4.47 (95% CI, 2.45- 8.14), respectively (P for trend, 6.11E-07).
Conclusions
Our results suggest that genetic variants in miRNA biogenesis pathway genes may be associated with breast cancer survival. Further studies in larger sample size and functional characterizations are warranted to validate these results.
doi:10.1186/1471-2407-12-195
PMCID: PMC3487887  PMID: 22639842
microRNA biogenesis pathway; Breast cancer; Survival; Single nucleotide polymorphism
18.  Identification of Serum MicroRNAs as Novel Non-Invasive Biomarkers for Early Detection of Gastric Cancer 
PLoS ONE  2012;7(3):e33608.
Background
To investigate the potential of serum miRNAs as biomarkers for early detection of gastric cancer (GC), a population-based study was conducted in Linqu, a high-risk area of GC in China.
Methodology/Principal Findings
All subjects were selected from two large cohort studies. Differential miRNAs were identified in serum pools of GC and control using TaqMan low density array, and validated in individual from 82 pairs of GC and control, and 46 pairs of dysplasia and control by real-time quantitative reverse transcription-polymerase chain reaction. The temporal trends of identified serum miRNA expression were further explored in a retrospective study on 58 GC patients who had at least one pre-GC diagnosis serum sample based on the long-term follow-up population. The miRNA profiling results demonstrated that 16 miRNAs were markedly upregulated in GC patients compared to controls. Further validation identified a panel of three serum miRNAs (miR-221, miR-744, and miR-376c) as potential biomarkers for GC detection, and receiver operating characteristic (ROC) curve-based risk assessment analysis revealed that this panel could distinguish GCs from controls with 82.4% sensitivity and 58.8% specificity. MiR-221 and miR-376c demonstrated significantly positive correlation with poor differentiation of GC, and miR-221 displayed higher level in dysplasia than in control. Furthermore, the retrospective study revealed an increasing trend of these three miRNA levels during GC development (P for trend<0.05), and this panel could classify serum samples collected up to 5 years ahead of clinical GC diagnosis with 79.3% overall accuracy.
Conclusions/Significance
These data suggest that serum miR-221, miR-376c and miR-744 have strong potential as novel non-invasive biomarkers for early detection of GC.
doi:10.1371/journal.pone.0033608
PMCID: PMC3303856  PMID: 22432036
19.  Genetic Susceptibility on CagA-Interacting Molecules and Gene-Environment Interaction with Phytoestrogens: A Putative Risk Factor for Gastric Cancer 
PLoS ONE  2012;7(2):e31020.
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.
doi:10.1371/journal.pone.0031020
PMCID: PMC3286459  PMID: 22383989
20.  Electrode Position and the Clinical Outcome after Bilateral Subthalamic Nucleus Stimulation 
Journal of Korean Medical Science  2011;26(10):1344-1355.
We compared the surgical outcome with electrode positions after bilateral subthalamic nucleus (STN) stimulation surgery for Parkinson's disease. Fifty-seven patients treated with bilateral STN stimulations were included in this study. Electrode positions were determined in the fused images of preoperative MRI and postoperative CT taken at six months after surgery. The patients were divided into three groups: group I, both electrodes in the STN; group II, only one electrode in the STN; group III, neither electrode in the STN. Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn and Yahr stage, and activities of daily living scores significantly improved at 6 and 12 months after STN stimulation in both group I and II. The off-time UPDRS III speech subscore significantly improved (1.6 ± 0.7 at baseline vs 1.3 ± 0.8 at 6 and 12 months, P < 0.01) with least L-dopa equivalent daily dose (LEDD) (844.6 ± 364.1 mg/day at baseline; 279.4 ± 274.6 mg/day at 6 months; and 276.0 ± 301.6 mg/day at 12 months, P < 0.001) at 6 and 12 months after STN deep brain stimulation (DBS) in the group I. Our findings suggest that the better symptom relief including speech with a reduced LEDD is expected in the patients whose electrodes are accurately positioned in both STN.
doi:10.3346/jkms.2011.26.10.1344
PMCID: PMC3192348  PMID: 22022189
Parkinson Disease; Bilateral STN Stimulation; Clinical Outcome; Electrode Position; Fused Images
21.  Body Mass Index and Diabetes in Asia: A Cross-Sectional Pooled Analysis of 900,000 Individuals in the Asia Cohort Consortium 
PLoS ONE  2011;6(6):e19930.
Background
The occurrence of diabetes has greatly increased in low- and middle-income countries, particularly in Asia, as has the prevalence of overweight and obesity; in European-derived populations, overweight and obesity are established causes of diabetes. The shape of the association of overweight and obesity with diabetes risk and its overall impact have not been adequately studied in Asia.
Methods and Findings
A pooled cross-sectional analysis was conducted to evaluate the association between baseline body mass index (BMI, measured as weight in kg divided by the square of height in m) and self-reported diabetes status in over 900,000 individuals recruited in 18 cohorts from Bangladesh, China, India, Japan, Korea, Singapore and Taiwan. Logistic regression models were fitted to calculate cohort-specific odds ratios (OR) of diabetes for categories of increasing BMI, after adjustment for potential confounding factors. OR were pooled across cohorts using a random-effects meta-analysis. The sex- and age-adjusted prevalence of diabetes was 4.3% in the overall population, ranging from 0.5% to 8.2% across participating cohorts. Using the category 22.5–24.9 Kg/m2 as reference, the OR for diabetes spanned from 0.58 (95% confidence interval [CI] 0.31, 0.76) for BMI lower than 15.0 kg/m2 to 2.23 (95% CI 1.86, 2.67) for BMI higher than 34.9 kg/m2. The positive association between BMI and diabetes prevalence was present in all cohorts and in all subgroups of the study population, although the association was stronger in individuals below age 50 at baseline (p-value of interaction<0.001), in cohorts from India and Bangladesh (p<0.001), in individuals with low education (p-value 0.02), and in smokers (p-value 0.03); no differences were observed by gender, urban residence, or alcohol drinking.
Conclusions
This study estimated the shape and the strength of the association between BMI and prevalence of diabetes in Asian populations and identified patterns of the association by age, country, and other risk factors for diabetes.
doi:10.1371/journal.pone.0019930
PMCID: PMC3120751  PMID: 21731609
22.  Oncogenic CagA Promotes Gastric Cancer Risk via Activating ERK Signaling Pathways: A Nested Case-Control Study 
PLoS ONE  2011;6(6):e21155.
Background
CagA cellular interaction via activation of the ERK signaling pathway may be a starting point in the development of gastric cancer. This study aimed to evaluate whether genes involved in ERK downstream signaling pathways activated by CagA are susceptible genetic markers for gastric cancer.
Methods
In the discovery phase, a total of 580 SNPs within +/−5 kbp of 30 candidate genes were genotyped to examine an association with gastric cancer risk in the Korean Multi-center Cancer Cohort (100 incident gastric cancer case-control sets). The most significant SNPs (raw or permutated p value<0.02) identified in the discovery analysis were re-evaluated in the extension phase using unconditional logistic regression model (400 gastric cancer case-control sets). Combined analyses including pooled- and meta-analysis were conducted to summarize all the results.
Results
24 SNPs in eight genes (ERK, Dock180, C3G, Rap1, Src, CrkL, Mek and Crk) were significantly associated with gastric cancer risk in the individual SNP analyses in the discovery phase (p<0.05). In the extension analyses, ERK rs5999749, Dock180 rs4635002 and C3G rs7853122 showed marginally significant gene-dose effects for gastric cancer. Consistently, final combined analysis presented the SNPs as significantly associated with gastric cancer risk (OR = 1.56, [95% CI: 1.19–2.06], OR = 0.61, [95% CI: 0.43–0.87], OR = 0.59, [95% CI: 0.54–0.76], respectively).
Conclusions
Our findings suggest that ERK rs5999749, Dock180 rs4635002 and C3G rs7853122 are genetic determinants in gastric carcinogenesis.
doi:10.1371/journal.pone.0021155
PMCID: PMC3116873  PMID: 21698158
23.  Fine scale mapping of the breast cancer 16q12 locus 
Human Molecular Genetics  2010;19(12):2507-2515.
Recent genome-wide association studies have identified a breast cancer susceptibility locus on 16q12 with an unknown biological basis. We used a set of single nucleotide polymorphism (SNP) markers to generate a fine-scale map and narrowed the region of association to a 133 kb DNA segment containing the largely uncharacterized hypothetical gene LOC643714, a short intergenic region and the 5′ end of TOX3. Re-sequencing this segment in European subjects identified 293 common polymorphisms, including a set of 26 highly correlated candidate causal variants. By evaluation of these SNPs in five breast cancer case–control studies involving more than 23 000 subjects from populations of European and Southeast Asian ancestry, all but 14 variants could be excluded at odds of <1:100. Most of the remaining variants lie in the intergenic region, which exhibits evolutionary conservation and open chromatin conformation, consistent with a regulatory function. African-American case–control studies exhibit a different pattern of association suggestive of an additional causative variant.
doi:10.1093/hmg/ddq122
PMCID: PMC2876886  PMID: 20332101
24.  Risk Factors and Control Strategies for the Rapidly Rising Rate of Breast Cancer in Korea 
Journal of Breast Cancer  2011;14(2):79-87.
Due to the aging population and tremendous changes in life style over the past decades, cancer has been the leading cause of death in Korea. The incidence rate of breast cancer is the second highest in Korea, and it has shown an annual increase of 6.8% for the past 6 years. The major risk factors of breast cancer in Korean women are as follows: Early menarche, late menopause, late full-term pregnancy (FTP), and low numbers of FTP. Height and body mass index increased the risk of breast cancer in postmenopausal women only. There are ethnic variations in breast cancer due to the differences in genetic susceptibility or exposure to etiologic agent. With the epidemiological evidences on the possibility of further increase of breast cancer in Korea, the Korean Government began implementing the National Cancer Screening Program against breast cancer in 2002. Five-year survival rates for female breast cancer have improved significantly from 78.0% in early 1993-1995 to 90.0% in 2004-2008. This data indicate that improvement of the survival rate may be partially due to the early diagnosis of breast cancer as well as the increased public awareness about the significance of early detection and organized cancer screening program. The current primary prevention programs are geared towards strengthening national prevention campaigns. In accordance with the improvement in 5-year survival rate, the overall cancer mortality has started to decrease. However, breast cancer death rate and incidence rates are still increasing, which need further organized effort by the Korean Government.
doi:10.4048/jbc.2011.14.2.79
PMCID: PMC3148542  PMID: 21847401
Breast neoplasms; Korea; Risk factors
25.  Cancer incidence among paraquat-exposed pesticide applicators in the Agricultural Health Study 
Paraquat (1,1′-dimethyl-4, 4′-bipyridinium dichloride), a nonselective herbicide, was once widely used in North America and is still used in some countries including the U.S.A. It is extremely toxic in animals and humans after acute exposure. Although there is little evidence that paraquat is a carcinogen, exposure has been associated with some types of cancer in humans, including melanoma, leukemia, and cancers of the penis, cervix and lung. We examined the relationship between cancer incidence and lifetime exposure to paraquat among 56,222 licensed pesticide applicators from Iowa and North Carolina enrolled in the Agricultural Health Study. Poisson regression was used to calculate rate ratios (RRs) and 95% confidence intervals (CIs) among paraquat users compared to non-users, while adjusting for potential confounders. There was no risk for cancer overall, nor for any of the cancers suggested by earlier epidemiologic studies. However, risk for non-Hodgkin’s lymphoma (NHL) was significantly elevated (RR=1.51, [95% CI=1.01–2.26]) when we compared those who ever used paraquat to those who never used paraquat. Among the 24,665 applicators (43.9%) who provided more detailed paraquat exposure information, those in the highest tertile of lifetime exposure-days (LE) and intensity-weighted lifetime exposure-days (IWLE) for paraquat had an increased risk of NHL, but the RRs were not significant (RR=1.74 [0.69–4.42] for LE; RR=1.86 [0.68–5.11] for IWLE, respectively) and there was not a significant exposure-response trend. Although we found some evidence for a link between paraquat exposure and NHL in this study, we cannot rule out the possibility that this is a chance finding.
PMCID: PMC3058830  PMID: 19650582

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