Association Of Breast Cancer Risk Research Articles

Chronic Low-Dose Exposure to Xenoestrogen Ambient Air Pollutants and Breast Cancer Risk: XENAIR Protocol for a Case-Control Study Nested Within the French E3N Cohort.

BackgroundBreast cancer is the most frequent cancer in women in industrialized countries. Lifestyle and environmental factors, particularly endocrine-disrupting pollutants, have been suggested to play a role in breast cancer risk. Current epidemiological studies, although not fully consistent, suggest a positive association of breast cancer risk with exposure to several International Agency for Research on Cancer Group 1 air-pollutant carcinogens, such as particulate matter, polychlorinated biphenyls (PCB), dioxins, Benzo[a]pyrene (BaP), and cadmium. However, epidemiological studies remain scarce and inconsistent. It has been proposed that the menopausal status could modify the relationship between pollutants and breast cancer and that the association varies with hormone receptor status.ObjectiveThe XENAIR project will investigate the association of breast cancer risk (overall and by hormone receptor status) with chronic exposure to selected air pollutants, including particulate matter, nitrogen dioxide (NO2), ozone (O3), BaP, dioxins, PCB-153, and cadmium.MethodsOur research is based on a case-control study nested within the French national E3N cohort of 5222 invasive breast cancer cases identified during follow-up from 1990 to 2011, and 5222 matched controls. A questionnaire was sent to all participants to collect their lifetime residential addresses and information on indoor pollution. We will assess these exposures using complementary models of land-use regression, atmospheric dispersion, and regional chemistry-transport (CHIMERE) models, via a Geographic Information System. Associations with breast cancer risk will be modeled using conditional logistic regression models. We will also study the impact of exposure on DNA methylation and interactions with genetic polymorphisms. Appropriate statistical methods, including Bayesian modeling, principal component analysis, and cluster analysis, will be used to assess the impact of multipollutant exposure. The fraction of breast cancer cases attributable to air pollution will be estimated.ResultsThe XENAIR project will contribute to current knowledge on the health effects of air pollution and identify and understand environmental modifiable risk factors related to breast cancer risk.ConclusionsThe results will provide relevant evidence to governments and policy-makers to improve effective public health prevention strategies on air pollution. The XENAIR dataset can be used in future efforts to study the effects of exposure to air pollution associated with other chronic conditions.International Registered Report Identifier (IRRID)DERR1-10.2196/15167

EQTL Colocalization Analyses Identify NTN4 as a Candidate Breast Cancer Risk Gene

Breast cancer genome-wide association studies (GWASs) have identified 150 genomic risk regions containing more than 13,000 credible causal variants (CCVs). The CCVs are predominantly noncoding and enriched in regulatory elements. However, the genes underlying breast cancer risk associations are largely unknown. Here, we used genetic colocalization analysis to identify loci at which gene expression could potentially explain breast cancer risk phenotypes. Using data from the Breast Cancer Association Consortium (BCAC) and quantitative trait loci (QTL) from the Genotype-Tissue Expression (GTEx) project and The Cancer Genome Project (TCGA), we identify shared genetic relationships and reveal novel associations between cancer phenotypes and effector genes. Seventeen genes, including NTN4, were identified as potential mediators of breast cancer risk. For NTN4, we showed the rs61938093 CCV at this region was located within an enhancer element that physically interacts with the NTN4 promoter, and the risk allele reduced NTN4 promoter activity. Furthermore, knockdown of NTN4 in breast cells increased cell proliferation invitro and tumor growth invivo. These data provide evidence linking risk-associated variation to genes that may contribute to breast cancer predisposition.

Abstract 29: Integrating computational epigenetic and statistical approaches to investigate how genome-wide transcription factor (TF)-DNA bindings affect breast cancer risk

Abstract Background: Fine-mapping and functional genomic studies of risk loci identified by genome wide association studies (GWAS) of breast cancer suggest that risk-associated regulatory variants may disrupt DNA binding affinities of transcription factors (TFs), such as FOXA1 and ESR1, thus altering gene expression and affecting breast cancer risk. To date, however, no studies have directly investigated how genome-wide TF-DNA bindings in a tissue-specific context affect breast cancer risk. Methods: We recently developed an analytic framework using computational epigenetic approaches and generalized mixed models to identify breast cancer risk associated cis-regulatory elements that are occupied by TFs. Summary statistics derived from GWAS of imputed data for approximately 11 million genetic variants were obtained from the Breast Cancer Association Consortium (BCAC). A total of 113 ChIP-seq datasets for TFs and chromatin features were annotated from the Encyclopedia of DNA Elements (ENCODE) and Roadmap projects and the Cistrome database (http://cistrome.org/) in multiple breast cancer cell lines..Chi-square values reported in the BCAC dataset were used to measure breast cancer risk associated with a genetic variant. To investigate TF-DNA bindings for breast cancer risk, we constructed generalized mixed models to evaluate the associations between the Chi-square values and binding sites of single TF or co-occupied by multiple TFs, given linkage disequilibrium (LD) blocks of variants to handle their dependence. To define approximately independent LD blocks similar to other studies, we defined LD blocks using non-overlapping segments of 100k bps. In addition, we investigated the effect of putative cis-regulatory elements characterized by TF-DNA bindings and chromatin features on breast cancer risk. Results: We identified a total of 22 TFs where their TF-DNA bindings were significantly associated with breast cancer risk at P < 1 × 10−5, with the top five TFs being FOXA1, SIN3AK, ESR1, TCF7l2, and AR (P < 1 × 10−10). We further observed stronger associations of breast cancer risk with co-occupied TF-TF DNA bindings, with the top five TF pairs (P < 1 × 10−16) being FOXA1+E2F1, FOXA1+NR2F2, FOXA1+ESR1, FOXA1+SIN3, and FOXA1+TCF12. The interactions of TF-TF DNA bindings for these five TF pairs were highly significant (P < 1 × 10−5). In addition, our results showed a significant interaction (P < 1 × 10−5) between chromatin features and the TF-DNA bindings. As compared with quiescent/low chromatin features, more TF-DNA bindings in enhancers, strong or weak transcription, or heterochromatin were associated with lower breast cancer risk. Conclusions: Our findings suggest that putative regulatory variants, which alter the TF-DNA binding affinities, particularly those located in TF-TF co-occupied sites, and TF-DNA binding colocalized with chromatin features, play an important role in breast cancer risk. Our approaches can be generalized to investigate the effect of genome-wide TF-DNA bindings on the risk of any human cancers that have comprehensive ChIP-seq and large-scale GWAS data. Citation Format: Wanqing Wen, Zhishan Chen, Quan Long, Wei Zheng, Xingyi Guo. Integrating computational epigenetic and statistical approaches to investigate how genome-wide transcription factor (TF)-DNA bindings affect breast cancer risk [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 29.

SNPs in lncRNA Regions and Breast Cancer Risk.

Long non-coding RNAs (lncRNAs) play crucial roles in human physiology, and have been found to be associated with various cancers. Transcribed ultraconserved regions (T-UCRs) are a subgroup of lncRNAs conserved in several species, and are often located in cancer-related regions. Breast cancer is the most common cancer in women worldwide and the leading cause of female cancer deaths. We investigated the association of genetic variants in lncRNA and T-UCR regions with breast cancer risk to uncover candidate loci for further analysis. Our focus was on low-penetrance variants that can be discovered in a large dataset. We selected 565 regions of lncRNAs and T-UCRs that are expressed in breast or breast cancer tissue, or show expression correlation to major breast cancer associated genes. We studied the association of single nucleotide polymorphisms (SNPs) in these regions with breast cancer risk in the 122970 case samples and 105974 controls of the Breast Cancer Association Consortium’s genome-wide data, and also by in silico functional analyses using Integrated Expression Quantitative trait and in silico prediction of GWAS targets (INQUISIT) and expression quantitative trait loci (eQTL) analysis. The eQTL analysis was carried out using the METABRIC dataset and analyses from GTEx and ncRNA eQTL databases. We found putative breast cancer risk variants (p < 1 × 10–5) targeting the lncRNA GABPB1-AS1 in INQUISIT and eQTL analysis. In addition, putative breast cancer risk associated SNPs (p < 1 × 10–5) in the region of two T-UCRs, uc.184 and uc.313, located in protein coding genes CPEB4 and TIAL1, respectively, targeted these genes in INQUISIT and in eQTL analysis. Other non-coding regions containing SNPs with the defined p-value and highly significant false discovery rate (FDR) for breast cancer risk association were discovered that may warrant further studies. These results suggest candidate lncRNA loci for further research on breast cancer risk and the molecular mechanisms.

Breast Cancer disease and Heavy Metal: Cadmium as Key in “Medical Geology”

Health problems arising from geological materials and processes are more common than most people believe. Geology may appear remote from human health. However, rocks are the fundamental building blocks of the Earth’s surface, full of important minerals and chemical elements. Rock weathering and alteration products not only form our soils to support our crops but provide essential elements to build biology. Drinking water travels through rocks and soils as part of the water cycle, and much of the dust and gases contained in the atmosphere are of ultimate geological origin. Without this tectonic “rock cycle” connection to atmosphere and water, there can be no life. Human evolution is also intimately bound to geology. The African rift valley unique geology and metallogenesis is fundamental to the cradle of human evolution and expansion, both physiographically and bio-geochemically. Facilitated by an amplified oscillating mosaic environments climate, biology and geology, particularly in the last 2.6Ma of the 30 Ma Cenozoic cooling and drying, hominoids were not only adapted to biological and climactic factors but also parent rock elements, including metal (loids) used to build their biological structures and functions. Numerous enzymes incorporate metal(loids) central to their catalytic functions. Over 1,200 are known to be involved in neurobiology alone, likely impacting evolution of Homo habilis to H. erectus, near doubling brain size, complexity and energy demand. Metalliferous enzyme homeostatic deregulation widely impacts health from cancer to neurological diseases. Pre-adapted to the African rift biogeochemistry mosaic, a far more skewed metalliferous anthropecen now adversely impacts metal homeostasis and our health. Concentrating on the Medical Geology of highly toxic cadmium (Cd), we explore its environmental relationship with Breast Cancer. We studied urinary Cd levels in 150 women with Breast Cancer (diagnosis age 20 to 69 years). Cd levels trend aggressive with different risk profile from later-onset disease “stage III”. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals. After correcting for differential calendar time of sample collection, statistically significant associations were observed between Cd levels and Breast Cancer risk amongst participants with localized breast cancer, Odds Ratio (OR): OR=1.35; 94% CI: 1.2- 1.8; p=0.004 and participants with regional/distal Breast Cancer: OR=1.81; 96% CI: 1.4-2.4; p=0.001. We concluded, the association of Breast Cancer risk with Cd levels did not differ between participants treated by surgery and/or radiation (p ≥ 0.05) only OR=1.34; 93% CI: 1.0-1.5 and those treated with chemotherapy OR=1.35; 94% CI: 1.0-1.6. Cd exposure probably related to the association between Cd and renal diseases, cardiovascular outcomes, cancer, especially Breast Cancer family history. Avoiding excessive metal(loid), including Cd, in all sources is advisable. These may include tattoo and or colorful cosmetics, Indian rice dietary habits, known higher in metal(loids) due to expensive local rice and smoking. We recommend women older than 40 years, particularly with family Breast Cancer history, to largely avail themselves of a plant based diet, along with adequate heavy metal ameliorating trace elements e.g. selenium, to drink anti-inflammatory herbal tea in daily diet, and non-smoking habits.

Abstract P5-08-02: Association of daily alcohol intake, volumetric density and breast cancer risk

Abstract Background: Alcohol intake and breast density are established risk factors for breast cancer (BC). A few studies suggest breast density is on the causal pathway between alcohol and BC but the literature is not consistent. We examine the interrelationship between alcohol, volumetric breast density and BC risk, specifically whether there is a stronger alcohol and BC association among women with dense breasts and/or whether breast density mediates the alcohol and BC association. Methods: We conducted a nested case-control study within the San Francisco Mammography Registry consisting of four breast screening centers. From 2006-2013, through linkages with the California cancer registry, we identified 2572 women diagnosed with BC who had screening mammograms performed at least six months prior to diagnosis. Controls (5119) were matched to cases on age, date of earliest mammogram, race/ethnicity, facility, and mammography machine. We obtained the raw format of digital mammograms on average 3.1 (standard deviation (SD) =1.7) years prior to diagnosis or corresponding date for controls. We ascertained usual daily alcohol intake and other risk factors from a clinical questionnaire at time of mammography. We obtained BI-RADS density from clinical records and used VolparaTM to assess volumetric percent density, dense volume and non-dense volume from the mammogram. We examined the associations of daily alcohol intake (none, one or less, two or more drinks per day) and volumetric density phenotypes (per 1 SD) with BC risk using logistic regression (odds ratios, OR; 95% confidence intervals, CI; and trend tests). We examined deviation from multiplicative interaction using chi-squared tests. We evaluated mediation of the alcohol and BC association by volumetric density measures using logistic regression to estimate the association between alcohol use and BC with and without adjustment for density measures. Percent mediation was estimated using the differences in the log OR estimates from the two models. All models were adjusted for age, 1/BMI and menopause and matching factors. Analyses were also stratified by menopausal status. Results: Alcohol intake was available on 2233 cases and 4562 controls, 88% of those eligible. BC cases and controls had similar age (57.2 years (SD=11.5) vs. 57.1 years (SD=11.5)), BMI (25.3 kg/m2 (SD=5.3) vs. 24.9 kg/ m2 (SD=5.1)) and race (69.0% vs. 68.2% Caucasian). Cases were more likely to drink alcohol daily than controls (52.1% vs. 49.0%), in particular two or more drinks per day (14.8% vs. 13.2%). Alcohol was associated with increased BC risk (OR=1.14, 95% CI:1.02-1.27, for one or less drinks per day and OR=1.22, 95% CI:1.05-1.42 for 2 or more drinks per day) compared to non-drinkers (p-trend=0.004). Percent volumetric density (OR=1.45 per SD, 95%CI: 1.36-1.56,) and dense volume (OR=1.30, 95% CI: 1.24-1.37) were also positively associated with BC risk; non-dense volume was inversely associated (OR=0.93, 95%CI: 0.86-1.01). Associations were similar by menopausal subgroup. There was no evidence for a differential association of alcohol and breast cancer risk by dense breasts assessed using any of the density phenotypes examined (all P’s&amp;gt;0.1). However, the association between alcohol and overall risk of BC was partially mediated by dense volume among all women (percent mediated=25%, P=0.01) and postmenopausal women (percent mediated=19%, P=0.03). Conclusions: The association of daily alcohol intake and breast cancer risk was similar among women with dense and non-dense breasts. However, dense volume partially mediated the association between alcohol and risk of breast cancer, particularly among postmenopausal women, suggesting that alcohol partially influences breast cancer risk through changes in breast tissue composition. Citation Format: Celine Marie Vachon, Christopher G. Scott, Stacey J Winham, John A Shepherd, Kathleen R Brandt, Matthew R Jensen, Carrie B Hruska, John J Heine, V. Shane Pankratz, Karla Kerlikowske. Association of daily alcohol intake, volumetric density and breast cancer risk [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-08-02.

Association of PON1-L55M Genetic Variation and Breast Cancer Risk: A Case-Control Trial.

Background:Paraoxonase 1 (PON1), a multifactorial antioxidant enzyme, has a defensive role against oxidative stress, which is believed to contribute to cancer development. This study aimed to investigate the association of PON1-L55M functional polymorphism with breast cancer risk. Material and methods:In the experimental study, blood samples were collected from 150 healthy women controls and 150 breast cancer subjects. The L55M genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism. Results:Our analysis showed that the genotypes distribution is in Hardy-Weinberg equilibrium for both case and control groups. Our data revealed that there are significant associations between PON1-L55M polymorphism and breast cancer risk in homozygote (OR= 2.13, 95%CI= 1.14-4.00, p= 0.018), dominant (OR= 1.72, 95%CI= 1.07-2.76, p= 0.024), and allelic (OR= 1.55, 95%CI= 1.12-2.15, p= 0.008) models. Conclusions:Our results suggest that the PON1-L55M genetic variation could be a genetic risk factor for breast cancer risk and it could be considered as a molecular biomarker for screening of susceptible women.

Interval breast cancer risk associations with breast density, family history and breast tissue aging.

Interval breast cancers (those diagnosed between recommended mammography screens) generally have poorer outcomes and are more common among women with dense breasts. We aimed to develop a risk model for interval breast cancer. We conducted a nested case–control study within the Melbourne Collaborative Cohort Study involving 168 interval breast cancer patients and 498 matched control subjects. We measured breast density using the CUMULUS software. We recorded first‐degree family history by questionnaire, measured body mass index (BMI) and calculated age‐adjusted breast tissue aging, a novel measure of exposure to estrogen and progesterone based on the Pike model. We fitted conditional logistic regression to estimate odds ratio (OR) or odds ratio per adjusted standard deviation (OPERA) and calculated the area under the receiver operating characteristic curve (AUC). The stronger risk associations were for unadjusted percent breast density (OPERA = 1.99; AUC = 0.66), more so after adjusting for age and BMI (OPERA = 2.26; AUC = 0.70), and for family history (OR = 2.70; AUC = 0.56). When the latter two factors and their multiplicative interactions with age‐adjusted breast tissue aging (p = 0.01 and 0.02, respectively) were fitted, the AUC was 0.73 (95% CI 0.69–0.77), equivalent to a ninefold interquartile risk ratio. In summary, compared with using dense breasts alone, risk discrimination for interval breast cancers could be doubled by instead using breast density, BMI, family history and hormonal exposure. This would also give women with dense breasts, and their physicians, more information about the major consequence of having dense breasts—an increased risk of developing an interval breast cancer.

Association of Breast Cancer Risk After Childhood Cancer With Radiation Dose to the Breast and Anthracycline Use

Chest irradiation for childhood cancer is associated with increases in breast cancer risk. Growing evidence suggests that anthracyclines increase this risk, but the outcome of combined anthracycline use and radiotherapy has not been studied. To evaluate breast cancer risk in childhood cancer survivors following radiotherapy and chemotherapy and assess whether risks varied by estrogen receptor (ER) status. In a North American hospital-based nested case-control study, a retrospective cohort of 14 358 five-year survivors of childhood cancer, diagnosed from 1970 to 1986 and followed up through December 31, 2016, was analyzed. Cases (n = 271) were defined as women with subsequent breast cancer. Controls (n = 1044) were matched 4:1 to cases by age at first cancer and duration of follow-up (± 2 years). Data analysis was conducted from September 2017 to July 2018. Radiation dose to breast tumor site and ovaries and cumulative chemotherapy doses, including anthracyclines and alkylating agents. Odds ratios (ORs) for subsequent breast cancer by ER status. A total of 271 women served as breast cancer cases (median age at first cancer diagnosis, 15 years [range, 3-20]; median age at breast cancer diagnosis, 39 years [range, 20-57]): 201 invasive (113 ER positive [ER+], 41 ER negative [ER-], and 47 unknown) and 70 in situ breast cancers. The OR for breast cancer increased with increasing radiation dose to the breast (OR per 10 Gy, 3.9; 95% CI, 2.5-6.5) and was similar for ER+ (OR per 10 Gy, 5.5; 95% CI, 2.8-12.6) and ER- (OR per 10 Gy, 4.8; 95% CI, 1.7-22.3) cancers. For women who received ovarian doses less than 1 Gy, the OR per 10 Gy to the breast was higher (OR, 6.8; 95% CI, 3.9-12.5) than for women who received ovarian doses greater than or equal to 15 Gy (OR, 1.4; 95% CI, 1.0-6.4). The OR for breast cancer increased with cumulative anthracycline dose (OR per 100 mg/m2, 1.23; 95% CI, 1.09-1.39; P < .01 for trend), and was 1.49 (95% CI, 1.21-1.83) for ER+ cancer vs 1.10 (95% CI, 0.84-1.45) for ER- cancers (P value for heterogeneity = .47). There was an additive interaction between radiotherapy and anthracycline treatment (P = .04) with the OR for the combined association between anthracycline therapy and breast radiation dose of 10 Gy or more (compared with 0 to less than 1 Gy) of 19.1 (95% CI, 7.6-48.0) vs 9.6 (95% CI, 4.4-20.7) without anthracycline use. This study provides the first evidence to date that the combination of anthracyclines and radiotherapy may increase breast cancer risks compared with use of neither treatment with a similar radiation dose response for ER+ and ER- cancers and possibly higher anthracycline risks for ER+ cancers. These results might help inform surveillance guidelines for childhood cancer survivors.

Two truncating variants in FANCC and breast cancer risk

Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44–1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.

Abstract 623: Iron intake, oxidative stress-related genes, and breast cancer risk

Abstract Background: Iron has been shown to enhance breast carcinogenesis in animal models through generation of oxidative stress, although epidemiological evidence of the association between iron intake and breast cancer risk remains inconclusive. This study investigated associations between different types of iron intake and breast cancer risk, and whether these associations were modified by genetic polymorphisms in antioxidant enzymes, including manganese superoxide dismutase (MnSOD) and glutathione S-transferases M1 (GSTM1) and T1 (GSTT1). Methods: A population-based case-control study in Ontario, Canada recruited 3,030 breast cancer cases identified from the Ontario Cancer Registry and 3,402 controls from random digit dialing. Iron intake from foods and supplements was assessed using a 178-item food frequency questionnaire. Multivariable logistic regression analyses were used to evaluate associations between breast cancer risk and intakes of dietary, supplemental, and total (dietary plus supplemental) iron, among all women and stratified by menopausal status. Associations were also examined by hormone receptor [estrogen receptor (ER)/progesterone receptor (PR)] tumor subtype. Among women providing saliva (DNA) samples (1,696 cases and 1,761 controls), interactions between iron intake and genetic polymorphisms were assessed using the likelihood ratio test. Results: Among all women, intakes of dietary, supplemental, and total iron were not associated with breast cancer risk, overall or by tumor subtype. Among premenopausal women, there was an increase in breast cancer risk for the ER–PR– subtype associated with higher intakes (highest vs. lowest quintile) of dietary [odds ratio (OR) = 1.4; 95% confidence interval (CI): 0.9–2.4] and total (OR = 1.8; 95% CI: 1.1–2.9) iron (P for trend &amp;lt; 0.05). Among postmenopausal women, supplemental iron intake (&amp;gt;18 vs. 0 mg/day) was associated with reduced breast cancer risk (OR = 0.7; 95% CI: 0.5–0.9), with similar associations across tumor subtypes. Associations of dietary and total iron intake with overall breast cancer risk were modified by GSTT1 and/or GSTM1/T1 combined genotypes (P for interaction &amp;lt; 0.05). For example, among women with deletions in both GSTM1 and GSTT1 loci, higher dietary iron intake was associated with increased breast cancer risk (OR = 2.1; 95% CI: 1.1–4.2), whereas null or inverse associations were found among women with other GSTM1/T1 genotypes. Conclusions: Results from this study suggest that higher dietary and total iron intake may be associated with increased risk of ER–PR– breast cancer among premenopausal women, whereas higher supplemental iron intake may be associated with reduced postmenopausal breast cancer risk. In addition, associations between iron intake and breast cancer risk may be modified by polymorphisms in oxidative stress-related genes. Our ongoing work will investigate heme and non-heme iron intake in relation to breast cancer risk. Citation Format: Vicky C. Chang, Michelle Cotterchio, Susan J. Bondy, Joanne Kotsopoulos. Iron intake, oxidative stress-related genes, and breast cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 623.

Fine-mapping of a novel premenopausal breast cancer susceptibility locus at Chr4q31.22 in Caucasian women and validation in African and Chinese women.

We previously identified a novel breast cancer susceptibility variant on chromosome 4q31.22 locus (rs1429142) conferring risk among women of European ancestry. Here, we report replication of findings, validation of the variant in diverse populations and fine‐mapping of the associated locus in Caucasian population. The SNP rs1429142 (C/T, minor allele frequency 18%) showed association for the overall breast cancer risk in Stages 1–4 (n = 4,331 cases/4271 controls; p = 4.35 × 10−8; odds ratio, ORC‐allele,1.25), and an elevated risk among premenopausal women (n = 1,503 cases/4271 controls; p = 5.81 × 10−10; ORC‐allele 1.40) in European populations. SNP rs1429142 was associated with premenopausal breast cancer risk in women of African (T/C; p‐value 1.45 × 10−02; ORC‐allele 1.2) but not from Chinese ancestry. Fine‐mapping of the locus revealed several potential causal variants which are present within a single association signal, revealed from the conditional regression analysis. Functional annotation of the potential causal variants revealed three putative SNPs rs1366691, rs1429139 and rs7667633 with active enhancer functions inferred based on histone marks, DNase hypersensitive sites in breast cell line data. These putative variants were bound by transcription factors (C‐FOS, STAT1/3 and POL2/3) with known roles in inflammatory pathways. Furthermore, Hi‐C data revealed several short‐range interactions in the fine‐mapped locus harboring the putative variants. The fine mapped locus was predicted to be within a single topologically associated domain, potentially facilitating enhancer–promoter interactions possibly leading to the regulation of nearby genes.

Correlation between Candidate Single Nucleotide Variants and Several Clinicopathological Risk Factors Related to Breast Cancer in Jordanian Women: A Genotype-Phenotype Study.

This study aim to investigate the association of breast cancer risk and prognostic factors with single nucleotide variants of the BRCA1, BRCA2, DAPK1, MMP9, TOX3, and TP53 genes in Jordanian women. Blood samples were collected from 230 Jordanian breast cancer patients for use in DNA extraction followed by genotyping and subsequent statistical analysis. We found that two single nucleotide variants (SNVs) of the BRCA2 gene, namely rs1799944 and rs766173, were significantly associated with breastfeeding status. Likewise, the rs11141901 and rs1041326 SNVs of the DAPK1 gene were linked with co-morbidity (p-value = 0.002) and family history of BC (p-value = 0.015), while the rs1045042 SNV of the same gene was associated with both allergy (p-value = 0.001) and family history of BC (p-value = 0.02). Tumor differentiation was correlated with the DAPK1 SNVs rs11141901 (p-value = 0.041) and rs1041326 (p-value = 0.005). Additionally, the rs2250889 SNV of the MMP9 gene was significantly associated with HER2 status, whereas the TP53 SNVs rs12951053 and rs1042522 were associated with age at menarche (p-value = 0.043) and breastfeeding status (p-value = 0.013), respectively. In contrast, the TP53 SNV rs2287497 was significantly linked to age at first pregnancy (p-value = 0.001), smoking (p-value = 0.041), and axillary lymph node status (p-value = 6e-4). No such association was found for the BRCA1 and TOX3 SNVs. The current findings suggest significant associations between certain SNVs and breast cancer risk and prognosis in Jordanian women.

Association of breast cancer risk with polymorphisms in genes involved in the metabolism of xenobiotics and interaction with tobacco smoking: A gene-set analysis.

Single nucleotide polymorphisms (SNPs) in genes involved in xenobiotics metabolism (XM) are suspected to play a role in breast cancer risk. However, previous findings based on a SNP by SNP approach need to be replicated taking into account the combined effects of multiple SNPs. We used a gene-set analysis method to study the association between breast cancer risk and genetic variation in XM genes (seen as a set of SNPs) and in the XM pathway (seen as a set of genes). We also studied the interaction between variants in XM genes and tobacco smoking. The analysis was conducted in a case-control study of 1,125 cases and 1,172 controls. Using a dedicated chip, genotyping data of 585 SNPs in 68 XM genes were available. Genetic variation in the whole XM pathway was significantly associated with premenopausal breast cancer risk (p = 0.008). This association was mainly driven by genetic variation in NAT2, CYP2C18, CYP2C19, AKR1C2 and ALDH1A3. The association between the XM gene pathway and breast cancer was observed among current and previous smokers, but not among never smokers (p = 0.013 for interaction between XM genes and tobacco smoking status). The association with breast cancer risk indicates that XM genes variants may play a role in breast carcinogenesis through their detoxification function of environmental pollutants, such as those contained in tobacco smoke.

Adherence to Mediterranean diet and the risk of breast cancer: a meta-analysis

Background: For a long period of time, the Mediterranean diet (MD) has been regarded by many as a very healthy and balanced daily diet that may be related to the incidences of many types of cancer. However, the association between an MD and breast cancer risk remains inconsistent even though many studies about the topic have been conducted. Hence, we performed a meta-analysis to evaluate the relationship between an MD and breast cancer risk. Methods: We searched PubMed, Medline, and EMBASE for relevant articles published earlier than May 2017. “Mediterranean diet” combined with “breast cancer” and “breast carcinoma” were used as search terms. The combined relative risk (RR) and corresponding 95% confidence interval (CI) were used to evaluate the association between an MD and breast cancer risk. Results: A total of 18 articles were included in our meta-analysis; the studies spanned 11 years, ranging from 2006 to May 2017. Ten cohort and 8 case-control studies were included. Seven studies analyzed breast cancer incidence separately in premenopausal and postmenopausal women, whereas 6 studies were performed only in postmenopausal women, for a total of 13 analyses in postmenopausal women and 7 analyses among premenopausal women. Our meta-analysis revealed a significant and inverse association of the MD and breast cancer risk (RR: 0.92, 95% CI: 0.86, 0.99). Stratification analysis by study design and menopause status revealed a significant inverse association between the MD and breast cancer risk in case-control studies (RR: 0.85, 95% CI: 0.73, 0.99) and postmenopausal women (RR: 0.91, 95% CI: 0.85, 0.97) but not in cohort studies and premenopausal women. Conclusions: Our meta-analysis revealed that an MD is significantly associated with a reduction of breast cancer risk in women, especially postmenopausal women. The MD can be suggested to women, especially postmenopausal women, as a healthy diet to reduce breast cancer risk.

Associations of obesity and circulating insulin and glucose with breast cancer risk: a Mendelian randomization analysis.

In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear. We conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98842 cases and 83464 controls of European descent in the Breast Cancer Association Consortium. All sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p = 5.09 × 10-4], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p = 4.02 × 10-4), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p = 5.05 × 10-19) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p = 9.22 × 10-6). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2-h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer. We confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer.

Abstract 3222: Evaluation of associations between circulating proteins and breast cancer risk using genetic variants

Abstract Breast cancer is the most commonly diagnosed cancer in women in many countries. Several circulating protein biomarkers have been identified in relation to breast cancer risk. However, previous studies either had small sample sizes or employed low-throughput techniques. To search for novel biomarkers, we utilized genetic variants as instruments and evaluated over 1,400 proteins in relation to breast cancer risk using data from the Breast Cancer Association Consortium (BCAC). We extracted beta coefficients from reported protein quantitative trait loci (pQTL) derived from genome-wide association studies of circulating proteins. Summary statistics of these pQTL variants associated with breast cancer risk were obtained from 122,977 cases and 105,974 controls of European descent in the BCAC. Associations of genetically predicted protein levels with breast cancer risk were evaluated using the inverse-variance weighted method. For proteins with a significant association, expression levels of the corresponding gene were predicted using genotyping and transcriptomic data from the Genotype-Tissue Expression project and then evaluated for their associations with breast cancer risk. We identified 56 protein biomarkers showing a significant association with breast cancer risk after accounting for multiple comparisons (false discovery rate &amp;lt; 0.05). Among them, levels of 32 proteins were influenced by variants close to a newly reported breast cancer susceptibility locus (9q34.2, ABO). Inverse associations of breast cancer risk were found with membrane proteins such as insulin receptor, insulin-like growth factor receptor 1, hepatocyte growth factor receptor, neurogenic locus notch homolog protein 1, and vascular endothelial growth factor receptor 2, with odds ratios ranging from 0.82 to 0.97 per unit increase in genetic risk scores (p-values ranging from 6.53x10-4 to 3.28x10-8). Genetically predicted expression of five genes, CPNE1, CTSF, TFPI, SCG3, and QSOX2, was found to be associated with breast cancer risk at p &amp;lt;0.05 in the same direction as the associations observed for the corresponding proteins. Results from our study suggest that multiple membrane proteins related to insulin resistance may be linked to breast cancer risk through genetic variants at 9q34.2. Citation Format: Xiang Shu, Jiandong Bao, Lang Wu, Jirong Long, Xingyi Guo, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang, Joe Dennis, Jacques Simard, Douglas F. Easton. Evaluation of associations between circulating proteins and breast cancer risk using genetic variants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3222.

Abstract A09: Urban neighborhood and residential factors associated with breast cancer in African American women: A systematic review

Abstract Certain residential characteristics in urban neighborhoods have shown to have negative impacts on health, especially in the African American population. The purpose of this systematic review is to understand the relationship between urban neighborhood and residential factors and breast cancer risk, incidence, stage at diagnosis/late stage diagnosis, survival, and mortality in African Americans. Using PubMed and Web of Science, the existing literature was reviewed. Observational, cross-sectional, cohort, and prospective studies until February 2017 were examined. Studies that included populations of African American women, setting in “urban” areas, and a measure of a neighborhood or residential factor were reviewed. Three parameters related to neighborhood/residential factors were extracted, including neighborhood socioeconomic status (SES), residential segregation, and residential pollution. Eighteen studies were identified for systematic review. 10 studies showed significantly higher odds of late-stage diagnosis, higher mortality, and lower survival in African American women living in lower socioeconomic neighborhoods. One study showed slightly higher odds of upward neighborhood change and probability of distant metastasis at diagnosis of African American woman compared to White women (OR=1.24). Similarly, 5 studies showed significantly high associations between residential segregation and late-stage diagnosis, as well as high associations of residential segregation and higher mortality in African American women. Two studies assessed residential pollution on breast cancer risk. The first study showed a weak rate of breast cancer risk in African American women between differentiating levels of trihalomethane in public water (RR=1.2). The second assessed the association of magnetic field exposure and breast cancer risk and found that the odds of getting breast cancer were not significant in African American women (OR=1.02). This review provides a qualitative synthesis of major neighborhood and residential factors on breast outcomes in African American women. By enacting health policies and utilizing tools such as health informatics, steps can be taken to drive the breast cancer disparity down in this population. Citation Format: Brandi Patrice Smith, Zeynep Madak-Erdogan. Urban neighborhood and residential factors associated with breast cancer in African American women: A systematic review [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr A09.

Emerging Trends in Family History of Breast Cancer and Associated Risk.

Background: Increase in breast cancer incidence associated with mammography screening diffusion may have attenuated risk associations between family history and breast cancer.Methods: The proportions of women ages 40 to 74 years reporting a first-degree family history of breast cancer were estimated in the Breast Cancer Surveillance Consortium cohort (BCSC: N = 1,170,900; 1996-2012) and the Collaborative Breast Cancer Study (CBCS: cases N = 23,400; controls N = 26,460; 1987-2007). Breast cancer (ductal carcinoma in situ and invasive) relative risk estimates and 95% confidence intervals (CI) associated with family history were calculated using multivariable Cox proportional hazard and logistic regression models.Results: The proportion of women reporting a first-degree family history increased from 11% in the 1980s to 16% in 2010 to 2013. Family history was associated with a >60% increased risk of breast cancer in the BCSC (HR, 1.61; 95% CI, 1.55-1.66) and CBCS (OR, 1.64; 95% CI, 1.57-1.72). Relative risks decreased slightly with age. Consistent trends in relative risks were not observed over time or across stage of disease at diagnosis in both studies, except among older women (ages 60-74) where estimates were attenuated from about 1.7 to 1.3 over the last 20 years (P trend = 0.08 for both studies).Conclusions: Although the proportion of women with a first-degree family history of breast cancer increased over time and by age, breast cancer risk associations with family history were nonetheless fairly constant over time for women under age 60.Impact: First-degree family history of breast cancer remains an important breast cancer risk factor, especially for younger women, despite its increasing prevalence in the mammography screening era. Cancer Epidemiol Biomarkers Prev; 26(12); 1753-60. ©2017 AACR.

Association of breast cancer risk and the mTOR pathway in women of African ancestry in 'The Root' Consortium.

Functional studies have elucidated the role of the mammalian target of rapamycin (mTOR) pathway in breast carcinogenesis, but to date, there is a paucity of data on its contribution to breast cancer risk in women of African ancestry. We examined 47628 SNPs in 61 mTOR pathway genes in the genome wide association study of breast cancer in the African Diaspora study (The Root consortium), which included 3686 participants (1657 cases). Pathway- and gene-level analyses were conducted using the adaptive rank truncated product (ARTP) test for 10994 SNPs that were not highly correlated (r2 < 0.8). Odds ratio (OR) and 95% confidence interval (CI) were estimated with logistic regression for each single-nucleotide polymorphism. The mTOR pathway was significantly associated with overall and estrogen receptor-negative (ER-) breast cancer risk (P = 0.003 and 0.03, respectively). PRKAG3 (Padj = 0.0018) and RPS6KA3 (Padj = 0.061) were the leading genes for the associations with overall breast cancer risk and ER- breast cancer risk, respectively. rs190843378 in PRKAG3 was statistically significant after gene-level adjustment for multiple comparisons (OR = 0.50 for each T allele, 95% CI = 0.38-0.66, Padj = 3.6E-05), with a statistical power of 0.914. These results provide new insights on the biological relevance of the mTOR pathway in breast cancer progression and underscore the need for more genetic epidemiology studies of breast cancer in the African Diaspora.