Multi-Ancestry Transcriptome-wide Association Studies Uncover New Insights into Breast Cancer Genetics and Biology.

Genome-wide association studies (GWAS) have identified over 200 genetic risk loci for breast cancer, yet the target genes in these loci remain largely unknown. To address this knowledge gap, we conducted a series of multi-ancestry transcriptome-wide association studies (TWAS) to discover potential breast cancer susceptibility genes. We developed and validated ancestry-specific genetic models to predict levels of gene expression, alternative splicing, and 3' UTR alternative polyadenylation, using genomic and transcriptomic data from normal breast tissue samples of 652 females of African, Asian, or European ancestry.

Sedentary time and breast cancer risk in the Sister Study Cohort.

Background: Previous research investigating sedentary behavior and breast cancer (BC) risk has shown mixed results. We investigated the association between sedentary time and BC incidence overall and by time-dependent menopausal status.

Methods: The Sister Study recruited 50,884 women from all 50 states and Puerto Rico aged 35-74 years who had not been diagnosed with BC but had at least one affected sister.

Integrating multi-ancestry genomic and proteomic data to identify blood risk biomarkers and target proteins for breast cancer genetic risk loci.

Genome-wide association studies (GWAS) have identified more than 200 risk loci for breast cancer. However, target genes and their encoded proteins in these loci remain largely unknown. In this study, we utilized genetic prediction models for 1349 circulating proteins derived from individuals of African (n = 1871) and European (n = 7213) ancestry to investigate genetically predicted protein levels in association with breast cancer risk among females of African (n = 40,138), Asian (n = 137,677), and European (n = 247,173) ancestry.

The African-Specific Variant in the Duffy Antigen Receptor for Chemokines Gene, CD8+ T-Cell Density, and Aggressive Breast Cancer Subtypes in Black Women.

Background: Immune response in blood varies by ancestry, linked to an African-specific variant (rs2814778) in the Duffy Antigen Receptor for Chemokines (DARC/ACKR1) gene. We examined associations between rs2814778, CD8+ T-cell density in breast tumors, and breast cancer risk in African-American/Black women.

Methods: CD8+ T-cell density in tumors from 428 Black women were examined in relation to the rs2814778 variant.

Hormone therapy use and young-onset breast cancer: a pooled analysis of prospective cohorts included in the Premenopausal Breast Cancer Collaborative Group.

Background: Oestrogen plus progestin hormone therapy is an established risk factor for breast cancer in postmenopausal women. We examined the less well-studied association between exogenous hormones and breast cancer in young women, who might use hormone therapy after gynaecological surgery or to relieve perimenopausal symptoms.

Methods: In this pooled cohort analysis, we investigated the relationship between exogenous hormones and breast cancer in young women using data from 10-13 prospective cohorts from North America, Europe, Asia, and Australia.

Pubertal Timing and Incident Ovarian Cancer in the Sister Study Cohort.

Background: Pubertal milestones such as menarche (first period) and thelarche (onset of breast development) are markers of hormonal changes that may be relevant to the hormonal etiology of ovarian cancer. Prior studies of the association between age at menarche and ovarian cancer risk have been inconsistent, whereas age at thelarche has not been examined in relation to ovarian cancer incidence.

Methods: With data from 40,809 women in the Sister Study, we used multivariable-adjusted Cox proportional hazards regression to estimate HRs and 95% confidence intervals (CI) for associations of self-reported ages at thelarche and menarche with incident ovarian cancer, both overall and by histotype.

Depression, antidepressant use, and breast cancer incidence in the Sister Study cohort.

Background: Depression could affect breast cancer risk; however, epidemiologic findings are mixed. We assessed the association of breast cancer risk with self-reported history of diagnosed depression and time-dependent antidepressant use.

Methods: We analyzed data from 45,746 women in the Sister Study cohort (2003-2009).

Association Between Body Iron Status and Biological Aging.

Background/objectives: Iron is necessary for bodily function, but abnormal levels can increase the risk of chronic diseases. Studies of leukocyte telomere length suggest blood iron levels are positively associated with cellular senescence and accelerated aging. However, associations between blood iron and more robust metrics of biological aging, specifically those based on DNA methylation, have not been examined.

Development and validation of a risk prediction model for premenopausal breast cancer in 19 cohorts.

Background: Incidence of premenopausal breast cancer (BC) has risen in recent years, though most existing BC prediction models are not generalizable to young women due to underrepresentation of this age group in model development.

Methods: Using questionnaire-based data from 19 prospective studies harmonized within the Premenopausal Breast Cancer Collaborative Group (PBCCG), representing 783,830 women, we developed a premenopausal BC risk prediction model. The data were split into training (2/3) and validation (1/3) datasets with equal distribution of cohorts in each.

Central and peripheral adiposity and premenopausal breast cancer risk: a pooled analysis of 440,179 women.

Background: Among premenopausal women, higher body mass index (BMI) is associated with lower breast cancer risk, although the underlying mechanisms are unclear. Investigating adiposity distribution may help clarify impacts on breast cancer risk. This study was initiated to investigate associations of central and peripheral adiposity with premenopausal breast cancer risk overall and by other risk factors and breast cancer characteristics.

In-utero and newborn factors and thyroid cancer incidence in adult women in the Sister Study cohort.

Background: Thyroid cancer is diagnosed at relatively young ages compared to other adult cancers, for reasons that remain unclear. Our study aimed to investigate associations of in-utero and newborn characteristics with differentiated thyroid cancer (DTC) incidence in adult women.

Methods: From the U.

Partial Effects in Environmental Mixtures: Evidence and Guidance on Methods and Implications.

Background: The effects of a mixture of exposures on health outcomes are of interest to public health but pose methodological hurdles. These exposures may impact the outcome in opposing ways, which we call the positive and negative partial effects of a mixture. There has been growing interest in estimating these partial effects and their ability to inform public health interventions.

DNA methylation-predicted plasma protein levels and breast cancer risk.

Background: Blood DNA methylation (DNAm) profiles have been used to show that changes in circulating leukocyte composition occur during breast cancer development, suggesting that peripheral immune system alterations are markers of breast cancer risk. Blood DNAm profiles have recently been used to predict plasma protein concentrations ("Protein EpiScores"), but their associations with breast cancer risk have not been examined in detail.

Methods: Whole blood DNAm profiles were obtained for a case-cohort sample of participants in the Sister Study and used to calculate 109 Protein EpiScores.

Periods of susceptibility for associations between phthalate exposure and preterm birth: Results from a pooled analysis of 16 US cohorts.

Background: Phthalate exposure during pregnancy has been associated with preterm birth, but mechanisms of action may depend on the timing of exposure.

Objective: Investigate critical periods of susceptibility during pregnancy for associations between urinary phthalate metabolite concentrations and preterm birth.

Methods: Individual-level data were pooled from 16 US cohorts (N = 6045, n = 539 preterm births).

Overlap of high-risk individuals across family history, genetic & non-genetic breast cancer risk models: Analysis of 180,398 women from European & Asian ancestries.

Background: Breast cancer is multifactorial. Focusing on limited risk factors may miss high-risk individuals.

Methods: We assessed the performance and overlap of various risk factors in identifying high-risk individuals for invasive breast cancer (BrCa) and ductal carcinoma in situ (DCIS) in 161,849 European-ancestry and 18,549 Asian-ancestry women.

Hair Straightener Use in Relation to Prevalent and Incident Fibroids in the Sister Study with a Focus on Black Women.

Background: Uterine fibroids disproportionately affect Black women, and exposure to chemicals from hair relaxers or straighteners ("straighteners") may contribute to fibroid development.

Objectives: We examined the association between straightener use and prevalent young-onset uterine fibroids (diagnosed before age 36 y), as well as incident fibroids (diagnosed age 36-60 y), with a focus on Black women. We also examined differences in associations across birth cohorts as proxies for formulation changes.

Refining breast cancer genetic risk and biology through multi-ancestry fine-mapping analyses of 192 risk regions.

Genome-wide association studies have identified approximately 200 genetic risk loci for breast cancer, but the causal variants and target genes are mostly unknown. We sought to fine-map all known breast cancer risk loci using genome-wide association study data from 172,737 female breast cancer cases and 242,009 controls of African, Asian and European ancestry. We identified 332 independent association signals for breast cancer risk, including 131 signals not reported previously, and for 50 of them, we narrowed the credible causal variants down to a single variant.

Association of Early-life Trauma With Gestational Diabetes and Hypertensive Disorders of Pregnancy.

Background: Early-life trauma (before age of 18 years) is hypothesized to increase the risk for adverse pregnancy outcomes through stress pathways, yet epidemiologic findings are mixed.

Methods: Sister Study participants (US women aged 35-74 years enrolled 2003-2009) completed an adapted Brief Betrayal Trauma Survey at the first follow-up visit. Lifetime history of gestational diabetes mellitus (GDM) or hypertensive disorders of pregnancy (HDP: pregnancy-related high blood pressure, pre-eclampsia/toxemia, or eclampsia) in pregnancies lasting ≥20 weeks was self-reported.

Association between two common SNPs, rs6564851 and rs6420424, and lutein and zeaxanthin levels in a cohort of US postmenopausal women with a family history of breast cancer.

A better understanding of the factors contributing to systemic concentrations of carotenoids is necessary given the weak correlations between circulating levels and dietary intake of carotenoids. Although genetic variation may play a key role in the interindividual variability in carotenoid concentrations, few genome-wide association studies (GWAS) have focused on carotenoids. We used a random sample ( = 519) of postmenopausal participants in the Sister Study with data on genotypes and plasma carotenoid levels to conduct GWAS for each of five carotenoids (mcg/mL): alpha-carotene, beta- carotene, cryptoxanthin, lycopene, and lutein/zeaxanthin.

Pathogenic Variants in Cancer Susceptibility Genes Predispose to Ductal Carcinoma In Situ of the Breast.

Purpose: To determine the relationship between germline pathogenic variants (PV) in cancer predisposition genes and the risk of ductal carcinoma in situ (DCIS).

Experimental Design: Germline PV frequencies in breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, PALB2, RAD51C, and RAD51D) were compared between DCIS cases and unaffected controls and between DCIS and invasive ductal breast cancer (IDC) cases from a clinical testing cohort (n = 9,887), a population-based cohort (n = 3,876), and the UK Biobank (n = 2,421). The risk of contralateral breast cancer (CBC) for DCIS cases with PV was estimated in the population-based cohort.

Considerations and targeted approaches to identifying bad actors in exposure mixtures.

Variable importance is a key statistical issue in exposure mixtures, as it allows a ranking of exposures as potential targets for intervention, and helps to identify bad actors within a mixture. In settings where mixtures have many constituents or high between-constituent correlations, estimators of importance can be subject to bias or high variance. Current approaches to assessing variable importance have major limitations, including reliance on overly strong or incorrect constraints or assumptions, excessive model extrapolation, or poor interpretability, especially regarding practical significance.