Overall Risk Of Breast Cancer Research Articles

Cis- and trans-eQTL TWASs of breast and ovarian cancer identify more than 100 susceptibility genes in the BCAC and OCAC consortia

Transcriptome-wide association studies (TWASs) have investigated the role of genetically regulated transcriptional activity in the etiologies of breast and ovarian cancer. However, methods performed to date have focused on the regulatory effects of risk-associated SNPs thought to act in cis on a nearby target gene. With growing evidence for distal (trans) regulatory effects of variants on gene expression, we performed TWASs of breast and ovarian cancer using a Bayesian genome-wide TWAS method (BGW-TWAS) that considers effects of both cis- and trans-expression quantitative trait loci (eQTLs). We applied BGW-TWAS to whole-genome and RNA sequencing data in breast and ovarian tissues from the Genotype-Tissue Expression project to train expression imputation models. We applied these models to large-scale GWAS summary statistic data from the Breast Cancer and Ovarian Cancer Association Consortia to identify genes associated with risk of overall breast cancer, non-mucinous epithelial ovarian cancer, and 10 cancer subtypes. We identified 101 genes significantly associated with risk with breast cancer phenotypes and 8 with ovarian phenotypes. These loci include established risk genes and several novel candidate risk loci, such as ACAP3, whose associations are predominantly driven by trans-eQTLs. We replicated several associations using summary statistics from an independent GWAS of these cancer phenotypes. We further used genotype and expression data in normal and tumor breast tissue from the Cancer Genome Atlas to examine the performance of our trained expression imputation models. This work represents an in-depth look into the role of trans eQTLs in the complex molecular mechanisms underlying these diseases.

Multiple xenoestrogen air pollutants and breast cancer risk: Statistical approaches to investigate combined exposures effect

Studies suggested that exposure to air pollutants, with endocrine disrupting (ED) properties, have a key role in breast cancer (BC) development. Although the population is exposed simultaneously to a mixture of multiple pollutants and ED pollutants may act via common biological mechanisms leading to synergic effects, epidemiological studies generally evaluate the effect of each pollutant separately. We aimed to assess the complex effect of exposure to a mixture of four xenoestrogen air pollutants (benzo-[a]-pyrene (BaP), cadmium, dioxin (2,3,7,8-Tétrachlorodibenzo-p-dioxin TCDD)), and polychlorinated biphenyl 153 (PCB153)) on the risk of BC, using three recent statistical methods, namely weighted quantile sum (WQS), quantile g-computation (QGC) and Bayesian kernel machine regression (BKMR). The study was conducted on 5222 cases and 5222 matched controls nested within the French prospective E3N cohort initiated in 1990. Annual average exposure estimates to the pollutants were assessed using a chemistry transport model, at the participants’ residence address between 1990 and 2011. We found a positive association between the WQS index of the joint effect and the risk of overall BC (adjusted odds ratio (OR) = 1.10, 95% confidence intervals (CI): 1.03–1.19). Similar results were found for QGC (OR = 1.11, 95%CI: 1.03–1.19). Despite the association did not reach statistical significance in the BKMR model, we observed an increasing trend between the joint effect of the four pollutants and the risk of BC, when fixing other chemicals at their median concentrations. BaP, cadmium and PCB153 also showed positive trends in the multi-pollutant mixture, while dioxin showed a modest inverse trend. Despite we found a clear evidence of a positive association between the joint exposure to pollutants and BC risk only from WQS and QGC regression, we observed a similar suggestive trend using BKMR. This study makes a major contribution to the understanding of the joint effects of air pollution.

Benign Breast Disease and Breast Cancer Risk in the Percutaneous Biopsy Era

Benign breast disease (BBD) comprises approximately 75% of breast biopsy diagnoses. Surgical biopsy specimens diagnosed as nonproliferative (NP), proliferative disease without atypia (PDWA), or atypical hyperplasia (AH) are associated with increasing breast cancer (BC) risk; however, knowledge is limited on risk associated with percutaneously diagnosed BBD. To estimate BC risk associated with BBD in the percutaneous biopsy era irrespective of surgical biopsy. In this retrospective cohort study, BBD biopsy specimens collected from January 1, 2002, to December 31, 2013, from patients with BBD at Mayo Clinic in Rochester, Minnesota, were reviewed by 2 pathologists masked to outcomes. Women were followed up from 6 months after biopsy until censoring, BC diagnosis, or December 31, 2021. Benign breast disease classification and multiplicity by pathology panel review. The main outcome was diagnosis of BC overall and stratified as ductal carcinoma in situ (DCIS) or invasive BC. Risk for presence vs absence of BBD lesions was assessed by Cox proportional hazards regression. Risk in patients with BBD compared with female breast cancer incidence rates from the Iowa Surveillance, Epidemiology, and End Results (SEER) program were estimated. Among 4819 female participants, median age was 51 years (IQR, 43-62 years). Median follow-up was 10.9 years (IQR, 7.7-14.2 years) for control individuals without BC vs 6.6 years (IQR, 3.7-10.1 years) for patients with BC. Risk was higher in the cohort with BBD than in SEER data: BC overall (standard incidence ratio [SIR], 1.95; 95% CI, 1.76-2.17), invasive BC (SIR, 1.56; 95% CI, 1.37-1.78), and DCIS (SIR, 3.10; 95% CI, 2.54-3.77). The SIRs increased with increasing BBD severity (1.42 [95% CI, 1.19-1.71] for NP, 2.19 [95% CI, 1.88-2.54] for PDWA, and 3.91 [95% CI, 2.97-5.14] for AH), comparable to surgical cohorts with BBD. Risk also increased with increasing lesion multiplicity (SIR: 2.40 [95% CI, 2.06-2.79] for ≥3 foci of NP, 3.72 [95% CI, 2.31-5.99] for ≥3 foci of PDWA, and 5.29 [95% CI, 3.37-8.29] for ≥3 foci of AH). Ten-year BC cumulative incidence was 4.3% for NP, 6.6% for PDWA, and 14.6% for AH vs an expected population cumulative incidence of 2.9%. In this contemporary cohort study of women diagnosed with BBD in the percutaneous biopsy era, overall risk of BC was increased vs the general population (DCIS and invasive cancer combined), similar to that in historical BBD cohorts. Development and validation of pathologic classifications including both BBD severity and multiplicity may enable improved BC risk stratification.

Causal effects of genetically predicted endometriosis on breast cancer: a two-sample Mendelian randomization study

This study used a Mendelian randomization (MR) approach to investigate the causal relationship between genetically predicted endometriosis (EMS) and breast cancer risk. A total of 122,977 cases and 105,974 controls were included in the analysis, with gene-level summary data obtained from the Breast Cancer Association Consortium (BCAC). An inverse variance-weighting approach was applied to assess the causal relationship between EMS and breast cancer risk, and weighted median and MR-Egger regression methods were used to evaluate pleiotropy. Results showed a causal relationship between EMS and a decreased risk of overall breast cancer (odds ratio [OR] 0.95; 95% CI 0.90–0.99, p = 0.02). Furthermore, EMS was associated with a lower risk for estrogen receptor (ER)-positive breast cancer in a subgroup analysis based on immunohistochemistry type (OR 0.91; 95% CI 0.86–0.97, p = 0.005). However, there was no causal association between ER-negative breast cancer and survival (OR 1.00; 95% CI 0.94–1.06, p = 0.89). Pleiotropy was not observed. These findings provide evidence of a relationship between EMS and reduced breast cancer risk in invasive breast cancer overall and specific tissue types, and support the results of a previous observational study. Further research is needed to elucidate the mechanisms underlying this association.

Effect of genetic liability to migraine and its subtypes on breast cancer: a mendelian randomization study

BackgroundThe relationship between migraine and breast cancer risk has generated conflicting findings. We attempted to assess the association between migraine and breast cancer risk using Mendelian randomization (MR) analysis.MethodsWe selected genetic instruments associated with migraine from a recently published genome-wide association studies (GWAS). Inverse variant weighted (IVW) analysis was adopted as the main method, and we also performed the weighted-median method and the MR‒Egger, MR pleiotropy residual sum and outlier (MR-PRESSO), and MR Robust Adjusted Profile Score (MR-RAPS) methods as supplements.ResultsOur MR suggested that any migraine (AM) was a risk factor for overall breast cancer (IVW: odds ratio (OR) = 1.072, 95% confidence intervals (CI) = 1.035–1.110, P = 8.78 × 10− 5, false discovery rate (FDR) = 7.36 × 10− 4) and estrogen receptor-positive (ER+) breast cancer (IVW: OR = 1.066, 95% CI = 1.023–1.111, P = 0.0024; FDR = 0.0108) but not estrogen receptor-negative (ER-) breast cancer. In its subtype analysis, women with a history of migraine without aura (MO) had an increased risk of ER- breast cancer (IVW: OR = 1.089, 95% CI = 1.019–1.163, P = 0.0118, FDR = 0.0354), and MO was suggestively associated with the risk of overall breast cancer (FDR > 0.05 and IVW P < 0.05). No significant heterogeneity or horizontal pleiotropy was found in the sensitivity analysis.ConclusionThis study suggested that women with AM have an increased risk of overall breast cancer and ER + breast cancer. MO was suggestively associated with the risk of overall breast cancer and ER- breast cancer.

Epidemiological and Genetic Analyses of Schizophrenia and Breast Cancer.

While the phenotypic association between schizophrenia and breast cancer has been observed, the underlying intrinsic link is not adequately understood. We aim to conduct a comprehensive interrogation on both phenotypic and genetic relationships between schizophrenia and breast cancer. We first used data from UK Biobank to evaluate a phenotypic association and performed an updated meta-analysis incorporating existing cohort studies. We then leveraged genomic data to explore the shared genetic architecture through a genome-wide cross-trait design. Incorporating results of our observational analysis, meta-analysis of cohort studies suggested a significantly increased incidence of breast cancer among women with schizophrenia (RR = 1.30, 95% CIs = 1.14-1.48). A positive genomic correlation between schizophrenia and overall breast cancer was observed (rg = 0.12, P = 1.80 × 10-10), consistent across ER+ (rg = 0.10, P = 5.74 × 10-7) and ER- subtypes (rg = 0.09, P = .003). This was further corroborated by four local signals. Cross-trait meta-analysis identified 23 pleiotropic loci between schizophrenia and breast cancer, including five novel loci. Gene-based analysis revealed 27 shared genes. Mendelian randomization demonstrated a significantly increased risk of overall breast cancer (OR = 1.07, P = 4.81 × 10-10) for genetically predisposed schizophrenia, which remained robust in subgroup analysis (ER+: OR = 1.10, P = 7.26 × 10-12; ER-: OR = 1.08, P = 3.50 × 10-6). No mediation effect and reverse causality was found. Our study demonstrates an intrinsic link underlying schizophrenia and breast cancer, which may inform tailored screening and management of breast cancer in schizophrenia.

Using human genetics to understand the phenotypic association between chronotype and breast cancer.

Little is known regarding the shared genetic influences underlying the observed phenotypic association between chronotype and breast cancer in women. Leveraging summary statistics from the hitherto largest genome-wide association study conducted in each trait, we investigated the genetic correlation, pleiotropic loci, and causal relationship of chronotype with overall breast cancer, and with its subtypes defined by the status of oestrogen receptor. We identified a negative genomic correlation between chronotype and overall breast cancer ( = -0.06, p = 3.00 × 10-4), consistent across oestrogen receptor-positive ( = -0.05, p = 3.30 × 10-3) and oestrogen receptor-negative subtypes ( = -0.05, p = 1.11 × 10-2). Five specific genomic regions were further identified as contributing a significant local genetic correlation. Cross-trait meta-analysis identified 78 loci shared between chronotype and breast cancer, of which 23 were novel. Transcriptome-wide association study revealed 13 shared genes, targeting tissues of the nervous, cardiovascular, digestive, and exocrine/endocrine systems. Mendelian randomisation demonstrated a significantly reduced risk of overall breast cancer (odds ratio 0.89, 95% confidence interval 0.83-0.94; p = 1.30 × 10-4) for genetically predicted morning chronotype. No reverse causality was found. Our work demonstrates an intrinsic link underlying chronotype and breast cancer, which may provide clues to inform management of sleep habits to improve female health.

Investigating the relationship between depression and breast cancer: observational and genetic analyses

BackgroundBoth depression and breast cancer (BC) contribute to a substantial global burden of morbidity and mortality among women, and previous studies have observed a potential depression-BC link. We aimed to comprehensively characterize the phenotypic and genetic relationships between depression and BC.MethodsWe first evaluated phenotypic association using longitudinal follow-up data from the UK Biobank (N = 250,294). We then investigated genetic relationships leveraging summary statistics from the hitherto largest genome-wide association study of European individuals conducted for depression (N = 500,199), BC (N = 247,173), and its subtypes based on the status of estrogen receptor (ER + : N = 175,475; ER − : N = 127,442).ResultsObservational analysis suggested an increased hazard of BC in depression patients (HR = 1.10, 95%CIs = 0.95–1.26). A positive genetic correlation between depression and overall BC was observed ({r}_{g} = 0.08, P = 3.00 × 10–4), consistent across ER + ({r}_{g} = 0.06, P = 6.30 × 10–3) and ER − subtypes ({r}_{g} = 0.08, P = 7.20 × 10–3). Several specific genomic regions showed evidence of local genetic correlation, including one locus at 9q31.2, and four loci at, or close, to 6p22.1. Cross-trait meta-analysis identified 17 pleiotropic loci shared between depression and BC. TWAS analysis revealed five shared genes. Bi-directional Mendelian randomization suggested risk of depression was causally associated with risk of overall BC (OR = 1.12, 95%Cis = 1.04–1.19), but risk of BC was not causally associated with risk of depression.ConclusionsOur work demonstrates a shared genetic basis, pleiotropic loci, and a putative causal relationship between depression and BC, highlighting a biological link underlying the observed phenotypic relationship; these findings may provide important implications for future studies aimed reducing BC risk.

Relationship between food-derived antioxidant vitamin intake and breast cancer risk: a mendelian randomized study.

In previous observational studies, food-derived antioxidant vitamins have been suggested to be associated with breast cancer. However, the findings were inconsistent and the causal relationship could not be clearly elucidated. To confirm the potential causal relationship between food-derived antioxidants (retinol, carotene, vitamin C and vitamin E) and the risk of breast cancer, we conducted a two-sample Mendelian randomization (MR) study. The instrumental variables (IVs) as proxies of genetic liability to food-derived antioxidant vitamins were obtained from the UK Biobank Database. We extracted breast cancer data (122,977 cases and 105,974 controls) from the Breast Cancer Consortium (BCAC). In addition, we studied estrogen expression status categorically, including estrogen receptor positive (ER+) breast cancer (69,501 cases and 105,974 controls) and versus estrogen receptor (ER-) negative breast cancer (21,468 cases and 105,974 controls). We performed two-sample Mendelian randomization study, and inverse variance-weighted (IVW) test was regarded as main analysis. Sensitivity analyses were further conducted to assess heterogeneity and horizontal pleiotropy. The results of IVW showed that among the four food-derived antioxidants, only vitamin E had protective effect on the risk of overall breast cancer (OR = 0.837, 95% CI 0.757-0.926, P = 0.001) and ER+ breast cancer (OR = 0.823, 95% CI 0.693-0.977, P = 0.026). However, we found no association between food-derived vitamin E and ER- breast cancer. Our study suggested food-derived vitamin E can decrease the risk of breast cancer overall and ER+ breast cancer, and the robustness of our results was confirmed by sensitivity analyses.

Abstract 1180: Identification of target proteins for breast cancer genetic risk loci and blood risk biomarkers in a large study by integrating genomic and proteomic data

Abstract Genome-wide association studies (GWAS) have identified around 200 loci associated with breast cancer risk. However, protein targets for these loci remain largely unknown. Identifying protein targets and biomarkers can improve the understanding of cancer biology and etiology and identify high-risk individuals for cancer prevention. In this study, we investigated genetically predicted levels of 1,142 circulating proteins with breast cancer risk in 133,384 cases and 113,789 controls of European ancestry included in the Breast Cancer Association Consortium (BCAC). We identified 22 blood protein biomarkers associated with the risk of overall breast cancer at a false discovery rate (FDR) &amp;lt;0.05, including nine proteins encoded by genes located at least 500kb away from previously reported risk variants for breast cancer. Analyses focusing on 124 encoding genes located at GWAS-identified breast cancer risk loci found 20 proteins associated with overall breast cancer risk and one protein associated with triple-negative breast cancer risk at FDR &amp;lt;0.05. Adjustment for the GWAS-identified risk variants significantly attenuated the association for 13 of these proteins, suggesting that these proteins may be the targets of these GWAS-identified risk loci. The identified proteins are involved in various biological processes, including glutathione conjugation, STAT5 signaling, and NF-kB signaling pathways. Our study identified novel protein targets and risk biomarkers for breast cancer risk. Citation Format: Guochong Jia, Yaohua Yang, Jie Ping, Shuai Xu, Lili Liu, Xingyi Guo, Ran Tao, Jirong Long, Wei Zheng. Identification of target proteins for breast cancer genetic risk loci and blood risk biomarkers in a large study by integrating genomic and proteomic data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1180.

Abstract 4213: Comparison of benign breast disease subtypes and breast cancer risk among Hispanic and non-Hispanic white women in New Mexico

Abstract Introduction: Benign breast disease (BBD) is an important breast cancer (BC) risk factor, which may be classified as non-proliferative disease (NPD), proliferative disease without atypia (PDWA), or atypical hyperplasia (AH) for risk stratification. Data related to the frequency of specific types of BBD and their relationship to BC risk in the Hispanic American population are limited. To address this knowledge gap, we compared BBD and associated BC risk among Hispanic white (HW) and non-Hispanic white (NHW) in New Mexico (NM). Methodology: A retrospective IRB-approved study was performed of women 19 years or older residing in six counties in NM (Bernalillo, Sandoval, Sante Fe, Socorro, Torrance, Cibola/Valencia) between 1996 and mid-2007 to compare the frequency of BBD subtypes and BC risk among HW and NHW. We excluded women who had a history of BC prior to BBD diagnosis or who were diagnosed with BC within 6 months after BBD biopsy. Race and ethnicity were self-reported by women at the time of biopsy. BBD was categorized as NPD, PDWA, or AH based on medical records. Incident BC (in-situ or invasive) was ascertained via linkage to the NM Surveillance Epidemiology End Results (SEER) Registry and BC risk was assessed using standardized incidence ratios (SIRs), comparing the observed number of BC events to that expected based on the NM SEER six-county race- and ethnicity-specific incidence rates, accounting for age and calendar period. Results: Our analysis included 3,870 HW and 6,996 NHW women with BBD. The HW were younger (47.1 vs. 51 years) compared to NHW. HW women had slightly more NPD (69.4% vs. 66.6%) but less PDWA (26.2% vs. 29.4%) and similar frequency of AH (4.3% vs. 3.9%) as compared to NHW. Over a median post-BBD follow-up period of 13 years (range 6 months-17 years), 644 BCs were observed (4.81% in HW and 6.55% in NHW). The observed BC risk among women with BBD was higher than population-based expected rates (SIR 1.98, 95% CI 1.82-2.13, p&amp;lt;0.001) and showed expected increases in risk with increasing degrees of BBD abnormality: SIR=1.90 for NPD, 2.00 for PDWA, and 3.01 for AH. Comparing BC risk by ethnic subgroups, HW women had an overall risk of BC after BBD that was statistically indistinguishable from NHW women (SIR=2.17, 95% CI 1.86-2.48 in HW women, and SIR=1.91, 95% CI 1.73-2.08 in NHW women). Within the major subgroups of the BBD findings, there were no significant differences in risk of BC after BBD for HW versus NHW women. Conclusions: In this population-based study, benign breast disease subtypes and their associated breast cancer risk were similar among the Hispanic and non-Hispanic white women. Citation Format: Kush Raj Lohani, Andrea M. Nibbe, Robert A. Vierkant, Laura M. Pacheco-Spann, Lisa R. Seymour, Celine M. Vachon, Mark E. Sherman, Amy C. Degnim, Deirdre Hill. Comparison of benign breast disease subtypes and breast cancer risk among Hispanic and non-Hispanic white women in New Mexico. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4213.

Abstract 3022: Prospective study of circulating metabolomic signatures and breast cancer incidence among predominantly premenopausal women

Abstract Background: Metabolomics has become a powerful tool to systematically examine metabolic pathways involved in carcinogenesis. Although several epidemiological studies examined the association between metabolites and breast cancer risk, metabolomic biomarkers of breast cancer measured in premenopausal women are still understudied. Herein, we prospectively investigated the associations between pre-diagnostic metabolomic signatures and subsequent risk of developing breast cancer among predominantly premenopausal women at blood collection. Methods: In the Nurses’ Health Study II, 29,611 healthy women (80% premenopausal) donated blood samples in 1996-1999. Between blood collection and 2011, 1,055 women were diagnosed with breast cancer, and each was matched with healthy control. Lipids, carbohydrates, and organic acid-related metabolites were profiled with liquid chromatography-tandem mass spectrometry. Multivariable (including adiposity) adjusted conditional logistic regression was used to estimate odds ratios (ORs) of breast cancer and 95% confidence intervals (CIs). Associations of metabolite groups with breast cancer were evaluated using metabolite set enrichment analysis and network analysis. All analyses were corrected for multiple comparisons. Results: Although no individual metabolites were statistically significantly associated with breast cancer risk after multiple comparisons correction, several individual metabolites were identified as nominally significant: taurodeoxycholate (OR=1.15; 95%CI=1.04-1.28), C16:1 cholesteryl ester (OR=0.88; 95%CI=0.79-0.97), C32:1 phosphatidylcholine (PC) (OR=0.88; 95%CI=0.79-0.98), C34:1 PC (OR=0.87; 95%CI=0.78-0.98), and C34:3 PC (OR=0.88; 95%CI=0.79-0.98). In analyses of grouped metabolites, triglycerides (TAGs) with &amp;lt;3 double bonds (DBs) (normalized enrichment score (NES)= -2.54; Padj&amp;lt;0.00001) and PCs (NES= -2.13; Padj=0.02) were significantly inversely associated with risk of overall breast cancer, with no obvious differences observed by menopausal or BMI status. Significant inverse associations of TAGs with ≥3 DBs were only observed among premenopausal women or among those with high BMI. Opposite enrichments of phospholipids, amino acids, and carbohydrate-related metabolites were observed by estrogen receptor (ER) status. Conclusions: In this prospective study of predominately premenopausal women, we found that the association between TAGs and breast cancer risk was dependent on the number of DBs. Notably, TAGs with &amp;lt;3 DBs, which have been associated with higher risk of type 2 diabetes, were strongly inversely associated with risk of developing breast cancer. Variations of associations with other metabolites were observed by menopausal, obesity, and ER status. Further validation of our findings in independent cohorts of premenopausal women is warranted. Citation Format: Tengteng Wang, Oana Zeleznik, Emma E. McGee, Kristen D. Brantley, Raji Balasubramanian, Bernard A. Rosner, Walter C. Willett, Clary B. Clish, A. Heather Eliassen. Prospective study of circulating metabolomic signatures and breast cancer incidence among predominantly premenopausal women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3022.

History of infertility and risk of breast cancer: a prospective cohort study.

Research on infertility and risk of breast cancer has been conflicting, potentially because many well-established breast cancer risk factors, such as pregnancy history, are strongly correlated with infertility. We followed participants in the Nurses' Health Study II from 1989 to 2015 (n = 103,080) for the development of invasive breast cancer and calculated Hazard Ratios (HR) and 95% confidence intervals (CI) using Cox regression. Participants with a self-reported history of infertility (12months of trying without conception) were compared to gravid women with no history of infertility. We classified breast cancer by menopausal status and investigated mediation by reproductive factors. Over 26years of follow-up, 26,208 (25.4%) women reported a history of infertility, and 3,201 women were newly diagnosed with invasive breast cancer. We observed no association between infertility history and risk of overall breast cancer (HR: 1.05, 95% CI: 0.97-1.14) or premenopausal breast cancer (RR: 0.93, 95% CI: 0.83-1.03). However, we observed a modest association between history of infertility and risk of postmenopausal breast cancer (HR: 1.13, 95% CI: 1.00-1.28), approximately 50% of which could be attributed to lower total parity and later age at first birth (95% CI: 8.2%-91.0%). Women with a history of infertility were at increased risk of postmenopausal breast cancer. Older age at first birth and lower total parity explained approximately half of the association between infertility and risk of postmenopausal breast cancer.

Identification of target proteins for breast cancer genetic risk loci and blood risk biomarkers in a large study by integrating genomic and proteomic data.

Genome-wide association studies (GWAS) have identified around 200 loci associated with breast cancer risk. However, protein targets for these loci remain largely unknown. Identifying protein targets and biomarkers can improve the understanding of cancer biology and etiology and identify high-risk individuals for cancer prevention. In this study, we investigated genetically predicted levels of 1142 circulating proteins with breast cancer risk in 133 384 cases and 113 789 controls of European ancestry included in the Breast Cancer Association Consortium (BCAC). We identified 22 blood protein biomarkers associated with the risk of overall breast cancer at a false discovery rate (FDR) <0.05, including nine proteins encoded by genes located at least 500 kb away from previously reported risk variants for breast cancer. Analyses focusing on 124 encoding genes located at GWAS-identified breast cancer risk loci found 20 proteins associated with overall breast cancer risk and one protein associated with triple-negative breast cancer risk at FDR <0.05. Adjustment for the GWAS-identified risk variants significantly attenuated the association for 13 of these proteins, suggesting that these proteins may be the targets of these GWAS-identified risk loci. The identified proteins are involved in various biological processes, including glutathione conjugation, STAT5 signaling and NF-κB signaling pathways. Our study identified novel protein targets and risk biomarkers for breast cancer risk.

Aspirin for the primary prevention of breast cancer: an unforeseen advantage

Aspirin for the primary prevention of breast cancer: an unforeseen advantage

Major depression disorder may causally associate with the increased breast cancer risk: Evidence from two-sample mendelian randomization analyses.

Major depression disorder (MDD) has been associated with increased breast cancer risk in epidemiological studies; however, it is still unknown whether this association is causal or not. The aim of this study is to determine the causal relationship between MDD and breast cancer risk. Two-sample Mendelian randomization (MR) analyses with 92 single-nucleotide polymorphisms (SNPs) significantly associated with MDD as instrumental variables (IVs) were performed. Effects of these SNPs on breast cancer in women were estimated in the Breast Cancer Association Consortium (122,977 cases and 105,974 controls) using inverse variance weighted (IVW), weighted median and multivariable MR models. Heterogeneity and pleiotropy effects were assessed based on IVW and MR-Egger regression model, respectively. An 8.7% increased risk of overall breast cancer [odds ratio (OR)=1.087; 95% confidence interval (CI) 1.011-1.170; P=0.025] per log-odds ratio increment of MDD risk based on the IVW model was noticed. Similar results were obtained with the multivariable MR model (OR=1.118, 95% CI=1.010-1.237; P=0.031). An increment but not statistically significant causality association was noticed between MDD and risk of ER+ (OR=1.098, 95% CI=0.984-1.227; P=0.093) or ER- (OR=1.129, 95% CI=0.982-1.297; P=0.089) breast cancer under multivariable MR model. No significant pleiotropy effects were observed for the IVs in the two-sample MR studies. The results suggested that a genetic predisposition of MDD is causally associated with overall breast cancer risk; however, the underlying biological mechanisms are worthy of further study.

Hypertensive diseases of pregnancy and risk of breast cancer in the Black Women's Health Study.

Compared to white women, Black women have increased risk of developing hypertensive diseases of pregnancy (HDOP) and have a higher incidence of aggressive breast cancer subtypes. Few studies of HDOP and breast cancer risk have included large numbers of Black women. This study examined the relation of HDOP to incidence of breast cancer overall and by estrogen receptor(ER) status in Black women. We followed 42,982 parous women in the Black Women's Health Study, a nationwide prospective study of Black women. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) to assess associations of self-reported HDOP, including preeclampsia and gestational hypertension, with breast cancer incidence overall and by ER subtype, adjusted for age and established breast cancer risk factors. Over 20years of follow-up, we identified 2376 incident breast cancer cases. History of HDOP (11.7%) was not associated with breast cancer risk overall (HR 0.98; 95% CI 0.87, 1.11). HRs for invasive ER+ and ER- breast cancer were 1.11 (95% CI 0.93, 1.34) and 0.81 (95% CI 0.61, 1.07), respectively. HDOP was not associated with risk of overall breast cancer in Black women. A suggestive inverse association with ER- breast cancer may reflect an anti-tumorigenic hormone profile in HDOP, but those results require confirmation in other studies.

Risk factors for breast cancer and their association with molecular subtypes in a population of Northeast Brazil

BackgroundThe risk factors for breast cancer (BC) among women in Brazilian populations are poorly understood. To date, few Brazilian studies have addressed the potential association between risk factors and molecular BC subtypes. This case-control study aimed to identify risk factors for BC in a population of Northeast Brazil. MethodsData from 313 patients with invasive BC and 321 healthy controls were obtained from medical records from two cancer treatment centres and personal interviews. Of the 313 BC patients, 224 (71.6%) had reached menopause. The following distribution of subtypes was found among 301 patients: (1) Luminal A: 54 (17.9%); (2) Luminal B: 175 (58.1%); (3) HER2/neu: 29 (9.7%); and (4) triple-negative breast cancer (TNBC): 43 (14.3%). Odds ratios (ORs) and confidence intervals (CIs) were determined using regression analysis. ResultsRegression modelling indicated that family history, obesity (≥ 30.0 kg/m2), alcohol consumption and contraceptive use increased the overall risk of BC 1.78 (95% CI: 1.22–2.59), 1.69 (95% CI: 1.08–2.63), 2.21 (95% CI: 1.44–3.39) and 2.99 (95% CI: 2.09–4.28) times, respectively. After stratification for menopausal status, alcohol consumption increased the risk of BC 4.15 (95% CI: 2.13–8.11) times, and obesity, as a single variable, increased the risk of BC 2.02 (95% CI: 1.22–3.37) times, only among postmenopausal women. In a case-control analysis, the risk of TNBC and Luminal B breast cancer were 4.06 (95% CI: 1.58–10.42) and 1.87 times (95% CI: 1.13–3.11) higher, respectively, in obese women than in non-obese women. Furthermore, alcohol consumption increased the risk of Luminal A and B subtypes 7.08 (3.40–14.73) and 1.77 (1.07–2.92) times, respectively. ConclusionFamily history, contraceptive use, obesity and alcohol consumption increased the risk of BC. Obesity and alcohol consumption differentially increased risk of TNBC and Luminal molecular subtypes.

The association between the inflammatory potential of diet and the risk of histopathological and molecular subtypes of breast cancer in northwestern Iran: Results from the Breast Cancer Risk and Lifestyle study.

This study explored the association between diet-associated inflammation and the risk of different molecular subtypes of breast cancer (BrCA) in a large, population-based case-control study conducted in northwestern Iran. The study consisted of 1007 women with histopathologically confirmed BrCA and 1004 controls admitted to hospitals in Tabriz, northwestern Iran, for nonneoplastic conditions. Dietary Inflammatory Index scores and energy-adjusted Dietary Inflammatory Index (E-DII) scores, with and without supplements, were computed on the basis of dietary intake collected using a validated 136-item food frequency questionnaire. Women with the highest E-DII scores (quartile 4) versus those with the lowest E-DII scores (quartile 1) showed a significantly increased BrCA risk (odds ratio for quartile 4 vs quartile 1 [ORQ4vsQ1 ], 1.87; 95% confidence interval [CI], 1.42-2.47), particularly for lobular carcinoma (ORQ4vsQ1 , 3.07; 95% CI, 1.34-7.02). Findings were similar for premenopausal women diagnosed with luminal A BrCA (ORQ4vsQ1 , 2.71; 95% CI, 1.74-4.22) or luminal B BrCA (ORQ4vsQ1 , 2.86; 95% CI, 1.39-5.89). Women consuming the most proinflammatory diets were 3 times more likely to have triple-negative BrCA (ORQ4vsQ1 , 3.00; 95% CI, 1.002-8.96) while compared to luminal A BrCA. The BrCA risk for women consuming diets in the highest half of E-DII scores (E-DII > 0) was 59% greater than the risk for those in the lowest half (95% CI, 1.29-1.97). Also, higher E-DII scores that took into account supplements were associated with larger tumor sizes (T3 > 5 cm; P < .05). A proinflammatory diet, as indicated by higher E-DII scores, appears to increase the risk of BrCA in Iranian women. Large increases in risk were seen in invasive molecular subtypes of BrCA. Anti-inflammatory diets are suggested to prevent the risk of overall BrCA and more aggressive forms of BrCA in particular.

Birth weight and the risk of overall breast cancer, premenopausal and postmenopausal breast cancer in adulthood: a dose-response meta-analysis of observational studies.

The effect of birth weight on breast cancer across different menopausal states remains unknown. The aim of this study was to systematically evaluate the association of birth weight with the risk of overall breast cancer (OBC) and premenopausal and postmenopausal breast cancer during adulthood. In parallel, the dose-response analyses were performed. Relevant studies were systematically searched from the PubMed, Embase, and the Cochrane Library databases from the inception to May 25, 2021, without language restrictions. All the results were pooled according to risk ratios (RRs). In total, 21 cohort studies comprising 1,139,032 participants were included. An increase in the birth weight was not associated with the risk of OBC and premenopausal and postmenopausal breast cancer. Compared with women having normal weight at birth, those with a high birth weight are likely to have an increased risk of invasive breast cancer (RR: 1.19, 95% confidence intervals: 1.03-1.38; I2: 28.6%). The dose-response analyses showed that the risk of premenopausal breast cancer increased significantly in unknown singleton status with birth weight over 2850 g (RR: 1.14 [1.02-1.30]). Similarly, postmenopausal breast cancer risk was increased in singleton births with birth weight over 3750 g (RR: 1.21 [1.00-1.47]). High weight at birth might be not significantly associated with the risk of OBC, premenopausal and postmenopausal breast cancer and ER+ and ER- breast cancer but is positively associated with the risk of invasive breast cancer, regardless of parity. Furthermore, with an increase in birth weight, the risk of postmenopausal breast cancer is likely to increase in the singleton births, whereas the risk of premenopausal breast cancer is likely to increase in unknown singleton status.