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.
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).
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.
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.
This study suggests that diabetes in lean people is more critical to CVD deaths than it is in obese people.
Diabetes mellitus; Body mass index; Cardiovascular diseases; Mortality
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.
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.
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.
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.
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.
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.
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).
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.
To examine the association between alcohol consumption habit, types of beverages, alcohol consumption quantity, and overall and cancer-specific mortality among Korean adults.
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.
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.
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.
Alcohol drinking; Mortality; Korean Multi-center Cancer Cohort; Korea
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.
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.
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).
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.
Breast cancer prognosis; One-carbon metabolism; Vitamin B2; Vitamin B6; Folate
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.
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.
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.
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).
This may be the first common susceptibility allele for breast cancer to be identified with a recessive mode of inheritance.
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.
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.
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).
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.
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.
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.
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).
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.
microRNA biogenesis pathway; Breast cancer; Survival; Single nucleotide polymorphism
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.
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.
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.
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.
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.
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).
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.
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.
Parkinson Disease; Bilateral STN Stimulation; Clinical Outcome; Electrode Position; Fused Images
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.
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.
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.
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.
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).
Our findings suggest that ERK rs5999749, Dock180 rs4635002 and C3G rs7853122 are genetic determinants in gastric carcinogenesis.
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.
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.
Breast neoplasms; Korea; Risk factors
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.
Polycyclic aromatic hydrocarbon (PAH) exposures and oxidative stress from such and other exposures have been associated with breast cancer in some studies. To further evaluate the role of PAH metabolites and oxidative stress on the development of breast cancer, we conducted a nested case-control study in the Shanghai Women’s Health Study (SWHS).
We measured urinary 1-hydroxypyrene (1-OHP) and 2-naphhol as PAH metabolites and urinary levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG) and malondialdehyde (MDA) as oxidative stress biomarkers in 327 breast cancer cases and 654 controls in the SWHS. Information on demographic characteristics, past medical history, lifestyles, history of menstruation, pregnancy history, eating and drinking habit, history of residence, employment history, family history, husband’s information and physical activity were collected by a self-administered questionnaire.
The mean age was 52.3 in breast cancer cases (n=354) and 52.5 in controls (n=708). Age at menarche (P=0.04), months of breast feeding the first baby (P=0.05) and grade of education (P-trend<0.01) were significantly different between cases and controls. No association was observed for PAH metabolites and the oxidative stress biomarkers of urinary MDA and 8-OHdG and risk of breast cancer.
This nested case-control study provides no evidence of association between PAH exposure and oxidative stress and risk of breast cancer in Shanghai women.
cohort study; nested case-control study; breast cancer; polycyclic aromatic hydrocarbon; oxidative stress; biomarker
To evaluate whether candidate genes in innate immunity are associated with childhood leukemia, we conducted an association study with the 1,536 SNPs in 203 genes related to innate immunity.
Incident childhood leukemia cases (n=136) aged from 0 to 18 were recruited from three teaching hospitals in Seoul between 2003 and 2006. Non-cancer controls (n=140) were frequency-matched to cases by age and gender. The information on the characteristics of children and their parents were collected by trained interviewers using structured questionnaire. Candidate genes were selected based on SNP databases (CGAP and SNP500 database), and genotype assay was performed using GoldenGate (Illumina) oligonucleotide pool assay (OPA). False discovery rate (FDR), permutation test, and haplotype analyses were used to identify the SNP with significant association with childhood leukemia. Childhood leukemia risk was estimated as ORs and 95% CIs adjusted for age, gender and birth weight.
Fourteen SNPs in 13 genes (LMAN1, TLR4, STAT4, CCR9, MBP, ZP1, C8B, XDH, C7, C1QG, FGF2, LOC390183, and STAT6) were significantly associated with childhood leukemia risk (FDR p-values <0.05). In particular, LMAN1 rs1127220, TLR4 rs11536897, STAT4 rs13020076, CCR9 rs1471962, and MBP rs10514234 were significant in 5,000 permutation tests (Permutation p-value <0.05). The most significant association with childhood leukemia risk was for the LMAN1 rs1127220 that is in the protein-coding region, this finding was also supported by haplotype analysis.
A number of innate immunity related genes are associated with childhood leukemia, suggesting possible links between the innate immunity system and development of the childhood leukemia.
Childhood Leukemia; Innate Immunity; Single Nucleotide Polymorphism
Genome-wide association studies have identified FGFR2 as a breast cancer (BC) susceptibility gene in populations of European and Asian descent, but a causative variant has not yet been conclusively identified. We hypothesized that the weaker linkage disequilibrium across this associated region in populations of African ancestry might help refine the set of candidate-causal single nucleotide polymorphisms (SNPs) previously identified by our group. Eight candidate-causal SNPs were evaluated in 1253 African American invasive BC cases and 1245 controls. A significant association with BC risk was found with SNP rs2981578 (unadjusted per-allele odds ratio = 1.20, 95% confidence interval 1.03–1.41, Ptrend = 0.02), with the odds ratio estimate similar to that reported in European and Asian subjects. To extend the fine-mapping, genotype data from the African American studies were analyzed jointly with data from European (n = 7196 cases, 7275 controls) and Asian (n = 3901 cases, 3205 controls) studies. In the combined analysis, SNP rs2981578 was the most strongly associated. Five other SNPs were too strongly correlated to be excluded at a likelihood ratio of < 1/100 relative to rs2981578. Analysis of DNase I hypersensitive sites indicated that only two of these map to highly accessible chromatin, one of which, SNP rs2981578, has previously been implicated in up-regulating FGFR2 expression. Our results demonstrate that the association of SNPs in FGFR2 with BC risk extends to women of African American ethnicity, and illustrate the utility of combining association analysis in datasets of diverse ethnic groups with functional experiments to identify disease susceptibility variants.
Nitric oxide (NO) induces cytotoxicity and angiogenesis, and may play a role in prostate carcinogenesis, potentially modulated by environmental exposures. We evaluated the association of prostate cancer with genetic polymorphisms in two genes related to intracellular NO: NOS2A [inducible nitric oxide synthase (NOS); −2892T>C, Ex16 + 14C>T (S608L), IVS16 + 88T>G and IVS20 + 524G>A] and NOS3 [endothelial NOS; IVS1 − 762C>T, Ex7 − 43C>T (D258D), IVS7 − 26A>G, Ex8 − 63G>T (E298D) and IVS15 − 62G>T]. Prostate cancer cases (n = 1320) from the screening arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial were frequency matched to controls (n = 1842), by age, race, time since initial screening and year of blood draw. An antioxidant score [range 3–12; low (3–7) versus high (8–12)] was created by summing the quartile levels of vitamin E, β-carotene and lycopene, which were coded from 1 to 4, respectively. The global tests for all eight single-nucleotide polymorphisms (SNPs) (excluding NOS2A −2892T>C, with low minor allele frequency) were statistically significant for prostate cancer (P = 0.005), especially for aggressive cancer (stage III–IV or Gleason score ≥ 7) (P = 0.01). The NOS2A IVS16 + 88 GT/TT was associated with increased prostate caner risk (odds ratio = 1.24, 95% confidence interval = 1.00–1.54), whereas the IVS20 + 524 AG/GG was associated with decreased risk (0.77, 0.66–0.90). The NOS3 IVS7 − 26GG was associated with increased prostate caner risk (1.33, 1.07–1.64). All these SNPs showed significant associations with aggressive cancer and not for non-aggressive cancer. In the evaluation of effect modification, the effect of the NOS2A IVS16 + 88 GT/TT on aggressive cancer was stronger among subjects with higher antioxidant intake (1.61, 1.18–2.19; Pinteraction = 0.01). Our results suggest that NOS gene polymorphisms are genetic susceptibility factors for aggressive prostate cancer.
Genetic factor is an important predisposing element influencing the susceptibility to osteoporosis and related complications. The purpose of the present study is to investigate whether genetic polymorphisms of farnesyl diphosphate synthase (FDPS) or geranylgeranyl diphosphate synthase (GGPS) genes were associated with the response to bisphosphonate therapy.
Materials and Methods
In the present study, 144 Korean women with osteoporosis were included. Among 13 genetic polymorphisms found within the FDPS and GGPS1 gene, 4 genetic polymorphisms with frequencies > 5% were selected for further study. Bone mineral density (BMD) response after 1 year treatment of bisphosphonate therapy was analyzed according to the genotypes.
Women with 2 deletion allele of GGPS1 -8188A ins/del (rs3840452) had significantly higher femoral neck BMD at baseline compared with those with one or no deletion allele (0.768 ± 0.127 vs. 0.695 ± 0.090 respectively; p = 0.041). The response rate of women with 2 deletion allele of GGPS1 -8188A ins/del (28.6%) was significantly lower than the rate of women with one (81.4%) or no deletion allele (75.0%) (p = 0.011). Women with 2 deletion allele of GGPS1 -8188A ins/del had 7-fold higher risk of non-response to bisphosphonate therapy compared with women with other genotypes in GGPS1 -8188 after adjusting for baseline BMD (OR = 7.48; 95% CI = 1.32-42.30; p = 0.023). Other polymorphisms in FDPS or GGPS1 were not associated with lumbar spine BMD or femoral neck BMD.
Our study suggested that GGPS1 - 8188A ins/del polymorphism may confer susceptibility to femoral neck BMD response to bisphosphonate therapy in Korean women. However, further study should be done to confirm the results in a larger population.
Polymorphism; osteoporosis; bisphosphonate
We conducted a case–control study to evaluate the association between paternal smoking and childhood leukemia and to evaluate potential modification by polymorphisms in CYP1A1. Histologically confirmed childhood leukemia cases (n = 164) and non-cancer controls (n = 164) were recruited from three teaching hospitals in Seoul, Korea. Five single nucleotide polymorphisms in CYP1A1 (–17961T>C, –9893G>A, I462V, 1188C>T (*2A), and 11599C>G) were genotyped and haplotypes were estimated by the expectation-maximization method. We also conducted a meta-analysis of 12 studies that have reported the association between paternal smoking and childhood leukemia risk. Paternal smoking at home was associated with all leukemias (OR = 1.8, 95% CI = 1.1–2.8) and acute lymphoblastic leukemia (ALL) (2.0, 1.2–3.4). An increasing trend in risk was observed for pack-years smoked after birth (Ptrend = 0.06 and 0.02, respectively) and the number of smokers in the home during the child's life (Ptrend = 0.05 and 0.03, respectively). Among those without the CGACC haplotype, ALL risk was significantly increased by the father's smoking at home (2.8, 1.5–5.3) and the presence of at least one smoker in the home (2.3, 1.2–4.4), and the test for interaction was significant (Pinteraction = 0.03 and 0.02, respectively). The meta-analysis showed that overall paternal smoking (1.13, 1.04–1.24) and smoking before the pregnancy of the child (1.12, 1.04–1.21) were significantly associated with childhood leukemia risk. Our results suggest that paternal smoking is a risk factor for childhood leukemia and the effect may be modified by CYP1A1 genotype.
Childhood leukemia; Paternal smoking; CYP1A1; Interaction; Haplotype
The aim of this study was to investigate the role of TNF genetic variants and the combined effect between TNF gene and cigarette smoking in the development of gastric cancer in the Korean population.
We selected 84 incident gastric cancer cases and 336 matched controls nested within the Korean Multi-Center Cancer Cohort. Six SNPs on the TNF gene, TNF-α-238 G/A, -308 G/A, -857 C/T, -863 C/A, -1031 T/C, and TNF-β 252 A/G were genotyped. The ORs (95% CIs) were calculated using unconditional logistic regression model to detect each SNP and haplotype-pair effects for gastric cancer. The combined effects between the TNF gene and smoking on gastric cancer risk were also evaluated. Multi dimensionality reduction (MDR) analyses were performed to explore the potential TNF gene-gene interactions.
TNF-α-857 C/T containing the T allele was significantly associated with an increased risk of gastric cancer and a linear trend effect was observed in the additive model (OR = 1.6, 95% CI 1.0–2.5 for CT genotype; OR = 2.6, 95% CI 1.0–6.4 for TT genotype). All haplotype-pairs that contained TCT or CCC of TNF-α-1031 T/C, TNF-α-863 C/A, and TNF-α-857 C/T were associated with a significantly higher risk for gastric cancer only among smokers. In the MDR analysis, regardless of smoking status, TNF-α-857 C/T was included in the first list of SNPs with a significant main effect.
TNF-α-857 C/T polymorphism may play an independent role in gastric carcinogenesis and the risk for gastric cancer by TNF genetic effect is pronounced by cigarette smoking.