Thomas U. Ahearn's research while affiliated with United States Institute of Peace and other places

Publications (130)

Article
Full-text available
Background Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Methods Among 106,571 invasive breast c...
Article
Full-text available
Objectives Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using ge...
Article
Background Reproductive factors have been shown to be differentially associated with risk of estrogen receptor (ER) positive and ER-negative breast cancer. However, their associations with intrinsic-like subtypes are less clear. Methods Analyses included up to 23,353 cases, and 71,072 controls pooled from 31 population-based case-control or cohort...
Article
Background: Studies have reported differences in associations between breast cancer risk factors and subtypes defined by hormone receptor status, particularly estrogen receptor (ER) positive versus ER negative tumors. Most studies have been conducted in women of European descent, and an expanding body of literature in other populations suggests dif...
Preprint
Reproducibility and replicability of research findings are central to the scientific integrity of epidemiology. In addition, many research questions require combiningdata from multiple sources to achieve adequate statistical power. However, barriers related to confidentiality, costs, and incentives often limit the extent and speed of sharing resour...
Article
The oral microbiome, like the fecal microbiome, may be related to breast cancer risk. Therefore, we investigated whether the oral microbiome was associated with breast cancer and non‐malignant breast disease, and its relationship with the fecal microbiome in a case‐control study in Ghana. A total of 881 women were included (369 breast cancers, 93 n...
Article
Background: Risk estimates for women carrying germline mutations in breast cancer susceptibility genes are mainly based on studies of European ancestry women. Methods: We investigated associations between pathogenic variants (PV) in 34 genes with breast cancer risk in 871 cases (307 estrogen receptor (ER)-positive, 321 ER-negative, and 243 ER-un...
Article
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Background Protein truncating variants in ATM , BRCA1 , BRCA2 , CHEK2 , and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. Methods We analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consorti...
Article
Polygenic risk scores (PRSs) are useful for predicting breast cancer risk, but the prediction accuracy of existing PRSs in women of African ancestry (AA) remains relatively low. We aim to develop optimal PRSs for prediction of overall and estrogen receptor (ER) subtype-specific breast cancer risk in AA women. The AA dataset comprised 9235 cases and...
Article
Full-text available
Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 obse...
Preprint
Polygenic risk scores are becoming increasingly predictive of complex traits, but subpar performance in non-European populations raises concerns about their potential clinical applications. We develop a powerful and scalable method to calculate PRS using GWAS summary-statistics from multi-ancestry training samples by integrating multiple techniques...
Article
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Genome-wide association studies (GWAS) have identified more than 200 susceptibility loci for breast cancer, but these variants explain less than a fifth of the disease risk. Although gene–environment interactions have been proposed to account for some of the remaining heritability, few studies have empirically assessed this. We obtained genotype an...
Preprint
Age-standardized incidence rates of estrogen receptor negative (ERN) breast cancers in the US are higher among Non-Hispanic Black (NHB) compared to Non-Hispanic White (NHW) women. We aimed to determine if incidence rates were similar between NHB and Ghanaians, given that a high proportion of NHB share West African genetic ancestry. We compared US r...
Article
Importance: Rare germline genetic variants in several genes are associated with increased breast cancer (BC) risk, but their precise contributions to different disease subtypes are unclear. This information is relevant to guidelines for gene panel testing and risk prediction. Objective: To characterize tumors associated with BC susceptibility ge...
Article
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Background: Several anthropometric measures have been associated with hormone-related cancers, and it has been shown that estrogen metabolism in postmenopausal women plays an important role in these relationships. However, little is known about circulating estrogen levels in African women, and the relevance to breast cancer or breast cancer risk f...
Article
Full-text available
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 test...
Article
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Hair relaxers and skin lighteners have been commonly used by African women, with suggestions that they may have hormonal activity. To investigate the relationship of hair relaxer and skin lightener use to serum estrogen/estrogen metabolite levels. We utilized the postmenopausal population-based controls of the Ghana Breast Health Study to estimate...
Article
Full-text available
Background Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Methods Among 106,571 invasive breast ca...
Preprint
Full-text available
Polygenic risk scores (PRSs) are useful to predict breast cancer risk, but the prediction accuracy of existing PRSs in women of African ancestry (AA) remain relatively low. We aim to develop optimal PRSs for prediction of overall and estrogen receptor (ER) subtype-specific breast cancer risk in women of African ancestry. The AA dataset comprised 9,...
Article
Full-text available
Background Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk. Methods We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both ind...
Article
Full-text available
Single germline nucleotide pathogenic variants have been identified in 12 breast cancer predisposition genes, but structural deletions in these genes remain poorly characterized. We conducted in-depth whole genome sequencing (WGS) in genomic DNA samples obtained from 1340 invasive breast cancer cases and 675 controls of African ancestry. We identif...
Preprint
Full-text available
BACKGROUND Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2 and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. METHODS Combining 59,639 breast cancer cases and 53,165 controls, we sampled training (80%) and validation (20%) sets to analyze rare missense varian...
Article
Full-text available
Abstract Circulating tumor DNA (ctDNA) sequencing studies could provide novel insights into the molecular pathology of cancer in sub-Saharan Africa. In 15 patient plasma samples collected at the time of diagnosis as part of the Ghana Breast Health Study and unselected for tumor grade and subtype, ctDNA was detected in a majority of patients based o...
Article
Full-text available
Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of Europe...
Article
Full-text available
Background: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. Methods: We performed genome-wide association analyses within 15 subgroups of breast cancer patients based...
Article
Full-text available
BACKGROUND: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. METHODS: We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on...
Article
Full-text available
Background: Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk. Methods: We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Bot...
Article
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Our study describes breast cancer risk loci using a cross-ancestry GWAS approach. We first identify variants that are associated with breast cancer at P < 0.05 from African ancestry GWAS meta-analysis (9241 cases and 10193 controls), then meta-analyze with European ancestry GWAS data (122977 cases and 105974 controls) from the Breast Cancer Associa...
Article
Full-text available
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 i...
Conference Paper
Purpose: Analysis of cell free DNA could provide a rapid and non-invasive approach to detect cancer and provide new molecular insights in many African countries where expert pathology is lacking. Hence, we tested whether whole-genome sequencing of cfDNA (WGS-cfDNA) could identify somatic alterations that drive breast cancer. Methods: We conducted a...
Preprint
Full-text available
Background 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. Results Gene b...
Article
Full-text available
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 i...
Preprint
Full-text available
Background 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. Results Gene...
Preprint
Full-text available
Background: Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. Methods: We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785...
Preprint
Full-text available
Background: Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. Methods: We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785...
Article
Background: Tumor-associated stroma is comprised of fibroblasts, tumor infiltrating lymphocytes (TILs), macrophages, endothelial, and other cells, that interactively influence tumor progression through inflammation and wound repair. Although gene expression signatures reflecting wound repair predict breast cancer survival, it is unclear whether co...
Article
Background Polygenic risk scores (PRS) have been demonstrated to identify women of European, Asian and Latino ancestry at elevated risk of developing breast cancer (BC). We evaluated the performance of existing PRSs trained in European ancestry populations among women of African ancestry. Methods We assembled genotype data for women of African anc...
Article
Full-text available
Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have...
Article
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Background Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. Methods We carried out a genome-wide association study of urinary oestrone-3-glucur...
Article
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Background: It is not known if modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype. Methods: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer-specific) over 10 years. Cox regression was...
Article
Background Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking. Methods We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 6...
Article
The gut microbiota may play a role in breast cancer etiology by regulating hormonal, metabolic, and immunologic pathways. We investigated associations of fecal bacteria with breast cancer and non‐malignant breast disease in a case‐control study conducted in Ghana, a country with rising breast cancer incidence and mortality. To do this, we sequence...
Preprint
Full-text available
Reproductive longevity is critical for fertility and impacts healthy ageing in women, yet insights into the underlying biological mechanisms and treatments to preserve it are limited. Here, we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in ~200,000 women of European ancestry...
Article
Full-text available
Loss of the tumor suppressor gene Pten in murine prostate recapitulates human carcinogenesis and causes stromal proliferation surrounding murine prostate intraepithelial neoplasia (mPIN), which is reactive to microinvasion. In turn, invasion has been shown to be regulated in part by de novo fatty acid synthesis in prostate cancer. We therefore inve...
Conference Paper
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Cancer incidence is rising and mortality rates are high in Africa, where access to molecular pathology is limited. Analysis of cancer-related mutations in circulating tumor DNA (ctDNA) from cell-free DNA (cfDNA) that is shed into the bloodstream by tumor cells could be transformative to the African continent and provide new molecular insights. Usin...
Preprint
Full-text available
Circulating tumor DNA (ctDNA) sequencing studies could provide novel insights into the molecular pathology of cancer in sub-Saharan Africa. ctDNA was readily detected in 15 blood samples collected in Ghana at the time of suspected breast cancer. Genomic alterations previously associated with unfavorable prognostic outcomes were observed in the majo...
Conference Paper
Background: Over 180 genetic variants have been identified as risk loci for breast cancer. However, most loci were discovered using European ancestry populations. As some common susceptibility loci are shared across populations, we aim to discover new risk loci for breast cancer using a cross-ancestry genome-wide association study (GWAS) approach....
Conference Paper
p> Background and objective: Breast cancer burden is rising in Africa; however, breast cancer risk factors remain largely understudied in this population. The gut microbiome may play a role in the etiology of breast cancer through the regulation of estrogen homeostasis and other metabolic or immunologic pathways. We investigated the association of...
Conference Paper
Background: A polygenic risk score (PRS) for breast cancer including 313 common variants developed by the Breast Cancer Association Consortium (BCAC) has been demonstrated to identify women who are at high risk of developing breast cancer [odds ratio (OR 95%CI) = 1.61 (1.57-1.65) per SD] in women of European ancestry. In the present study, we exami...
Preprint
Full-text available
Structural deletions in breast cancer susceptibility genes could confer to cancer risk, but remain poorly characterized. Here, we conducted in-depth whole genome sequencing (WGS) in germline DNA samples from 1,340 invasive breast cancer cases and 675 controls of African ancestry to discover such deletions. We identified 33 deletions, including five...
Article
Full-text available
In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study...
Article
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Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1–3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel m...
Article
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We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72,284 cases and 80,354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression, and a newly developed case-only method, fo...
Article
Cancers are routinely classified into subtypes according to various features, including histopathological characteristics and molecular markers. Previous genome-wide association studies have reported heterogeneous associations between loci and cancer subtypes. However, it is not evident what is the optimal modeling strategy for handling correlated...
Article
Higher proportions of early‐onset and estrogen receptor (ER) negative cancers are observed in women of African ancestry than in women of European ancestry. Differences in risk factor distributions and associations by age at diagnosis and ER status may explain this disparity. We analyzed data from1,126 cases (aged 18–74 years) with invasive breast c...
Article
Background: genome-wide association studies have identified over 170 common breast cancer susceptibility loci, many of them with differential associations by estrogen receptor (ER). How these variants are related to other tumor features is unclear. Methods: analyses included 106,571 invasive breast cancer cases and 95,762 controls of European anc...
Article
Full-text available
Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and tr...
Preprint
Full-text available
Background Higher proportions of early onset and estrogen receptor (ER) negative cancers are observed in women of African ancestry than in women of European ancestry. Differences in risk factor distributions and associations by age at diagnosis and ER status may explain this disparity. Methods We analyzed data from 1,126 women (aged 18 to 74 years)...
Article
Purpose: Statins are associated with lower risk of aggressive prostate cancer, but lethal prostate cancer is understudied and contributing mechanisms unclear. We prospectively examined statins and lethal prostate cancer risk in the Health Professionals Follow-up Study (HPFS), tested associations with molecular subtypes, and integrated gene express...
Preprint
PURPOSE Risk-stratified breast cancer prevention requires accurate identification of women at sufficiently different levels of risk. We conducted a comprehensive evaluation of a model integrating classical risk factors and a recently developed 313-variant polygenic risk score (PRS) to predict breast cancer risk. METHODS Fifteen prospective cohorts...
Article
Full-text available
Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and tr...
Article
Background Previous gene-environment interaction studies of breast cancer risk have provided sparse evidence of interactions. Using the largest available dataset to date, we performed a comprehensive assessment of potential effect modification of 205 common susceptibility variants by 13 established breast cancer risk factors, including replication...