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IntroductionWe have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age ≤50 years.MethodsWe further investigated the association of rs10235235 with breast cancer risk in a large case control study of 47,346 cases and 47,570 controls from 52 studies participating in the Breast Cancer Association Consortium. Genotyping of rs10235235 was conducted using a custom Illumina Infinium array. Stratified analyses were conducted to determine whether this association was modified by age at diagnosis, ethnicity, age at menarche or tumor characteristics.ResultsWe confirmed the association of rs10235235 with breast cancer risk for women of European ancestry but found no evidence that this association differed with age at diagnosis. Heterozygote and homozygote odds ratios (ORs) were OR = 0.98 (95% CI 0.94, 1.01; P = 0.2) and OR = 0.80 (95% CI 0.69, 0.93; P = 0.004), respectively (P(trend) = 0.02). There was no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche in controls (P(trend) = 0.005) but not cases (P(trend) = 0.97). Consequently the association between rs10235235 and breast cancer risk differed according to age at menarche (P(het) = 0.02); the rare allele of rs10235235 was associated with a reduction in breast cancer risk for women who had their menarche age ≥15 years (OR(het) = 0.84, 95% CI 0.75, 0.94; OR(hom) = 0.81, 95% CI 0.51, 1.30; P(trend) = 0.002) but not for those who had their menarche age ≤11 years (OR(het) = 1.06, 95% CI 0.95, 1.19, OR(hom) = 1.07, 95% CI 0.67, 1.72; P(trend) = 0.29).ConclusionsTo our knowledge rs10235235 is the first single nucleotide polymorphism to be associated with both breast cancer risk and age at menarche consistent with the well-documented association between later age at menarche and a reduction in breast cancer risk. These associations are likely mediated via an effect on circulating hormone levels.

Triple-negative (TN) breast cancer is an aggressive subtype of breast cancer associated with a unique set of epidemiologic and genetic risk factors. We conducted a two-stage genome-wide association study of TN breast cancer (stage 1: 1529 TN cases, 3399 controls; stage 2: 2148 cases, 1309 controls) to identify loci that influence TN breast cancer risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide significant associations (P < 5 × 10(-) (8)) in stage 1 and 2 combined. Results also suggested a substantial enrichment of significantly associated variants among the single nucleotide polymorphisms (SNPs) analyzed in stage 2. Variants from 25 of 74 known breast cancer susceptibility loci were also associated with risk of TN breast cancer (P < 0.05). Associations with TN breast cancer were confirmed for 10 loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3, 19p13.1, RALY), and we identified associations with TN breast cancer for 15 additional breast cancer loci (P < 0.05: PEX14, 2q24.1, 2q31.1, ADAM29, EBF1, TCF7L2, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, BRCA2, RAD51L1-rs2588809, MKL1). Further, two SNPs independent of previously reported signals in ESR1 [rs12525163 odds ratio (OR) = 1.15, P = 4.9 × 10(-) (4)] and 19p13.1 (rs1864112 OR = 0.84, P = 1.8 × 10(-) (9)) were associated with TN breast cancer. A polygenic risk score (PRS) for TN breast cancer based on known breast cancer risk variants showed a 4-fold difference in risk between the highest and lowest PRS quintiles (OR = 4.03, 95% confidence interval 3.46-4.70, P = 4.8 × 10(-) (69)). This translates to an absolute risk for TN breast cancer ranging from 0.8% to 3.4%, suggesting that genetic variation may be used for TN breast cancer risk prediction.

Genes that alter disease risk only in combination with certain environmental exposures may not be detected in genetic association analysis. By using methods accounting for gene-environment (G × E) interaction, we aimed to identify novel genetic loci associated with breast cancer risk. Up to 34,475 cases and 34,786 controls of European ancestry from up to 23 studies in the Breast Cancer Association Consortium were included. Overall, 71,527 single nucleotide polymorphisms (SNPs), enriched for association with breast cancer, were tested for interaction with 10 environmental risk factors using three recently proposed hybrid methods and a joint test of association and interaction. Analyses were adjusted for age, study, population stratification, and confounding factors as applicable. Three SNPs in two independent loci showed statistically significant association: SNPs rs10483028 and rs2242714 in perfect linkage disequilibrium on chromosome 21 and rs12197388 in ARID1B on chromosome 6. While rs12197388 was identified using the joint test with parity and with age at menarche (P-values = 3 × 10(-07)), the variants on chromosome 21 q22.12, which showed interaction with adult body mass index (BMI) in 8,891 postmenopausal women, were identified by all methods applied. SNP rs10483028 was associated with breast cancer in women with a BMI below 25 kg/m(2) (OR = 1.26, 95% CI 1.15-1.38) but not in women with a BMI of 30 kg/m(2) or higher (OR = 0.89, 95% CI 0.72-1.11, P for interaction = 3.2 × 10(-05)). Our findings confirm comparable power of the recent methods for detecting G × E interaction and the utility of using G × E interaction analyses to identify new susceptibility loci.

PurposeWe tested the hypotheses that CHEK2*1100delC heterozygosity is associated with increased risk of early death, breast cancer-specific death, and risk of a second breast cancer in women with a first breast cancer.Patients and methodsFrom 22 studies participating in the Breast Cancer Association Consortium, 25,571 white women with invasive breast cancer were genotyped for CHEK2*1100delC and observed for up to 20 years (median, 6.6 years). We examined risk of early death and breast cancer-specific death by estrogen receptor status and risk of a second breast cancer after a first breast cancer in prospective studies.ResultsCHEK2*1100delC heterozygosity was found in 459 patients (1.8%). In women with estrogen receptor-positive breast cancer, multifactorially adjusted hazard ratios for heterozygotes versus noncarriers were 1.43 (95% CI, 1.12 to 1.82; log-rank P = .004) for early death and 1.63 (95% CI, 1.24 to 2.15; log-rank P < .001) for breast cancer-specific death. In all women, hazard ratio for a second breast cancer was 2.77 (95% CI, 2.00 to 3.83; log-rank P < .001) increasing to 3.52 (95% CI, 2.35 to 5.27; log-rank P < .001) in women with estrogen receptor-positive first breast cancer only.ConclusionAmong women with estrogen receptor-positive breast cancer, CHEK2*1100delC heterozygosity was associated with a 1.4-fold risk of early death, a 1.6-fold risk of breast cancer-specific death, and a 3.5-fold risk of a second breast cancer. This is one of the few examples of a genetic factor that influences long-term prognosis being documented in an extensive series of women with breast cancer.

Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I(2) = 49.3%; p =

BackgroundUsing the Breast Cancer Association Consortium, the authors previously reported that the single nucleotide polymorphism 7q21-rs6964587 (AKAP9-M463I) is associated with breast cancer risk. The authors have now assessed this association more comprehensively using 16 independent case-control studies.MethodsThe authors genotyped 14,843 invasive case patients and 19,852 control subjects with white European ancestry and 2595 invasive case patients and 2192 control subjects with Asian ancestry. ORs were estimated by logistic regression, adjusted for study. Heterogeneity in ORs was assessed by fitting interaction terms or by subclassifying case patients and applying polytomous logistic regression.ResultsFor white European women, the minor T allele of 7q21-rs6964587 was associated with breast cancer risk under a recessive model (OR 1.07, 95% CI 1.00 to 1.13, p = 0.04). Results were inconclusive for Asian women. From a combined analysis of 24 154 case patients and 33,376 control subjects of white European ancestry from the present and previous series, the best-fitting model was recessive, with an estimated OR of 1.08 (95% CI 1.03 to 1.13, p = 0.001). The OR was greater at younger ages (p trend = 0.01).ConclusionThis may be the first common susceptibility allele for breast cancer to be identified with a recessive mode of inheritance.

BackgroundPrevious studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors.MethodsWe pooled tumor marker and epidemiological risk factor data from 35,568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case-case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case-control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided.ResultsIn case-case analyses, of the epidemiological risk factors examined, early age at menarche (≤12 years) was less frequent in case patients with PR(-) than PR(+) tumors (P = .001). Nulliparity (P = 3 × 10(-6)) and increasing age at first birth (P = 2 × 10(-9)) were less frequent in ER(-) than in ER(+) tumors. Obesity (body mass index [BMI] ≥ 30 kg/m(2)) in younger women (≤50 years) was more frequent in ER(-)/PR(-) than in ER(+)/PR(+) tumors (P = 1 × 10(-7)), whereas obesity in older women (>50 years) was less frequent in PR(-) than in PR(+) tumors (P = 6 × 10(-4)). The triple-negative (ER(-)/PR(-)/HER2(-)) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6(+) and/or epidermal growth factor receptor [EGFR](+)) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case-control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER(+) or PR(+) tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P = .61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P = .34; obesity in younger women, OR = 1.36, 95% CI = 0.95 to 1.94, P = .09) or CBP tumors.ConclusionsThis study shows that reproductive factors and BMI are most clearly associated with hormone receptor-positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology.

BackgroundTraditional prognostic factors for survival and treatment response of patients with breast cancer do not fully account for observed survival variation. We used available genotype data from a previously conducted two-stage, breast cancer susceptibility genome-wide association study (ie, Studies of Epidemiology and Risk factors in Cancer Heredity [SEARCH]) to investigate associations between variation in germline DNA and overall survival.MethodsWe evaluated possible associations between overall survival after a breast cancer diagnosis and 10 621 germline single-nucleotide polymorphisms (SNPs) from up to 3761 patients with invasive breast cancer (including 647 deaths and 26 978 person-years at risk) that were genotyped previously in the SEARCH study with high-density oligonucleotide microarrays (ie, hypothesis-generating set). Associations with all-cause mortality were assessed for each SNP by use of Cox regression analysis, generating a per rare allele hazard ratio (HR). To validate putative associations, we used patient genotype information that had been obtained with 5' nuclease assay or mass spectrometry and overall survival information for up to 14 096 patients with invasive breast cancer (including 2303 deaths and 70 019 person-years at risk) from 15 international case-control studies (ie, validation set). Fixed-effects meta-analysis was used to generate an overall effect estimate in the validation dataset and in combined SEARCH and validation datasets. All statistical tests were two-sided.ResultsIn the hypothesis-generating dataset, SNP rs4778137 (C>G) of the OCA2 gene at 15q13.1 was statistically significantly associated with overall survival among patients with estrogen receptor-negative tumors, with the rare G allele being associated with increased overall survival (HR of death per rare allele carried = 0.56, 95% confidence interval [CI] = 0.41 to 0.75, P = 9.2 x 10(-5)). This association was also observed in the validation dataset (HR of death per rare allele carried = 0.88, 95% CI = 0.78 to 0.99, P = .03) and in the combined dataset (HR of death per rare allele carried = 0.82, 95% CI = 0.73 to 0.92, P = 5 x 10(-4)).ConclusionThe rare G allele of the OCA2 polymorphism, rs4778137, may be associated with improved overall survival among patients with estrogen receptor-negative breast cancer.

BackgroundA recent genome-wide association study identified single-nucleotide polymorphism (SNP) 2q35-rs13387042 as a marker of susceptibility to estrogen receptor (ER)-positive breast cancer. We attempted to confirm this association using the Breast Cancer Association Consortium.Methods2q35-rs13387042 SNP was genotyped for 31 510 women with invasive breast cancer, 1101 women with ductal carcinoma in situ, and 35 969 female control subjects from 25 studies. Odds ratios (ORs) were estimated by logistic regression, adjusted for study. Heterogeneity in odds ratios by each of age, ethnicity, and study was assessed by fitting interaction terms. Heterogeneity by each of invasiveness, family history, bilaterality, and hormone receptor status was assessed by subclassifying case patients and applying polytomous logistic regression. All statistical tests were two-sided.ResultsWe found strong evidence of association between rs13387042 and breast cancer in white women of European origin (per-allele OR = 1.12, 95% confidence interval [CI] = 1.09 to 1.15; P(trend) = 1.0 x 10(-19)). The odds ratio was lower than that previously reported (P = .02) and did not vary by age or ethnicity (all P > or = .2). However, it was higher when the analysis was restricted to case patients who were selected for a strong family history (P = .02). An association was observed for both ER-positive (OR = 1.14, 95% CI = 1.10 to 1.17; P = 10(-15)) and ER-negative disease (OR = 1.10, 95% CI = 1.04 to 1.15; P = .0003) and both progesterone receptor (PR)-positive (OR = 1.15, 95% CI = 1.11 to 1.19; P = 5 x 10(-14)) and PR-negative disease (OR = 1.10, 95% CI = 1.06 to 1.15; P = .00002).ConclusionThe rs13387042 is associated with both ER-positive and ER-negative breast cancer in European women.

We have conducted a three-stage, comprehensive single nucleotide polymorphism (SNP)-tagging association study of ESR1 gene variants (SNPs) in more than 55,000 breast cancer cases and controls from studies within the Breast Cancer Association Consortium (BCAC). No large risks or highly significant associations were revealed. SNP rs3020314, tagging a region of ESR1 intron 4, is associated with an increase in breast cancer susceptibility with a dominant mode of action in European populations. Carriers of the c-allele have an odds ratio (OR) of 1.05 [95% Confidence Intervals (CI) 1.02-1.09] relative to t-allele homozygotes, P = 0.004. There is significant heterogeneity between studies, P = 0.002. The increased risk appears largely confined to oestrogen receptor-positive tumour risk. The region tagged by SNP rs3020314 contains sequence that is more highly conserved across mammalian species than the rest of intron 4, and it may subtly alter the ratio of two mRNA splice forms.

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. [Display omitted] • We report the joint effect of four xenoestrogens on breast cancer risk. • Weighted quantile sum regression and g-computation show significant mixture effects. • A similar suggestive trend is observed with the Bayesian kernel machine regression. • Benzo [a]pyrene, cadmium and Polychlorinated biphenyl (153) dominate the effect. • Our study greatly improves the understanding of joint effects of air pollutants. [ABSTRACT FROM AUTHOR]

Molecular studies suggest that cadmium due to its estrogenic properties, might play a role in breast cancer (BC) progression. However epidemiological evidence is limited. This study explored the association between long-term exposure to airborne cadmium and risk of BC by stage, grade of differentiation, and histological types at diagnosis. A nested case–control study of 4401 cases and 4401 matched controls was conducted within the French E3N cohort. A Geographic Information System (GIS)-based metric demonstrated to reliably characterize long-term environmental exposures was employed to evaluate airborne exposure to cadmium. Multivariable adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression models. There was no relationship between cadmium exposure and stage of BC. Also, no association between cadmium exposure and grade of differentiation of BC was observed. However, further analyses by histological type suggested a positive association between cadmium and risk of invasive tubular carcinoma (ITC) BC [ORQ5 vs Q1 = 3.4 (95% CI 1.1–10.7)]. The restricted cubic spline assessment suggested a dose–response relationship between cadmium and ITC BC subtype. Our results do not support the hypothesis that airborne cadmium exposure may play a role in advanced BC risk, but suggest that cadmium may be associated with an increased risk of ITC. [ABSTRACT FROM AUTHOR]

Résumé: En France, comme au niveau mondial, l'incidence du cancer du sein a doublé en 30 ans. Outre le vieillissement de la population et les progrès du dépistage, les facteurs environnementaux à effet perturbateur endocrinien ont été suggérés pour expliquer cette augmentation. Parmi eux, on retrouve les dioxines, produites lors de la combustion de produits chlorés. L'objectif du projet GEO3N était d'étudier l'association entre l'exposition environnementale (alimentaire et atmosphérique) aux dioxines et le risque de cancer du sein dans la cohorte E3N (98 995 femmes adhérentes de la Mutuelle générale de l'Éducation nationale [MGEN], suivies depuis 1990). Aucune association statistiquement significative n'a été mise en évidence entre exposition alimentaire aux dioxines et risque de cancer du sein dans la cohorte E3N (n = 63 830 dont 3 465 cas de cancer du sein ; risque relatif [RR] = 0,94 ; intervalle de confiance à 95 % IC [IC 95 %] = 0,86-1,04 pour les plus exposées versus les moins exposées). Les expositions atmosphériques ont été estimées grâce à un indicateur spatialisé créé pour les besoins de l'étude. Il prend en compte : 1) les émissions de 2 620 sources industrielles identifiées et localisées sur le territoire français entre 1990 et 2008 ; 2) l'histoire résidentielle des sujets de la cohorte E3N (dont 78 % sont localisés à l'adresse) ; 3) des paramètres météorologiques ; 4) des paramètres techniques des sources. Cet outil a permis d'étudier l'exposition atmosphérique de 4 529 cas de cancer du sein et 4 529 témoins appariés. L'étude sur la région Rhône-Alpes (429 cas et 716 témoins appariés) n'a pas montré d'association statistiquement significative entre l'augmentation de l'exposition atmosphérique aux dioxines et le risque de cancer du sein. Les résultats de l'étude nationale (4 529 cas et 4 529 témoins appariés) sont en cours d'analyse. Les hypothèses fortes ainsi que les résultats d'études précédentes encouragent tout de même à étudier de manière plus large l'effet de la pollution atmosphérique sur le risque de cancer du sein. In France, breast cancer is the leading cause of death in women. Its incidence has doubled over the last 30 years. In addition to an aging population and more widespread breast cancer screening, the hypothesis of environmental factors with endocrine-disrupting properties has been suggested to explain the rise in breast cancer incidence. These factors include dioxins, which are released during combustion processes of chlorinated organic materials. The French E3N national cohort (98 995 women who have been followed up since 1990) offers the opportunity to study the impact of environmental exposure to dioxins on breast cancer risk while taking the residential history of its members and their individual breast cancer risk factors into account. The objective of the GEO3N project was to study the association between environmental exposure to dietary and airborne dioxins and breast cancer risk. We assessed the association between estimated dietary dioxin exposure and breast cancer risk in 63 830 women from the E3N cohort (including 3 465 women with breast cancer). No statistically significant association was observed. The dioxin-emitting industrial sources in mainland France between 1990 and 2008 were identified (N=2620). The residential history of the E3N participants was geocoded, and 78% were located at the address level. A spatialized indicator for airborne dioxin exposure was developed by using a Geographic Information System (GIS) that took into account major dioxin dispersion parameters. Breast cancer risk associated with airborne dioxin exposure was estimated in 4529 case women with breast cancer matched to 4529 control women without it. In the Rhône-Alpes region (429 breast cancer cases matched to 716 controls), no statistically significant association was observed between airborne dioxin exposure and breast cancer risk. Analyses are still ongoing at the national level. Strong biological hypothesis and results from previous studies support the utility of further investigation into the effect of pollution exposure on breast cancer risk. [ABSTRACT FROM AUTHOR]

Endocrine‐disrupting chemicals are proposed to increase breast cancer (BC) incidence. Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), two perfluorinated alkylated substances (PFASs), are suspected to be ubiquitously present in the blood of human population worldwide. We investigated the associations between serum concentrations of these substances and BC risk. Etude Epidémiologique auprès de femmes de l'Education Nationale is a cohort of 98,995 French women born in 1925–1950 and followed up since 1990. We sampled 194 BC cases and 194 controls from women with available blood samples. Serum concentrations of PFASs were measured by liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS). Adjusted conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). All statistical tests were two sided. While PFASs concentrations were not associated with BC risk overall, we found positively linear associations between PFOS concentrations and the risk of ER+ (3rd quartile: OR = 2.22 [CI = 1.05–4.69]; 4th quartile: OR = 2.33 [CI = 1.11–4.90]); Ptrend = 0.04) and PR+ tumors (3rd quartile: OR = 2.47 [CI = 1.07–5.65]; 4th quartile: OR = 2.76 [CI = 1.21–6.30]; Ptrend = 0.02). When considering receptor‐negative tumors, only the 2nd quartile of PFOS was associated with risk (ER−: OR = 15.40 [CI = 1.84–129.19]; PR−: OR = 3.47 [CI = 1.29–9.15]). While there was no association between PFOA and receptor‐positive BC risk, the 2nd quartile of PFOA was positively associated with the risk of receptor‐negative tumors (ER−: OR = 7.73 [CI = 1.46–41.08]; PR−: OR = 3.44 [CI = 1.30–9.10]). PFAS circulating levels were differentially associated with BC risk. While PFOS concentration was linearly associated with receptor‐positive tumors, only low concentrations of PFOS and PFOA were associated with receptor‐negative tumors. Our findings highlight the importance of considering exposure to PFASs as a potential risk factor for BC. What's new? Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are two environmental endocrine‐disrupting chemicals suspected to be ubiquitously present in the blood of the human population. This nested case‐control study including non‐occupationally exposed postmenopausal French women suggests a linear dose‐response relationship between PFOS serum concentrations and the risk of developing hormone receptor‐positive breast cancer. Furthermore, an increased risk of developing ER– and PR– tumors is associated to middle‐low serum concentrations of PFOA and PFOS. Exposure to endocrine‐disrupting chemicals should be considered as a potential risk factor for breast cancer, thus a serious public health issue. [ABSTRACT FROM AUTHOR]

Cadmium, due to its estrogen‐like activity, has been suspected to increase the risk of breast cancer; however, epidemiological studies have reported inconsistent findings. We conducted a case–control study (4,059 cases and 4,059 matched controls) nested within the E3N French cohort study to estimate the risk of breast cancer associated with long‐term exposure to airborne cadmium pollution, and its effect according to molecular subtype of breast cancer (estrogen receptor negative/positive [ER−/ER+] and progesterone receptor negative/positive [PR−/PR+]). Atmospheric exposure to cadmium was assessed using a Geographic Information System‐based metric, which included subject's residence‐to‐cadmium source distance, wind direction, exposure duration and stack height. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. Overall, there was no significant association between cumulative dose of airborne cadmium exposure and the risk of overall, premenopausal and postmenopausal breast cancer. However, by ER and PR status, inverse associations were observed for ER− (ORQ5 vs. Q1 = 0.63; 95% CI: 0.41–0.95, ptrend = 0.043) and for ER−/PR− breast tumors (ORQ4 vs. Q1 = 0.62; 95% CI: 0.40–0.95, ORQ5 vs. Q1 = 0.68; 95% CI: 0.42–1.07, ptrend = 0.088). Our study provides no evidence of an association between exposure to cadmium and risk of breast cancer overall but suggests that cadmium might be related to a decreased risk of ER− and ER−/PR− breast tumors. These observations and other possible effects linked to hormone receptor status warrant further investigations. What's new? Cadmium is a common environmental contaminant that exerts estrogen‐like activity in human cells. While this activity suggests that cadmium might influence breast cancer risk, the relationship between cadmium exposure and breast cancer remains unclear. In this study, the authors employed a Geographic Information System (GIS)‐based metric to assess atmospheric cadmium exposure in women in France. No significant association was found between airborne cadmium and overall breast cancer risk. Risk varied, however, according to menopausal status and tumor hormone receptor status. Significant inverse associations were indicated for estrogen receptor‐negative breast cancers. Additional research is needed to assess cadmium exposure‐associated cancer risks. [ABSTRACT FROM AUTHOR]

Age‐ and body mass index (BMI)‐adjusted mammographic density is one of the strongest breast cancer risk factors. DNA methylation is a molecular mechanism that could underlie inter‐individual variation in mammographic density. We aimed to investigate the association between breast cancer risk‐predicting mammographic density measures and blood DNA methylation. For 436 women from the Australian Mammographic Density Twins and Sisters Study and 591 women from the Melbourne Collaborative Cohort Study, mammographic density (dense area, nondense area and percentage dense area) defined by the conventional brightness threshold was measured using the CUMULUS software, and peripheral blood DNA methylation was measured using the HumanMethylation450 (HM450) BeadChip assay. Associations between DNA methylation at >400,000 sites and mammographic density measures adjusted for age and BMI were assessed within each cohort and pooled using fixed‐effect meta‐analysis. Associations with methylation at genetic loci known to be associated with mammographic density were also examined. We found no genome‐wide significant (p < 10−7) association for any mammographic density measure from the meta‐analysis, or from the cohort‐specific analyses. None of the 299 methylation sites located at genetic loci associated with mammographic density was associated with any mammographic density measure after adjusting for multiple testing (all p > 0.05/299 = 1.7 × 10−4). In summary, our study did not find evidence for associations between blood DNA methylation, as measured by the HM450 assay, and conventional mammographic density measures that predict breast cancer risk. What's new? While breast density is a strong predictor of breast cancer risk, little is known about the molecular mechanisms that determine breast density and their influence on cancer risk. Here, in women aged 40 to 70 in two Australian study cohorts, including one twin cohort, genome‐wide association analysis was used to investigate relationships between DNA methylation and mammographic density measures that predict breast cancer. DNA methylation assessed from peripheral blood and conventional mammographic density measures were not significantly associated. Moreover, no associations were detected between breast density measures and DNA methylation at genetic loci known to be associated with mammographic density. [ABSTRACT FROM AUTHOR]

Background: Dioxins are environmental and persistent organic carcinogens with endocrine disrupting properties. A positive association with several cancers, including risk of breast cancer has been suggested.Objectives: This study aimed to develop and assess performances of an exposure metric based on a Geographic Information System (GIS) through comparison with a validated dispersion model to estimate historical industrial dioxin exposure for its use in a case-control study nested within a prospective cohort.Methods: Industrial dioxin sources were inventoried over the whole French territory (n > 2500) and annual average releases were estimated between 1990 and 2008. In three selected areas (rural, urban and urban-costal), dioxin dispersion was modelled using SIRANE, an urban Gaussian model and exposure of the French E3N cohort participants was estimated. The GIS-based metric was developed, calibrated and compared to SIRANE results using a set of parameters (local meteorological data, characteristics of industrial sources, e.g. emission intensity and stack height), by calculating weighted kappa statistics (wκ) and coefficient of determination (R2). Furthermore, as performance evaluation, the final GIS-based metric was tested to assess atmospheric exposure to cadmium.Results: The concordance between the GIS-based metric and the dispersion model for dioxin exposure estimate was strong (wκ median = 0.78 (1st quintile = 0.72, 3rd quintile =0.82) and R2 median = 0.82 (1st quintile = 0.71, 3rd quintile = 0.87)). We observed similar performance for cadmium.Conclusions: Our study demonstrated the ability of the GIS-based metric to reliably characterize long-term environmental dioxin and cadmium exposures as well as the pertinence of using dispersion modelling to construct and calibrate the GIS-based metric. [ABSTRACT FROM AUTHOR]

Many studies have demonstrated that lifestyle factors, including diet, may influence cancer survival. The number of cancer survivors is increasing worldwide and little is known about long‐term diet changes in people who had cancer. We studied 53,981 women from the prospective E3N‐EPIC cohort study with available dietary data in 1993 and 2005, among whom 4,619 had a cancer diagnosis inbetween (including n = 2,699 breast cancers). We evaluated the potential impact of a cancer diagnosis (comparing women with cancer to women with no cancer) on changes in FV consumption using multivariable linear regression models considering cancer site, stage at diagnosis and socioeconomic factors. Compared to women with no cancer, a statistically significant increase in FV consumption (β=+2.65%, [1.22–4.09]) was observed in women who had cancer, and this association appeared to be driven by breast cancer exclusively. The increase in FV consumption was larger in women who had an advanced stage of breast cancer (stages II–IV) (β=+7.23%, [3.92–10.5]) than in women with stages 0–I (β=+2.03%, [−0.20 to 4.26]). Women with no partner and no children were those having the highest increase in FV consumption (β=+18.71%, [6.51–30.91]). These changes were only observed in specific SE groups. When considering adherence to guidelines, the proportion of women who consumed less than 7.5 portions a day in 1993 and more in 2005 was greater in women with advanced breast cancer. More research is now needed to understand how the inequities we observed impact the long‐term health after cancer. [ABSTRACT FROM AUTHOR]

Nitrogen dioxide (NO 2) is an important air pollutant due to its adverse effects on human health. Yet, current evidence on the association between NO 2 and the risk of breast cancer lacks consistency. In this study, we investigated the association between long-term exposure to NO 2 and breast cancer risk in the French E3N cohort study. Association of breast cancer risk with NO 2 exposure was assessed in a nested case-control study within the French E3N cohort including 5222 breast cancer cases identified over the 1990–2011 follow-up period and 5222 matched controls. Annual mean concentrations of NO 2 at participants' residential addresses for each year from recruitment 1990 through 2011, were estimated using a land use regression (LUR) model. Multivariable conditional logistic regression models were used to compute odds ratios (ORs) and their 95% confidence intervals (CIs). Additional analyses were performed using NO 2 concentrations estimated by CHIMERE, a chemistry transport model. Overall, the mean NO 2 exposure was associated with an increased risk of breast cancer. In all women, for each interquartile range (IQR) increase in NO 2 levels (LUR: 17.8 μg/m3), the OR of the model adjusted for confounders was 1.09 (95% CI: 1.01–1.18). The corresponding OR in the fully adjusted model (additionally adjusted for established breast cancer risk factors) was 1.07 (95% CI: 0.98–1.15). By menopausal status, results for postmenopausal women were comparable to those for all women, while no association was observed among premenopausal women. By hormone receptor status, the OR of estrogen receptor positive breast cancer = 1.07 (95% CI: 0.97–1.19) in the fully adjusted model. Additional analyses using the CHIMERE model showed slight differences in ORs estimates. The results of this study indicate an increased risk of breast cancer associated with long-term exposure to NO 2 air pollution. Observing comparable effects of NO 2 exposure estimated by two different models, reinforces these findings. [Display omitted] • NO 2 levels were estimated over a 22 years period, by two exposure assessment models. • Breast cancer risk was increased in association with exposure to NO 2 air pollution. • By menopausal status, the associations appear to be limited to postmenopausal women. • NO 2 air pollution was positively associated with risk of ER + breast cancer. • Consistent associations were observed for the two exposure assessment methods. [ABSTRACT FROM AUTHOR]

Background: Interest in the potential of DNA methylation in peripheral blood as a biomarker of cancer risk is increasing. We aimed to assess whether epigenome-wide DNA methylation measured in peripheral blood samples obtained before onset of the disease is associated with increased risk of breast cancer. We report on three independent prospective nested case-control studies from the European Prospective Investigation into Cancer and Nutrition (EPIC-Italy; n = 162 matched case-control pairs), the Norwegian Women and Cancer study (NOWAC; n = 168 matched pairs), and the Breakthrough Generations Study (BGS; n = 548 matched pairs). We used the Illumina 450k array to measure methylation in the EPIC and NOWAC cohorts. Whole-genome bisulphite sequencing (WGBS) was performed on the BGS cohort using pooled DNA samples, combined to reach 50x coverage across ~16 million CpG sites in the genome including 450k array CpG sites. Mean β values over all probes were calculated as a measurement for epigenome-wide methylation. Results: In EPIC, we found that high epigenome-wide methylation was associated with lower risk of breast cancer (odds ratio (OR) per 1 SD = 0.61, 95 % confidence interval (CI) 0.47-0.80; -0.2 % average difference in epigenome-wide methylation for cases and controls). Specifically, this was observed in gene bodies (OR = 0.51, 95 % CI 0.38-0.69) but not in gene promoters (OR = 0.92, 95 % CI 0.64-1.32). The association was not replicated in NOWAC (OR = 1.03 95 % CI 0.81-1.30). The reasons for heterogeneity across studies are unclear. However, data from the BGS cohort was consistent with epigenome-wide hypomethylation in breast cancer cases across the overlapping 450k probe sites (difference in average epigenome-wide methylation in case and control DNA pools = -0.2 %). Conclusions: We conclude that epigenome-wide hypomethylation of DNA from pre-diagnostic blood samples may be predictive of breast cancer risk and may thus be useful as a clinical biomarker. [ABSTRACT FROM AUTHOR]

Approximately 15–30% of all breast cancer tumors are estrogen receptor negative (ER−). Compared with ER-positive (ER+) disease they have an earlier age at onset and worse prognosis. Despite the vast number of risk variants identified for numerous cancer types, only seven loci have been unambiguously identified for ER-negative breast cancer. With the aim of identifying new susceptibility SNPs for this disease we performed a pleiotropic genome-wide association study (GWAS). We selected 3079 SNPs associated with a human complex trait or disease at genome-wide significance level (P<5×10−8) to perform a secondary analysis of an ER-negative GWAS from the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3), including 1998 cases and 2305 controls from prospective studies. We then tested the top ten associations (i.e. with the lowest P-values) using three additional populations with a total sample size of 3509 ER+ cases, 2543 ER− cases and 7031 healthy controls. None of the 3079 selected variants in the BPC3 ER-GWAS were significant at the adjusted threshold. 186 variants were associated with ER− breast cancer risk at a conventional threshold of P<0.05, with P-values ranging from 0.049 to 2.3×10−4. None of the variants reached statistical significance in the replication phase. In conclusion, this study did not identify any novel susceptibility loci for ER-breast cancer using a “pleiotropic approach”. [ABSTRACT FROM AUTHOR]

Women using menopausal hormone therapy (MHT) are at increased risk of developing breast cancer (BC). To detect genetic modifiers of the association between current use of MHT and BC risk, we conducted a meta-analysis of four genome-wide case-only studies followed by replication in 11 caseÂ-control studies. We used a case-only design to assess interactions between single-nucleotide polymorphisms (SNPs) and current MHT use on risk of overall and lobular BC. The discovery stage included 2920 cases (541 lobular) from four genome-wide association studies. The top 1391 SNPs showing P values for interaction (Pint) !3.0!10K3 were selected for replication using pooled caseÂ-control data from 11 studies of the Breast Cancer Association Consortium, including 7689 cases (676 lobular) and 9266 controls. Fixed-effects meta-analysis was used to derive combined Pint. No SNP reached genome-wide significance in either the discovery or combined stage. We observed effect modification of current MHT use on overall BC risk by two SNPs on chr13 near POMP (combined Pint%8.9!10K6), two SNPs in SLC25A21 (combined Pint%4.8!10K5), and three SNPs in PLCG2 (combined Pint%4.5!10K5). The association between lobular BC risk was potentially modified by one SNP in TMEFF2 (combined Pint%2.7!10K5), one SNP in CD80 (combined Pint%8.2!10K6), three SNPs on chr17 near TMEM132E (combined Pint%2.2! 10K6), and two SNPs on chr18 near SLC25A52 (combined Pint%4.6!10K5). In conclusion, polymorphisms in genes related to solute transportation in mitochondria, transmembrane signaling, and immune cell activation are potentially modifying BC risk associated with current use of MHT. These findings warrant replication in independent studies. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. METHODS: Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). RESULTS: We found no association with risk of ovarian cancer (OR=0.99, 95% CI 0.94-1.04, p=0.74) or breast cancer (OR=0.98, 95% CI 0.94-1.01, p=0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR=1.09, 95% CI 0.97-1.23, p=0.14, breast cancer HR=1.04, 95% CI 0.97-1.12, p=0.27; BRCA2, ovarian cancer HR=0.89, 95% CI 0.71-1.13, p=0.34, breast cancer HR=1.06, 95% CI 0.94-1.19, p=0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR=0.94, 95% CI 0.83-1.07, p=0.38), breast cancer (HR=0.96, 95% CI 0.87-1.06, p=0.38), and all other previously-reported associations. CONCLUSIONS: rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers., Other Research Unit

Approximately 15–30% of all breast cancer tumors are estrogen receptor negative (ER−). Compared with ER-positive (ER+) disease they have an earlier age at onset and worse prognosis. Despite the vast number of risk variants identified for numerous cancer types, only seven loci have been unambiguously identified for ER-negative breast cancer. With the aim of identifying new susceptibility SNPs for this disease we performed a pleiotropic genome-wide association study (GWAS). We selected 3079 SNPs associated with a human complex trait or disease at genome-wide significance level (P<5×10−8) to perform a secondary analysis of an ER-negative GWAS from the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3), including 1998 cases and 2305 controls from prospective studies. We then tested the top ten associations (i.e. with the lowest P-values) using three additional populations with a total sample size of 3509 ER+ cases, 2543 ER− cases and 7031 healthy controls. None of the 3079 selected variants in the BPC3 ER-GWAS were significant at the adjusted threshold. 186 variants were associated with ER− breast cancer risk at a conventional threshold of P<0.05, with P-values ranging from 0.049 to 2.3×10−4. None of the variants reached statistical significance in the replication phase. In conclusion, this study did not identify any novel susceptibility loci for ER-breast cancer using a “pleiotropic approach”.

Background: Environmental and genetic factors play an important role in the etiology of breast cancer. Several small blood-based DNA methylation studies have reported risk associations with methylation at individual CpGs and average methylation levels; however, these findings require validation in larger prospective cohort studies. To investigate the role of blood DNA methylation on breast cancer risk, we conducted a meta-analysis of four prospective cohort studies, including a total of 1663 incident cases and 1885 controls, the largest study of blood DNA methylation and breast cancer risk to date.Methods: We assessed associations with methylation at 365,145 CpGs present in the HumanMethylation450 (HM450K) Beadchip, after excluding CpGs that did not pass quality controls in all studies. Each of the four cohorts estimated odds ratios (ORs) and 95% confidence intervals (CI) for the association between each individual CpG and breast cancer risk. In addition, each study assessed the association between average methylation measures and breast cancer risk, adjusted and unadjusted for cell-type composition. Study-specific ORs were combined using fixed-effect meta-analysis with inverse variance weights. Stratified analyses were conducted by age at diagnosis (< 50, ≥ 50), estrogen receptor (ER) status (+/-), and time since blood collection (< 5, 5-10, > 10 years). The false discovery rate (q value) was used to account for multiple testing.Results: The average age at blood draw ranged from 52.2 to 62.2 years across the four cohorts. Median follow-up time ranged from 6.6 to 8.4 years. The methylation measured at individual CpGs was not associated with breast cancer risk (q value > 0.59). In addition, higher average methylation level was not associated with risk of breast cancer (OR = 0.94, 95% CI = 0.85, 1.05; P = 0.26; P for study heterogeneity = 0.86). We found no evidence of modification of this association by age at diagnosis (P = 0.17), ER status (P = 0.88), time since blood collection (P = 0.98), or CpG location (P = 0.98).Conclusions: Our data indicate that DNA methylation measured in the blood prior to breast cancer diagnosis in predominantly postmenopausal women is unlikely to be associated with substantial breast cancer risk on the HM450K array. Larger studies or with greater methylation coverage are needed to determine if associations exist between blood DNA methylation and breast cancer risk. [ABSTRACT FROM AUTHOR]

The article discusses a study which examined the association between the rs12975333 variant in the miR-125a and breast cancer risk using case control series from Germany Australia, Spain, and Italy. The study showed that rs12975333, together with many other variants located in miRNAs, has been investigated as a possible contributor to genetic susceptibility to various diseases. Further, it revealed that rs12975333 is extremely rare in breast cancer cases and controls from the said countries.