Genome- and transcriptome-wide association studies of 386,000 Asian and European-ancestry women provide new insights into breast cancer genetics.

By combining data from 160,500 individuals with breast cancer and 226,196 controls of Asian and European ancestry, we conducted genome- and transcriptome-wide association studies of breast cancer. We identified 222 genetic risk loci and 137 genes that were associated with breast cancer risk at a p < 5.0 × 10-8 and a Bonferroni-corrected p < 4.6 × 10-6, respectively. Of them, 32 loci and 15 genes showed a significantly different association between ER-positive and ER-negative breast cancer after Bonferroni correction. Significant ancestral differences in risk variant allele frequencies and their association strengths with breast cancer risk were identified. Of the significant associations identified in this study, 17 loci and 14 genes are located 1Mb away from any of the previously reported breast cancer risk variants. Pathways analyses including 221 putative risk genes identified multiple signaling pathways that may play a significant role in the development of breast cancer. Our study provides a comprehensive understanding of and new biological insights into the genetics of this common malignancy.

Differential patterns of reproductive and lifestyle risk factors for breast cancer according to birth cohorts among women in China, Japan and Korea.

BACKGROUND: The birth cohort effect has been suggested to influence the rate of breast cancer incidence and the trends of associated reproductive and lifestyle factors. We conducted a cohort study to determine whether a differential pattern of associations exists between certain factors and breast cancer risk based on birth cohorts. METHODS: This was a cohort study using pooled data from 12 cohort studies. We analysed associations between reproductive (menarche age, menopause age, parity and age at first delivery) and lifestyle (smoking and alcohol consumption) factors and breast cancer risk. We obtained hazard ratios (HRs) with 95% confidence intervals (CIs) using the Cox proportional hazard regression analysis on the 1920s, 1930s, 1940s and 1950s birth cohorts. RESULTS: Parity was found to lower the risk of breast cancer in the older but not in the younger birth cohort, whereas lifestyle factors showed associations with breast cancer risk only among the participants born in the 1950s. In the younger birth cohort group, the effect size was lower for parous women compared to the other cohort groups (HR [95% CI] 0.86 [0.66-1.13] compared to 0.60 [0.49-0.73], 0.46 [0.38-0.56] and 0.62 [0.51-0.77]). Meanwhile, a higher effect size was found for smoking (1.45 [1.14-1.84] compared to 1.25 [0.99-1.58], 1.06 [0.85-1.32] and 0.86 [0.69-1.08]) and alcohol consumption (1.22 [1.01-1.48] compared to 1.10 [0.90-1.33], 1.15 [0.96-1.38], and 1.07 [0.91-1.26]). CONCLUSION: We observed different associations of parity, smoking and alcohol consumption with breast cancer risk across various birth cohorts.

Association of female reproductive and hormonal factors with gallbladder cancer risk in Asia: A pooled analysis of the Asia Cohort Consortium.

The female predominance of gallbladder cancer (GBC) has led to a hypothesis regarding the hormone-related aetiology of GBC. We aimed to investigate the association between female reproductive factors and GBC risk, considering birth cohorts of Asian women. We conducted a pooled analysis of 331,323 women from 12 cohorts across 4 countries (China, Japan, Korea, and Singapore) in the Asia Cohort Consortium. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) to assess the association between reproductive factors (age at menarche, parity, age at first delivery, breastfeeding, and age at menopause) and GBC risk. We observed that a later age at menarche was associated with an increased risk of GBC (HR 1.4, 95% CI 1.16-1.70 for 17 years and older vs. 13-14 years), especially among the cohort born in 1940 and later (HR 2.5, 95% CI 1.50-4.35). Among the cohort born before 1940, women with a later age at first delivery showed an increased risk of GBC (HR 1.56, 95% CI 1.08-2.24 for 31 years of age and older vs. 20 years of age and younger). Other reproductive factors did not show a clear association with GBC risk. Later ages at menarche and at first delivery were associated with a higher risk of GBC, and these associations varied by birth cohort.

Association between reproductive factors with lung cancer incidence and mortality: A pooled analysis of over 308,000 females in the Asia cohort consortium.

Previous studies have investigated the association between reproductive factors and lung cancer risk; however, findings have been inconsistent. In order to assess this association among Asian women, a total of 308,949 female participants from 11 prospective cohorts and four Asian countries (Japan, Korea, China, and Singapore) were included. Cox proportional hazards regression models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CIs). A total of 3,119 primary lung cancer cases and 2247 lung cancer deaths were identified with a mean follow-up of 16.4 years. Parous women had a lower risk of lung cancer incidence and mortality as compared with nulliparous women, with HRs of 0.82 (95% CI = 0.70-0.96) and 0.78 (95% CI = 0.65-0.94). The protective association of parity and lung cancer incidence was greater among ever-smokers (HR = 0.66, 95% CI = 0.49-0.87) than in never-smokers (HR = 0.90, 95% CI = 0.74-1.09) (P-interaction = 0.029). Compared with age at first delivery ≤20 years, older age at first delivery (21-25, ≥26 years) was associated with a lower risk of lung cancer incidence and mortality. Women who ever used hormone replacements had a higher likelihood of developing non-small cell lung cancer (HR = 1.31, 95% CI = 1.02-1.68), compared to those who never used hormone replacements. Future studies are needed to assess the underlying mechanisms, the relationships within these female reproductive factors, and the potential changes in smoking habits over time.

Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element.

A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10-31).

Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk.

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.

Assessments of dietary intake and polygenic risk score in associations with colorectal cancer risk: evidence from the UK Biobank.

BACKGROUND: This study aimed to explore the potential interaction between dietary intake and genetics on incident colorectal cancer (CRC) and whether adherence to healthy dietary habits could attenuate CRC risk in individuals at high genetic risk. METHODS: We analyzed prospective cohort data of 374,004 participants who were free of any cancers at enrollment in UK Biobank. Dietary scores were created based on three dietary recommendations of the World Cancer Research Fund (WCRF) and the overall effects of 11 foods on CRC risks using the inverse-variance (IV) method. Genetic risk was assessed using a polygenic risk score (PRS) capturing overall CRC risk. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% CIs (confidence intervals) of associations. Interactions between dietary factors and the PRS were examined using a likelihood ratio test to compare models with and without the interaction term. RESULTS: During a median follow-up of 12.4 years, 4,686 CRC cases were newly diagnosed. Both low adherence to the WCRF recommendations (HR = 1.12, 95% CI = 1.05-1.19) and high IV-weighted dietary scores (HR = 1.27, 95% CI = 1.18-1.37) were associated with CRC risks. The PRS of 98 genetic variants was associated with an increased CRC risk (HRT3vsT1 = 2.12, 95% CI = 1.97-2.29). Participants with both unfavorable dietary habits and a high PRS had a more than twofold increased risk of developing CRC; however, the interaction was not significant. Adherence to an overall healthy diet might attenuate CRC risks in those with high genetic risks (HR = 1.21, 95% CI = 1.08-1.35 for high vs. low IV-weighted dietary scores), while adherence to WCRF dietary recommendations showed marginal effects only (HR = 1.09, 95% CI = 1.00-1.19 for low vs. high WCRF dietary scores). CONCLUSION: Dietary habits and the PRS were independently associated with CRC risks. Adherence to healthy dietary habits may exert beneficial effects on CRC risk reduction in individuals at high genetic risk.

A time-dependent subdistribution hazard model for major dental treatment events in cancer patients: a nationwide cohort study.

BACKGROUND: Dental care in cancer patients tends to be less prioritized. However, limited research has focused on major dental treatment events in cancer patients after the diagnosis. This study aimed to examine dental treatment delays in cancer patients compared to the general population using a national claims database in South Korea. METHOD: The Korea National Health Insurance Service-National Sample Cohort version 2.0, collected from 2002 to 2015, was analyzed. Treatment events were considered for stomatitis, tooth loss, dental caries/pulp disease, and gingivitis/periodontal disease. For each considered event, time-dependent hazard ratios and associated 95% confidence intervals were calculated by applying a subdistribution hazard model with time-varying covariates. Mortality was treated as a competing event. Subgroup analyses were conducted by type of cancer. RESULTS: The time-dependent subdistribution hazard ratios (SHRs) of stomatitis treatment were greater than 1 in cancer patients in all time intervals, 2.04 within 30 days after cancer diagnosis, and gradually decreased to 1.15 after 5 years. The SHR for tooth loss was less than 0.70 within 3 months after cancer diagnosis and increased to 1 after 5 years. The trends in SHRs of treatment events for other dental diseases were similar to those observed for tooth loss. Subgroup analyses by cancer type suggested that probability of all dental treatment event occurrence was higher in head and neck cancer patients, particularly in the early phase after cancer diagnosis. CONCLUSION: Apart from treatments that are associated with cancer therapy, dental treatments in cancer patients are generally delayed and cancer patients tend to refrain from dental treatments. Consideration should be given to seeking more active and effective means for oral health promotion in cancer patients.

The Association of Serum High-Sensitivity C-Reactive Protein Level With the Risk of Site-Specific Cancer Mortality: The Health Examinees (HEXA) Study Cohort.

Few studies have investigated the association between high-sensitivity C-reactive protein (hsCRP) level and site-specific cancer mortality. In this study, we aimed to examine the associations of hsCRP with overall and site-specific cancer mortality among South Koreans using data on the Health Examinees (HEXA) Study cohort (41,070 men and 81,011 women aged ≥40 years). We obtained mortality information from the National Statistical Office of Korea, which provided the dates and causes of all deaths occurring through December 31, 2015, by linking mortality data with each participant's unique national identifier. Cox proportional hazards and restricted cubic spline models were used to assess the association between hsCRP and cancer mortality with adjustment for covariates. An analysis of site-specific cancer mortality was focused on 5 major cancers (lung, liver, gastric, colorectal, and breast/prostate). Median hsCRP levels were 0.77 mg/L and 0.59 mg/L for men and women, respectively. A dose-response association between hsCRP and overall cancer mortality was observed in men but disappeared in women after exclusion of deaths occurring in the first 1 or 2 years of follow-up. Elevated hsCRP levels increased the risks of lung, liver, and gastric cancer mortality in men, but the risks of colorectal and breast cancer mortality were not increased. The dose-response association between hsCRP and cancer mortality was observed differently depending on site-specific cancer mortality by sex.

Polygenic risk scores for prediction of breast cancer risk in Asian populations.

PURPOSE: Non-European populations are under-represented in genetics studies, hindering clinical implementation of breast cancer polygenic risk scores (PRSs). We aimed to develop PRSs using the largest available studies of Asian ancestry and to assess the transferability of PRS across ethnic subgroups. METHODS: The development data set comprised 138,309 women from 17 case-control studies. PRSs were generated using a clumping and thresholding method, lasso penalized regression, an Empirical Bayes approach, a Bayesian polygenic prediction approach, or linear combinations of multiple PRSs. These PRSs were evaluated in 89,898 women from 3 prospective studies (1592 incident cases). RESULTS: The best performing PRS (genome-wide set of single-nucleotide variations [formerly single-nucleotide polymorphism]) had a hazard ratio per unit SD of 1.62 (95% CI = 1.46-1.80) and an area under the receiver operating curve of 0.635 (95% CI = 0.622-0.649). Combined Asian and European PRSs (333 single-nucleotide variations) had a hazard ratio per SD of 1.53 (95% CI = 1.37-1.71) and an area under the receiver operating curve of 0.621 (95% CI = 0.608-0.635). The distribution of the latter PRS was different across ethnic subgroups, confirming the importance of population-specific calibration for valid estimation of breast cancer risk. CONCLUSION: PRSs developed in this study, from association data from multiple ancestries, can enhance risk stratification for women of Asian ancestry.

Socioecological approach for identifying the determinants of objectively measured physical activity: A prospective study of the UK Biobank.

The socioecological approach emphasises that health promotion should focus on a variety of factors that surround individuals simultaneously, yet there is little evidence on how these factors relatively affect physical activity (PA). The main objective was to identify relevant determinants of PA by examining the associations between factors within multilayered socioecological categories and PA. A prospective analysis was conducted with 84,052 participants participating in the accelerometer measurement from the UK Biobank. Time spent in moderate-to-vigorous PA (MVPA) was calculated from participants who wore a wrist-worn accelerometer for seven days; a questionnaire-based self-reported leisure-time physical activity was also assessed. A categorical principal component analysis was conducted to reduce the dimensions of 184 variables. The associations between principal components (PCs) and PA were evaluated using general linear models. A network of PCs was constructed to assess the comprehensive association with PA. PCs related to body composition and chronic diseases were suggested as key determinants of objectively measured MVPA and found to be clustered in the network. PCs related to body composition and socio-economic status were proposed as the key regulatory hubs in the network because they exhibited the highest level of indirect linkages with other components. In the environmental category, PCs related to greenness and air pollution were revealed to be key factors in the self-reported walking for pleasure. Using a socioecological approach, it was discovered that obesity and disease-related factors were the most important determinants, and they had an integrative influence with other factors in different categories.

Sustained Responses of Neutralizing Antibodies Against Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in Recovered Patients and Their Therapeutic Applicability.

BACKGROUND: Zoonotic coronaviruses have emerged as a global threat by causing fatal respiratory infections. Given the lack of specific antiviral therapies, application of human convalescent plasma retaining neutralizing activity could be a viable therapeutic option that can bridges this gap. METHODS: We traced antibody responses and memory B cells in peripheral blood collected from 70 recovered Middle East respiratory syndrome coronavirus (MERS-CoV) patients for 3 years after the 2015 outbreak in South Korea. We also used a mouse infection model to examine whether the neutralizing activity of collected sera could provide therapeutic benefit in vivo upon lethal MERS-CoV challenge. RESULTS: Anti-spike-specific IgG responses, including neutralizing activity and antibody-secreting memory B cells, persisted for up to 3 years, especially in MERS patients who suffered from severe pneumonia. Mean antibody titers gradually decreased annually by less than 2-fold. Levels of antibody responses were significantly correlated with fever duration, viral shedding periods, and maximum viral loads observed during infection periods. In a transgenic mice model challenged with lethal doses of MERS-CoV, a significant reduction in viral loads and enhanced survival was observed when therapeutically treated with human plasma retaining a high neutralizing titer (> 1/5000). However, this failed to reduce pulmonary pathogenesis, as revealed by pathological changes in lungs and initial weight loss. CONCLUSIONS: High titers of neutralizing activity are required for suppressive effect on the viral replication but may not be sufficient to reduce inflammatory lesions upon fatal infection. Therefore, immune sera with high neutralizing activity must be carefully selected for plasma therapy of zoonotic coronavirus infection.

Relative Effects of Demographic, Psychological, Behavioral, and Social Factors on the Initiation and Maintenance of Leisure-time Physical Activity: Results From a Confirmatory Path Analysis in a Longitudinal Study.

BACKGROUND: There is a lack of evidence of the complicated pathways of underlying determinants in the phases of physical activity. The purpose of this study was to evaluate simultaneously a set of potential determinants on the initiation and maintenance phases of leisure-time physical activity (LTPA). METHODS: The longitudinal data of 54,359 Korean adults aged 40-69 years from the Health Examinees study were used. The median follow-up duration was 4.2 years. The self-reported durations per week of LTPA was repeatedly assessed. Based on previous longitudinal studies, the potential determinants were selected, and hypothetical models were constructed that consider the complex associations between the determinants. The standardized coefficients for direct and indirect effects were estimated using path analysis to differentiate contributions of mediation from the total effects. RESULTS: In the total population, age, education, chronic diseases, smoking, depression symptoms, and self-rated health were significantly associated with both initiation and maintenance phases. Income (B = 0.025) and social supports (B = 0.019) were associated only with the initiation phase. Waist-to-hip ratio (B = -0.042) and stress (B = -0.035) were associated only with the maintenance phase. After stratifying by sex, the significant effects of education, chronic diseases, and smoking were found only in men. The initiation phase-specific effects of income and social supports and the maintenance phase-specific effects of stress were found only in women. It was estimated that indirect effects contributed approximately 15% of the total effect. CONCLUSION: The findings suggested that there were initiation- or maintenance-specific determinants of leisure-time physical activity according to sex.

Optimal cutoff values for anthropometric indices of obesity as discriminators of metabolic abnormalities in Korea: results from a Health Examinees study.

BACKGROUND: Obesity is well known as a risk factor for cardiovascular disease. We aimed to determine the performance of and the optimal cutoff values for obesity indices to discriminate the presence of metabolic abnormalities as a primary risk factor for cardiovascular diseases in a Health Examinees study (HEXA). METHODS: The current study analyzed 134,195 participants with complete anthropometric and laboratory information in a Health Examinees study, consisting of the Korean population aged 40 to 69 years. The presence of metabolic abnormality was defined as having at least one of the following: hypertension, hyperglycemia, or dyslipidemia. The area under the receiver operating characteristic curve (AUC) and 95% confidence intervals (CIs) were calculated for body mass index, waist to hip ratio, waist to height ratio, waist circumference, and conicity index. RESULTS: The AUC of metabolic abnormalities was the highest for waist-to-height ratio (AUC [95% CIs], 0.677 [0.672-0.683] among men; 0.691 [0.687-0.694] among women), and the lowest for the C index (0.616 [0.611-0.622] among men; 0.645 [0.641-0.649] among women) among both men and women. The optimal cutoff values were 24.3 kg/m2 for the body mass index, 0.887 for the waist-to-hip ratio, 0.499 for the waist-to-height ratio, 84.4 cm for waist circumference and 1.20 m3/2/kg1/2 for the conicity index among men, and 23.4 kg/m2 for the body mass index, 0.832 for the waist-to-hip ratio, 0.496 for the waist-to-height ratio, 77.0 cm for the waist circumference and 1.18 m3/2/kg1/2 for the conicity index among women. CONCLUSION: The waist-to-height ratio is the best index to discriminate metabolic abnormalities among middle-aged Koreans. The optimal cutoff of obesity indices is lower than the international guidelines for obesity. It would be appropriate to use the indices for abdominal obesity rather than general obesity and to consider a lower level of body mass index and waist circumference than the current guidelines to determine obesity-related health problems in Koreans.

Breast Cancer-Related Low Penetrance Genes.

Susceptibility genes involved in disease etiology and prognosis are categorized into two groups: high penetrance genes (i.e., BRCA1, CHEK2, ATM, etc.) and low penetrance genes (i.e., NATs, GSTs, CYPs, etc., and variants identified by genome-wide association studies). Since low penetrance genes have high population attributable risk, the usefulness of those genes to research on breast cancer prevention is not small. In this chapter, the previous studies on low-penetrance genetic susceptibility through a candidate gene approach and genome-wide association of breast cancer were summarized. The contribution of low-penetrance susceptibility genes to the breast cancer risk prediction models will also be discussed on the utility in clinical or public health application.

Appraising the role of previously reported risk factors in epithelial ovarian cancer risk: A Mendelian randomization analysis.

BACKGROUND: Various risk factors have been associated with epithelial ovarian cancer risk in observational epidemiological studies. However, the causal nature of the risk factors reported, and thus their suitability as effective intervention targets, is unclear given the susceptibility of conventional observational designs to residual confounding and reverse causation. Mendelian randomization (MR) uses genetic variants as proxies for risk factors to strengthen causal inference in observational studies. We used MR to evaluate the association of 12 previously reported risk factors (reproductive, anthropometric, clinical, lifestyle, and molecular factors) with risk of invasive epithelial ovarian cancer, invasive epithelial ovarian cancer histotypes, and low malignant potential tumours. METHODS AND FINDINGS: Genetic instruments to proxy 12 risk factors were constructed by identifying single nucleotide polymorphisms (SNPs) that were robustly (P < 5 × 10-8) and independently associated with each respective risk factor in previously reported genome-wide association studies. These risk factors included genetic liability to 3 factors (endometriosis, polycystic ovary syndrome, type 2 diabetes) scaled to reflect a 50% higher odds liability to disease. We obtained summary statistics for the association of these SNPs with risk of overall and histotype-specific invasive epithelial ovarian cancer (22,406 cases; 40,941 controls) and low malignant potential tumours (3,103 cases; 40,941 controls) from the Ovarian Cancer Association Consortium (OCAC). The OCAC dataset comprises 63 genotyping project/case-control sets with participants of European ancestry recruited from 14 countries (US, Australia, Belarus, Germany, Belgium, Denmark, Finland, Norway, Canada, Poland, UK, Spain, Netherlands, and Sweden). SNPs were combined into multi-allelic inverse-variance-weighted fixed or random effects models to generate effect estimates and 95% confidence intervals (CIs). Three complementary sensitivity analyses were performed to examine violations of MR assumptions: MR-Egger regression and weighted median and mode estimators. A Bonferroni-corrected P value threshold was used to establish strong evidence (P < 0.0042) and suggestive evidence (0.0042 < P < 0.05) for associations. In MR analyses, there was strong or suggestive evidence that 2 of the 12 risk factors were associated with invasive epithelial ovarian cancer and 8 of the 12 were associated with 1 or more invasive epithelial ovarian cancer histotypes. There was strong evidence that genetic liability to endometriosis was associated with an increased risk of invasive epithelial ovarian cancer (odds ratio [OR] per 50% higher odds liability: 1.10, 95% CI 1.06-1.15; P = 6.94 × 10-7) and suggestive evidence that lifetime smoking exposure was associated with an increased risk of invasive epithelial ovarian cancer (OR per unit increase in smoking score: 1.36, 95% CI 1.04-1.78; P = 0.02). In analyses examining histotypes and low malignant potential tumours, the strongest associations found were between height and clear cell carcinoma (OR per SD increase: 1.36, 95% CI 1.15-1.61; P = 0.0003); age at natural menopause and endometrioid carcinoma (OR per year later onset: 1.09, 95% CI 1.02-1.16; P = 0.007); and genetic liability to polycystic ovary syndrome and endometrioid carcinoma (OR per 50% higher odds liability: 0.89, 95% CI 0.82-0.96; P = 0.002). There was little evidence for an association of genetic liability to type 2 diabetes, parity, or circulating levels of 25-hydroxyvitamin D and sex hormone binding globulin with ovarian cancer or its subtypes. The primary limitations of this analysis include the modest statistical power for analyses of risk factors in relation to some less common ovarian cancer histotypes (low grade serous, mucinous, and clear cell carcinomas), the inability to directly examine the association of some ovarian cancer risk factors that did not have robust genetic variants available to serve as proxies (e.g., oral contraceptive use, hormone replacement therapy), and the assumption of linear relationships between risk factors and ovarian cancer risk. CONCLUSIONS: Our comprehensive examination of possible aetiological drivers of ovarian carcinogenesis using germline genetic variants to proxy risk factors supports a role for few of these factors in invasive epithelial ovarian cancer overall and suggests distinct aetiologies across histotypes. The identification of novel risk factors remains an important priority for the prevention of epithelial ovarian cancer.

Trends and Correlates of High-Risk Alcohol Consumption and Types of Alcoholic Beverages in Middle-Aged Korean Adults: Results From the HEXA-G Study.

BACKGROUND: We aimed to report the prevalence and correlates of high-risk alcohol consumption and types of alcoholic beverages. METHODS: The baseline data of the Health Examinees-Gem (HEXA-G) study participants, including 43,927 men and 85,897 women enrolled from 2005 through 2013, were used for analysis. Joinpoint regression was performed to estimate trends in the age-standardized prevalence of alcohol consumption. Associations of demographic and behavioral factors, perceived health-related effects, social relationships, and the diagnostic history of diseases with alcohol consumption were assessed using multinomial logistic regression. RESULTS: The prevalence of alcohol consumption remained higher in men during the study period and increased in women. The amount of alcohol consumed has increased in women, especially that from beer and makgeolli, a traditional Korean fermented rice wine. Older participants were less likely to be high-risk drinkers (men and women who drink more than 40 or 20 g/day of alcohol, respectively) and drink Soju, a distilled liquor, and beer, and more likely to drink makgeolli. Educational level was negatively associated with high-risk drinking. However, it was positively associated with the consumption of strong spirits and wine. Smoking was associated with high-risk drinking and the consumption of soju and strong spirits. Engaging in regular exercise and having stress were associated with drinking all types of beverages except for soju. CONCLUSIONS: Sex-specific trends in alcohol consumption were influenced by demographic, behavioral, and perceived health-related factors. The findings will help improve the understanding of alcohol-related problems and provide evidence for establishing country-specific policies and campaigns in Korea.

Genome-wide association study in East Asians identifies two novel breast cancer susceptibility loci.

Breast cancer is one of the most common malignancies among women worldwide. Genetic factors have been shown to play an important role in breast cancer aetiology. We conducted a two-stage genome-wide association study (GWAS) including 14 224 cases and 14 829 controls of East Asian women to search for novel genetic susceptibility loci for breast cancer. Single nucleotide polymorphisms (SNPs) in two loci were found to be associated with breast cancer risk at the genome-wide significance level. The first locus, represented by rs12118297 at 1p22.3 (near the LMO4 gene), was associated with breast cancer risk with odds ratio (OR) and (95% confidence interval (CI)) of 0.91 (0.88-0.94) and a P-value of 4.48 × 10- 8 This association was replicated in another study, DRIVE GAME-ON Consortium, including 16 003 cases and 41 335 controls of European ancestry (OR = 0.95, 95% CI = 0.91-0.99, P-value = 0.019). The second locus, rs16992204 at 21q22.12 (near the LINC00160 gene), was associated with breast cancer risk with OR (95% CI) of 1.13 (1.07-1.18) and a P-value of 4.63 × 10 - 8 The risk allele frequency for this SNP is zero in European-ancestry populations in 1000 Genomes Project and thus its association with breast cancer risk cannot be assessed in DRIVE GAME-ON Consortium. Functional annotation using the ENCODE data indicates that rs12118297 might be located in a repressed element and locus 21q22.12 may affect breast cancer risk through regulating LINC00160 expressions and interaction with oestrogen receptor signalling. Our findings provide additional insights into the genetics of breast cancer.

Associations between genetic polymorphisms of membrane transporter genes and prognosis after chemotherapy: meta-analysis and finding from Seoul Breast Cancer Study (SEBCS).

Membrane transporters can be major determinants of the pharmacokinetic profiles of anticancer drugs. The associations between genetic variations of ATP-binding cassette (ABC) and solute carrier (SLC) genes and cancer survival were investigated through a meta-analysis and an association study in the Seoul Breast Cancer Study (SEBCS). Including the SEBCS, the meta-analysis was conducted among 38 studies of genetic variations of transporters on various cancer survivors. The population of SEBCS consisted of 1338 breast cancer patients who had been treated with adjuvant chemotherapy. A total of 7750 SNPs were selected from 453 ABC and/or SLC genes typed by an Affymetrix 6.0 chip. ABCB1 rs1045642 was associated with poor progression-free survival in a meta-analysis (HR = 1.33, 95% CI: 1.07-1.64). ABCB1, SLC8A1, and SLC12A8 were associated with breast cancer survival in SEBCS (Pgene < 0.05). ABCB1 rs1202172 was differentially associated with survival depending on the chemotherapy (Pinteraction = 0.035). Our finding provides suggestive associations of membrane transporters on cancer survival.

Evaluating genetic variants associated with breast cancer risk in high and moderate-penetrance genes in Asians.

Over the past 20 years, high-penetrance pathogenic mutations in genes BRCA1, BRCA2, TP53, PTEN, STK11 and CDH1 and moderate-penetrance mutations in genes CHEK2, ATM, BRIP1, PALB2, RAD51C, RAD50 and NBN have been identified for breast cancer. In this study, we investigated whether there are additional variants in these 13 genes associated with breast cancer among women of Asian ancestry. We analyzed up to 654 single nucleotide polymorphisms (SNPs) from 6269 cases and 6624 controls of Asian descent included in the Breast Cancer Association Consortium (BCAC), and up to 236 SNPs from 5794 cases and 5529 controls included in the Shanghai Breast Cancer Genetics Study (SBCGS). We found three missense variants with minor allele frequency (MAF) <0.05: rs80358978 (Gly2508Ser), rs80359065 (Lys2729Asn) and rs11571653 (Met784Val) in the BRCA2 gene, showing statistically significant associations with breast cancer risk, with P-values of 1.2 × 10-4, 1.0 × 10-3 and 5.0 × 10-3, respectively. In addition, we found four low-frequency variants (rs8176085, rs799923, rs8176173 and rs8176258) in the BRCA1 gene, one common variant in the CHEK2 gene (rs9620817), and one common variant in the PALB2 gene (rs13330119) associated with breast cancer risk at P < 0.01. Our study identified several new risk variants in BRCA1, BRCA2, CHEK2, and PALB2 genes in relation to breast cancer risk in Asian women. These results provide further insights that, in addition to the high/moderate penetrance mutations, other low-penetrance variants in these genes may also contribute to breast cancer risk.