Differences in polygenic score distributions in European ancestry populations: implications for breast cancer risk prediction.

The 313-variant polygenic risk score (PRS313) provides a promising tool for breast cancer risk prediction. However, evaluation of the PRS313 across different European populations which could influence risk estimation has not been performed. Here, we explored the distribution of PRS313 across European populations using genotype data from 94,072 females without breast cancer, of European-ancestry from 21 countries participating in the Breast Cancer Association Consortium (BCAC) and 225,105 female participants from the UK Biobank. The mean PRS313 differed markedly across European countries, being highest in south-eastern Europe and lowest in north-western Europe. Using the overall European PRS313 distribution to categorise individuals leads to overestimation and underestimation of risk in some individuals from south-eastern and north-western countries, respectively. Adjustment for principal components explained most of the observed heterogeneity in mean PRS. Country-specific PRS distributions may be used to calibrate risk categories in individuals from different countries.

Perspectives of clinical stakeholders and patients from four VA liver clinics to tailor practice facilitation for implementing evidence-based alcohol-related care.

BACKGROUND: Unhealthy alcohol use (UAU) is particularly dangerous for people with chronic liver disease. Liver clinics may be an important setting in which to provide effective alcohol-related care by integrating evidence-based strategies, such as brief intervention and medications for alcohol use disorder. We conducted qualitative interviews with clinical stakeholders and patients at liver clinics in four Veterans Health Administration (VA) medical centers to understand barriers and facilitators of integrating alcohol-related care and to support tailoring of a practice facilitation implementation intervention. METHODS: Data collection and analysis were guided by the Consolidated Framework for Implementation Research (CFIR). Interviews were transcribed and qualitatively analyzed using a Rapid Assessment Process (RAP) guided by the CFIR. RESULTS: We interviewed 46 clinical stakeholders and 41 patient participants and analyzed findings based on the CFIR. Clinical stakeholders described barriers and facilitators that ranged from operations/clinic resource-based (e.g., time and capacity, desire for additional provider types, referral processes) to individual perspective and preference-based (e.g., supportiveness of leadership, individual experiences/beliefs). Patient participants shared barriers and facilitators that ranged from relationship-based (e.g., trusting the provider and feeling judged) to resource and education-based (e.g., connection to a range of treatment options, education about impact of alcohol). Many barriers and facilitators to integrating alcohol-related care in liver clinics were similar to those identified in other clinical settings (e.g., time, resources, role clarity, stigmatizing beliefs). However, some barriers (e.g., fellow-led care and lack of integration of liver clinics with addictions specialists) and facilitators (e.g., presence of quality improvement staff in clinics and integrated pharmacists and behavioral health specialists) were more unique to liver clinics. CONCLUSIONS: These findings support the possibility of integrating alcohol-related care into liver clinics but highlight the importance of tailoring efforts to account for variation in provider beliefs and experiences and clinic resources. The barriers and facilitators identified in these interviews were used to tailor a practice facilitation implementation intervention in each clinic setting.

International Pooled Analysis of Leisure-Time Physical Activity and Premenopausal Breast Cancer in Women From 19 Cohorts.

PURPOSE: There is strong evidence that leisure-time physical activity is protective against postmenopausal breast cancer risk but the association with premenopausal breast cancer is less clear. The purpose of this study was to examine the association of physical activity with the risk of developing premenopausal breast cancer. METHODS: We pooled individual-level data on self-reported leisure-time physical activity across 19 cohort studies comprising 547,601 premenopausal women, with 10,231 incident cases of breast cancer. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% CIs for associations of leisure-time physical activity with breast cancer incidence. HRs for high versus low levels of activity were based on a comparison of risk at the 90th versus 10th percentiles of activity. We assessed the linearity of the relationship and examined subtype-specific associations and effect modification across strata of breast cancer risk factors, including adiposity. RESULTS: Over a median 11.5 years of follow-up (IQR, 8.0-16.1 years), high versus low levels of leisure-time physical activity were associated with a 6% (HR, 0.94 [95% CI, 0.89 to 0.99]) and a 10% (HR, 0.90 [95% CI, 0.85 to 0.95]) reduction in breast cancer risk, before and after adjustment for BMI, respectively. Tests of nonlinearity suggested an approximately linear relationship (Pnonlinearity = .94). The inverse association was particularly strong for human epidermal growth factor receptor 2-enriched breast cancer (HR, 0.57 [95% CI, 0.39 to 0.84]; Phet = .07). Associations did not vary significantly across strata of breast cancer risk factors, including subgroups of adiposity. CONCLUSION: This large, pooled analysis of cohort studies adds to evidence that engagement in higher levels of leisure-time physical activity may lead to reduced premenopausal breast cancer risk.

A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry.

BACKGROUND: Genome-wide studies of gene-environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of ~ 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer. METHODS: Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene-environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs. RESULTS: Assuming a 1 × 10-5 prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability < 15%, we identified two independent SNP-risk factor pairs: rs80018847(9p13)-LINGO2 and adult height in association with overall breast cancer risk (ORint = 0.94, 95% CI 0.92-0.96), and rs4770552(13q12)-SPATA13 and age at menarche for ER + breast cancer risk (ORint = 0.91, 95% CI 0.88-0.94). CONCLUSIONS: Overall, the contribution of G×E interactions to the heritability of breast cancer is very small. At the population level, multiplicative G×E interactions do not make an important contribution to risk prediction in breast cancer.

Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel.

BACKGROUND: Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. METHODS: We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. RESULTS: In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). CONCLUSIONS: Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.

Prevalence of social and economic stressors among transgender veterans with alcohol and other drug use disorders.

Transgender persons have high rates of alcohol and other drug use disorders (AUD and DUD, respectively) and commonly experience social and economic stressors that may compound risk for adverse substance-related outcomes. National VA electronic health record data were extracted for all outpatients in each facility with documented alcohol screening 10/1/09-7/31/17. We describe the prevalence of eight individual-level social and economic stressors (barriers to accessing care, economic hardship, housing instability, homelessness, social and family problems, legal problems, military sexual trauma, and other victimization) among transgender patients with and without AUD and DUD (alone and in combination), overall and compared to cisgender patients in a national sample of VA outpatients. Among 8,872,793 patients, 8619 (0.1%) were transgender; the prevalence of AUD, DUD, and both was 8.6%, 7.2%, and 3.1% among transgender patients and 6.1%, 3.9%, and 1.7% among cisgender patients, respectively. Among all patients, prevalence of stressors was higher among those with AUD, DUD, or both, relative to those with neither. Within each of these groups, prevalence was 2-3 times higher among transgender compared to cisgender patients. For instance, prevalence of housing instability for transgender vs. cisgender patients with AUD, DUD, and both was: 40.8% vs 24.1%, 45.8% vs. 36.6%, and 57.4% vs. 47.0%, respectively. (all p-values <0.001). Social and economic stressors were prevalent among patients with AUD, DUD, or both, and the experience of these disorders and social and economic stressors was more common among transgender than cisgender patients in all groups. Further research regarding experiences of transgender persons and influences of stressors on risk of AUD and DUD, substance-related outcomes, and treatment uptake are needed. Routine screening for social and economic stressors among patients with substance use disorders (SUDs) could improve equitable substance-related care and outcomes. Treatment of SUDs among all persons should consider social and economic risk factors.

Comparison of Substance Use Disorder Diagnosis Rates From Electronic Health Record Data With Substance Use Disorder Prevalence Rates Reported in Surveys Across Sociodemographic Groups in the Veterans Health Administration.

Importance: Substance use disorders (SUDs) are major contributors to morbidity and mortality globally, but they are often underrecognized and underdiagnosed, particularly in some sociodemographic subgroups. Understanding the extent to which clinical diagnoses underestimate these conditions within subgroups is imperative to achieving equitable treatment, regardless of race, ethnicity, gender, or age, and to informing and improving performance monitoring. Objective: To compare clinically documented diagnosis rates of alcohol use disorder (AUD), drug use disorder (DUD), and total SUD (AUD and/or DUD) with the prevalence of these disorders as reported in surveys-based on structured, validated diagnostic assessments-across demographic subgroups. Design, Setting, and Participants: A telephone-based survey was conducted from January 8, 2018, to April 30, 2019, among 5995 Veterans Health Administration (VHA) outpatients who were randomly sampled from 30 VHA facilities and were 18 years of age or older, could complete the survey in English, and had a valid address and telephone number. Survey data were linked to electronic health record (EHR) data for all participants. Statistical analysis was performed between January 29, 2020, and April 20, 2021. Exposures: Demographic subgroups based on self-report: gender (male or female), age (18-34, 35-49, 50-64, 65-74, and ≥75 years), and race and ethnicity (Black non-Hispanic, Hispanic, multiracial, other [Asian or Asian-American, American Indian or Alaskan Native, Native Hawaiian or Pacific Islander, and any other race endorsed by the participant], and White non-Hispanic). Main Outcomes and Measures: Survey-based prevalence rates of AUD, DUD, and SUD were assessed using the Mini International Neuropsychiatric Interview, version 7.0, the only validated instrument available at study outset that measured Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria for past 12-month diagnoses. Clinically documented diagnosis rates were measured using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnoses from VHA EHR data. Analyses compared survey-based prevalence rates of AUD, DUD, and SUD with diagnosis rates using sensitivity and specificity and difference-in-difference analysis. All analyses were weighted with survey weights to account for nonresponse. Results: Of 5995 participants, 4115 (68.6%) were White non-Hispanic, and 5429 (91.1%) were male; the mean (SD) age was 61.5 (15.3) years. The survey-based prevalence rates of AUD, DUD, and SUD were higher than the diagnosis rates among all patients (AUD, 608 [10.1%] vs 360 [6.0%]; DUD, 282 [4.7%] vs 275 [4.6%]; SUD, 768 [12.8%] vs 515 [8.6%]). Survey-based prevalence rates of AUD and SUD exceeded the diagnosis rates in every demographic subgroup. Gaps between diagnosis rates and survey-based prevalence rates for AUD and SUD were largest among patients aged 18 to 34 years (AUD diagnosis rate, 27 [6.9%; 95% CI, 4.8%-9.9%] vs AUD prevalence rate, 88 [22.4%; 95% CI, 17.3%-28.5%]; SUD diagnosis rate, 41 [10.5%; 95% CI, 8.1%-13.4%] vs SUD prevalence rate, 109 [27.7%; 95% CI, 22.6%-33.3%]) and Hispanic and Latinx patients (AUD diagnosis rate, 31 [7.6%; 95% CI, 5.3%-10.8%] vs AUD prevalence rate, 72 [17.7%; 95% CI, 14.0%-22.1%]; and SUD diagnosis rate, 48 [11.7%; 95% CI, 7.9%-16.9%] vs SUD prevalence rate, 88 [21.6%; 95% CI, 18.0%-25.8%]). For DUD, only patients aged 18 to 34 years had a true prevalence rate that significantly exceeded the diagnosis rate (diagnosis rate, 21 [5.4%; 95% CI, 3.7%-7.8%] vs prevalence rate, 40 [10.1%; 95% CI, 7.2%-14.0%]). Conclusions and Relevance: The results of this survey study suggest that existing diagnostic procedures and tools are insufficient to capture SUD prevalence rates, particularly among younger patients and Hispanic and Latinx patients. Clinics and health systems should implement standardized SUD assessments to ensure the provision of equitable care and the optimal identification of underlying conditions for performance monitoring.

'Friendly' and 'noisy surveillance' through MapMyRun during the COVID-19 pandemic.

This paper considers the nature of social surveillance through the physical activity tracking app MapMyRun and examines how this was experienced during the COVID-19 pandemic during the UK and USA summer 2020 lockdowns. In contributing to debates in digital geographies around the entanglements of the fleshy and digital body, the paper responds to calls for research to recognise the increasing sociality of self-tracking (Couture, 2021), specifically considering how, during the COVID-19 pandemic, these apps offered a form of connection during a time of isolation. Using data from email and video interviews, I argue that whilst a Foucauldian account of surveillance can be used as a point of departure, it is limited in accounting for the social aspects of self-tracking. I therefore propose that applying Robinson's (2000) concept of 'noisy surveillance' to self-tracking is useful for understanding the messiness of surveillance in terms of the complications and noisiness involved in interactions in digital spaces, as well as the opportunities for performance management online particularly during lockdown.

Rare germline copy number variants (CNVs) and breast cancer risk.

Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.

Functional annotation of breast cancer risk loci: current progress and future directions.

Genome-wide association studies coupled with large-scale replication and fine-scale mapping studies have identified more than 150 genomic regions that are associated with breast cancer risk. Here, we review efforts to translate these findings into a greater understanding of disease mechanism. Our review comes in the context of a recently published fine-scale mapping analysis of these regions, which reported 352 independent signals and a total of 13,367 credible causal variants. The vast majority of credible causal variants map to noncoding DNA, implicating regulation of gene expression as the mechanism by which functional variants influence risk. Accordingly, we review methods for defining candidate-regulatory sequences, methods for identifying putative target genes and methods for linking candidate-regulatory sequences to putative target genes. We provide a summary of available data resources and identify gaps in these resources. We conclude that while much work has been done, there is still much to do. There are, however, grounds for optimism; combining statistical data from fine-scale mapping with functional data that are more representative of the normal "at risk" breast, generated using new technologies, should lead to a greater understanding of the mechanisms that influence an individual woman's risk of breast cancer.

Epigenetic quantification of circulating immune cells in peripheral blood of triple-negative breast cancer patients.

BACKGROUND: A shift in the proportions of blood immune cells is a hallmark of cancer development. Here, we investigated whether methylation-derived immune cell type ratios and methylation-derived neutrophil-to-lymphocyte ratios (mdNLRs) are associated with triple-negative breast cancer (TNBC). METHODS: Leukocyte subtype-specific unmethylated/methylated CpG sites were selected, and methylation levels at these sites were used as proxies for immune cell type proportions and mdNLR estimation in 231 TNBC cases and 231 age-matched controls. Data were validated using the Houseman deconvolution method. Additionally, the natural killer (NK) cell ratio was measured in a prospective sample set of 146 TNBC cases and 146 age-matched controls. RESULTS: The mdNLRs were higher in TNBC cases compared with controls and associated with TNBC (odds ratio (OR) range (2.66-4.29), all Padj. < 1e-04). A higher neutrophil ratio and lower ratios of NK cells, CD4 + T cells, CD8 + T cells, monocytes, and B cells were associated with TNBC. The strongest association was observed with decreased NK cell ratio (OR range (1.28-1.42), all Padj. < 1e-04). The NK cell ratio was also significantly lower in pre-diagnostic samples of TNBC cases compared with controls (P = 0.019). CONCLUSION: This immunomethylomic study shows that a shift in the ratios/proportions of leukocyte subtypes is associated with TNBC, with decreased NK cell showing the strongest association. These findings improve our knowledge of the role of the immune system in TNBC and point to the possibility of using NK cell level as a non-invasive molecular marker for TNBC risk assessment, early detection, and prevention.

Evaluation of the Association of Polymorphisms With Palbociclib-Induced Neutropenia: Pharmacogenetic Analysis of PALOMA-2/-3.

BACKGROUND: The most frequently reported treatment-related adverse event in clinical trials with the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor palbociclib is neutropenia. Allelic variants in ABCB1 and ERCC1 might be associated with early occurrence (i.e., end of week 2 treatment) of grade 3/4 neutropenia. Pharmacogenetic analyses were performed to uncover associations between single nucleotide polymorphisms (SNPs) in these genes, patient baseline characteristics, and early occurrence of grade 3/4 neutropenia. MATERIALS AND METHODS: ABCB1 (rs1045642, rs1128503) and ERCC1 (rs3212986, rs11615) were analyzed in germline DNA from palbociclib-treated patients from PALOMA-2 (n = 584) and PALOMA-3 (n = 442). SNP, race, and cycle 1 day 15 (C1D15) absolute neutrophil count (ANC) data were available for 652 patients. Univariate and multivariable analyses evaluated associations between SNPs, patient baseline characteristics, and early occurrence of grade 3/4 neutropenia. Analyses were stratified by Asian (n = 122) and non-Asian (n = 530) ethnicity. Median progression-free survival (mPFS) was estimated using the Kaplan-Meier method. The effect of genetic variants on palbociclib pharmacokinetics was analyzed. RESULTS: ABCB1 and ERCC1_rs11615 SNP frequencies differed between Asian and non-Asian patients. Multivariable analysis showed that low baseline ANC was a strong independent risk factor for C1D15 grade 3/4 neutropenia regardless of race (Asians: odds ratio [OR], 6.033, 95% confidence interval [CI], 2.615-13.922, p < .0001; Non-Asians: OR, 6.884, 95% CI, 4.138-11.451, p < .0001). ABCB1_rs1128503 (C/C vs. T/T: OR, 0.57, 95% CI, 0.311-1.047, p = .070) and ERCC1_rs11615 (A/A vs. G/G: OR, 1.75, 95% CI, 0.901-3.397, p = .098) were potential independent risk factors for C1D15 grade 3/4 neutropenia in non-Asian patients. Palbociclib mPFS was consistent across genetic variants; exposure was not associated with ABCB1 genotype. CONCLUSION: This is the first comprehensive assessment of pharmacogenetic data in relationship to exposure to a CDK4/6 inhibitor. Pharmacogenetic testing may inform about potentially increased likelihood of patients developing severe neutropenia (NCT01740427, NCT01942135). IMPLICATIONS FOR PRACTICE: Palbociclib plus endocrine therapy improves hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer outcomes, but is commonly associated with neutropenia. Genetic variants in ABCB1 may influence palbociclib exposure, and in ERCC1 are associated with chemotherapy-induced severe neutropenia. Here, the associations of single nucleotide polymorphisms in these genes and baseline characteristics with neutropenia were assessed. Low baseline absolute neutrophil count was a strong risk factor (p < .0001) for grade 3/4 neutropenia. There was a trend indicating that ABCB1_rs1128503 and ERCC1_rs11615 were potential risk factors (p < .10) for grade 3/4 neutropenia in non-Asian patients. Pharmacogenetic testing could inform clinicians about the likelihood of severe neutropenia with palbociclib.

Identifying high-confidence capture Hi-C interactions using CHiCANE.

The ability to identify regulatory interactions that mediate gene expression changes through distal elements, such as risk loci, is transforming our understanding of how genomes are spatially organized and regulated. Capture Hi-C (CHi-C) is a powerful tool to delineate such regulatory interactions. However, primary analysis and downstream interpretation of CHi-C profiles remains challenging and relies on disparate tools with ad-hoc input/output formats and specific assumptions for statistical modeling. Here we present a data processing and interaction calling toolkit (CHiCANE), specialized for the analysis and meaningful interpretation of CHi-C assays. In this protocol, we demonstrate applications of CHiCANE to region capture Hi-C (rCHi-C) and promoter capture Hi-C (pCHi-C) libraries, followed by quality assessment of interaction peaks, as well as downstream analysis specific to rCHi-C and pCHi-C to aid functional interpretation. For a typical rCHi-C/pCHi-C dataset this protocol takes up to 3 d for users with a moderate understanding of R programming and statistical concepts, although this is dependent on dataset size and compute power available. CHiCANE is freely available at https://cran.r-project.org/web/packages/chicane .

Patterns of Alcohol Use Among Transgender Patients Receiving Care at the Veterans Health Administration: Overall and Relative to Nontransgender Patients.

OBJECTIVE: Alcohol use is understudied among transgender persons--persons whose sex differs from their gender identity. We compare patterns of alcohol use between Veterans Health Administration (VA) transgender and nontransgender outpatients. METHOD: National VA electronic health record data were used to identify all patients' last documented Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) screen (October 1, 2009-July 31, 2017). Transgender patients were identified using diagnostic codes. Logistic regression models estimated four past-year primary outcomes: (a) alcohol use (AUDIT-C > 0); (b) unhealthy alcohol use (AUDIT-C ≥ 5); (c) high-risk alcohol use (AUDIT-C ≥ 8); and (d) heavy episodic drinking (HED; ≥6 drinks on ≥1 occasion). Two secondary diagnostic-based outcomes, alcohol use disorder (AUD) and alcohol-specific conditions, were also examined. RESULTS: Among 8,872,793 patients, 8,619 (0.10%) were transgender. For transgender patients, unadjusted prevalence estimates were as follows: 52.8% for any alcohol use, 6.6% unhealthy alcohol use, 2.8% high-risk use, 10.4% HED, 8.6% AUD, and 1.3% alcohol-specific conditions. After adjustment for demographic characteristics, transgender patients had lower odds of patient-reported alcohol use but higher odds of alcohol-related diagnoses compared with nontransgender patients. Differences in alcohol-related diagnoses were attenuated after adjustment for comorbid conditions and utilization. CONCLUSIONS: This is the largest study of patterns of alcohol use among transgender persons and among the first to directly compare patterns to nontransgender persons. Findings suggest nuanced associations with patterns of alcohol use and provide a base for further disparities research to explore alcohol use within the diverse transgender community. Research with self-reported measures of gender identity and sex-at-birth and structured assessment of alcohol use and disorders is needed.

Common Susceptibility Loci for Male Breast Cancer.

BACKGROUND: The etiology of male breast cancer (MBC) is poorly understood. In particular, the extent to which the genetic basis of MBC differs from female breast cancer (FBC) is unknown. A previous genome-wide association study of MBC identified 2 predisposition loci for the disease, both of which were also associated with risk of FBC. METHODS: We performed genome-wide single nucleotide polymorphism genotyping of European ancestry MBC case subjects and controls in 3 stages. Associations between directly genotyped and imputed single nucleotide polymorphisms with MBC were assessed using fixed-effects meta-analysis of 1380 cases and 3620 controls. Replication genotyping of 810 cases and 1026 controls was used to validate variants with P values less than 1 × 10-06. Genetic correlation with FBC was evaluated using linkage disequilibrium score regression, by comprehensively examining the associations of published FBC risk loci with risk of MBC and by assessing associations between a FBC polygenic risk score and MBC. All statistical tests were 2-sided. RESULTS: The genome-wide association study identified 3 novel MBC susceptibility loci that attained genome-wide statistical significance (P < 5 × 10-08). Genetic correlation analysis revealed a strong shared genetic basis with estrogen receptor-positive FBC. Men in the top quintile of genetic risk had a fourfold increased risk of breast cancer relative to those in the bottom quintile (odds ratio = 3.86, 95% confidence interval = 3.07 to 4.87, P = 2.08 × 10-30). CONCLUSIONS: These findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic etiology with FBC and identifying a fourfold high-risk group of susceptible men.

Practice facilitation to implement alcohol-related care in Veterans Health Administration liver clinics: a study protocol.

BACKGROUND: Alcohol-related care, including screening, brief intervention, and provision of/referral to medication or behavioral treatments for alcohol use disorder, could be delivered in liver clinics to better reach patients with chronic liver conditions. However, the provision of alcohol-related care in liver clinics is currently suboptimal. Practice facilitation is an evidence-based implementation strategy that may address barriers, harness facilitators, and optimize the implementation of alcohol-related care in liver clinic settings using a clinic-centered approach. We report the protocol of a study to test a practice facilitation intervention to implement alcohol-related care in four Veterans Health Administration liver clinics. METHODS: This study will employ a Hybrid Type 3 effectiveness-implementation design, in which implementation outcomes are considered primary and clinical outcomes secondary. Intervention and evaluation design were informed by the Consolidated Framework for Implementation Research. Qualitative data collected from clinical stakeholders and patients were used to tailor the intervention. The intervention involves a 6-month period of external practice facilitation, including regular meetings to identify clinic goals, challenges, and solutions; engagement of clinic champions; provision of training and development of educational materials for clinic staff and patients; and performance monitoring and feedback. Ongoing formative evaluation involves the collection of quantitative facilitator tracking data and qualitative data from meeting notes and patient interviews to describe intervention acceptability, feasibility, and adoption, and adjust implementation as needed. In the summative evaluation, implementation outcomes (clinic rates of screening, brief intervention, and treatment referral/receipt) and clinical outcomes (unhealthy alcohol use, liver health) will be assessed among patients in participating clinics using secondary electronic health record data and interrupted time series analysis. DISCUSSION: This will be the first study to our knowledge to test practice facilitation to implement alcohol-related care in liver clinic settings. Results from formative and summative evaluation will inform a framework for the successful implementation of effective alcohol-related care through practice facilitation in liver clinics, which may ultimately lead to better health outcomes for patients with chronic liver disease.

DNA methylation of the long intergenic noncoding RNA 299 gene in triple-negative breast cancer: results from a prospective study.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype associated with a high rate of recurrence and poor prognosis. Recently we identified a hypermethylation in the long noncoding RNA 299 (LINC00299) gene in blood-derived DNA from TNBC patients compared with healthy controls implying that LINC00299 hypermethylation may serve as a circulating biomarker for TNBC. In the present study, we investigated whether LINC00299 methylation is associated with TNBC in a prospective nested breast cancer case-control study within the Generations Study. Methylation at cg06588802 in LINC00299 was measured in 154 TNBC cases and 159 breast cancer-free matched controls using MethyLight droplet digital PCR. To assess the association between methylation level and TNBC risk, logistic regression was used to calculate odd ratios and 95% confidence intervals, adjusted for smoking status. We found no evidence for association between methylation levels and TNBC overall (P = 0.062). Subgroup analysis according to age at diagnosis and age at blood draw revealed increased methylation levels in TNBC cases compared with controls in the young age groups [age 26-52 (P = 0.0025) and age 22-46 (P = 0.001), respectively]. Our results suggest a potential association of LINC00299 hypermethylation with TNBC in young women.

Epigenome-wide association study for lifetime estrogen exposure identifies an epigenetic signature associated with breast cancer risk.

BACKGROUND: It is well established that estrogens and other hormonal factors influence breast cancer susceptibility. We hypothesized that a woman's total lifetime estrogen exposure accumulates changes in DNA methylation, detectable in the blood, which could be used in risk assessment for breast cancer. METHODS: An estimated lifetime estrogen exposure (ELEE) model was defined using epidemiological data from EPIC-Italy (n = 31,864). An epigenome-wide association study (EWAS) of ELEE was performed using existing Illumina HumanMethylation450K Beadchip (HM450K) methylation data obtained from EPIC-Italy blood DNA samples (n = 216). A methylation index (MI) of ELEE based on 31 CpG sites was developed using HM450K data from EPIC-Italy and the Generations Study and evaluated for association with breast cancer risk in an independent dataset from the Generations Study (n = 440 incident breast cancer cases matched to 440 healthy controls) using targeted bisulfite sequencing. Lastly, a meta-analysis was conducted including three additional cohorts, consisting of 1187 case-control pairs. RESULTS: We observed an estimated 5% increase in breast cancer risk per 1-year longer ELEE (OR = 1.05, 95% CI 1.04-1.07, P = 3 × 10-12) in EPIC-Italy. The EWAS identified 694 CpG sites associated with ELEE (FDR Q < 0.05). We report a DNA methylation index (MI) associated with breast cancer risk that is validated in the Generations Study targeted bisulfite sequencing data (ORQ4_vs_Q1 = 1.77, 95% CI 1.07-2.93, P = 0.027) and in the meta-analysis (ORQ4_vs_Q1 = 1.43, 95% CI 1.05-2.00, P = 0.024); however, the correlation between the MI and ELEE was not validated across study cohorts. CONCLUSION: We have identified a blood DNA methylation signature associated with breast cancer risk in this study. Further investigation is required to confirm the interaction between estrogen exposure and DNA methylation in the blood.

Attitudes toward alcohol use during pregnancy among women recruited from alcohol-serving venues in Cape Town, South Africa: A mixed-methods study.

BACKGROUND: The Western Cape Province of South Africa has one of the highest rates of fetal alcohol spectrum disorder (FASD) globally. Effective prevention of FASD requires understanding women's attitudes about alcohol use during pregnancy and whether these attitudes translate into behavior. OBJECTIVE: The goal of this mixed-methods study was to describe attitudes toward alcohol use during pregnancy and examine how these attitudes influence drinking behaviors during pregnancy. METHOD: Over a five month period, 200 women were recruited from alcohol-serving venues in a township in Cape Town; a sub-set of 23 also completed in-depth interviews. Potential gaps between attitudes and behavior were described, and logistic regression models examined predictors of harmful attitudes toward alcohol use during pregnancy. Interviews were reviewed and coded for emergent themes. RESULTS: Most women (n = 176) reported at least one pregnancy. Among these, the majority (83%) had positive preventive attitudes, but more than half of these still reported alcohol use during a previous pregnancy. The strongest predictors of harmful attitudes were a history of physical or sexual abuse and drinking during a previous pregnancy. Qualitative analysis revealed several themes that contributed to alcohol use during pregnancy: 1) having an unplanned pregnancy; 2) drinking because of stress or to cope with abuse/trauma; 3) reliance on the venue for support; 4) socialization; and 5) feelings of invincibility. CONCLUSIONS: The findings highlight an attitude-behavior gap and suggest that positive preventive attitudes are insufficient to elicit FASD preventive behavior. Interventions are needed that go beyond education to build intrinsic motivation and structural support to refrain from alcohol use during pregnancy.

Capture Hi-C identifies putative target genes at 33 breast cancer risk loci.

Genome-wide association studies (GWAS) have identified approximately 100 breast cancer risk loci. Translating these findings into a greater understanding of the mechanisms that influence disease risk requires identification of the genes or non-coding RNAs that mediate these associations. Here, we use Capture Hi-C (CHi-C) to annotate 63 loci; we identify 110 putative target genes at 33 loci. To assess the support for these target genes in other data sources we test for associations between levels of expression and SNP genotype (eQTLs), disease-specific survival (DSS), and compare them with somatically mutated cancer genes. 22 putative target genes are eQTLs, 32 are associated with DSS and 14 are somatically mutated in breast, or other, cancers. Identifying the target genes at GWAS risk loci will lead to a greater understanding of the mechanisms that influence breast cancer risk and prognosis.