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Background: Plausible biological reasons exist regarding why smoking could affect breast cancer risk, but epidemiological evidence is inconsistent.Methods: We used serial questionnaire information from the Generations Study cohort (United Kingdom) to estimate HRs for breast cancer in relation to smoking adjusted for potentially confounding factors, including alcohol intake.Results: Among 102,927 women recruited 2003-2013, with an average of 7.7 years of follow-up, 1815 developed invasive breast cancer. The HR (reference group was never smokers) was 1.14 (95% CI 1.03-1.25; P = 0.010) for ever smokers, 1.24 (95% CI 1.08-1.43; P = 0.002) for starting smoking at ages < 17 years, and 1.23 (1.07-1.41; P = 0.004) for starting smoking 1-4 years after menarche. Breast cancer risk was not statistically associated with interval from initiation of smoking to first birth (P-trend = 0.97). Women with a family history of breast cancer (ever smoker vs never smoker HR 1.35; 95% CI 1.12-1.62; P = 0.002) had a significantly larger HR in relation to ever smokers (P for interaction = 0.039) than women without (ever smoker vs never smoker HR 1.07; 95% CI 0.96-1.20; P = 0.22). The interaction was prominent for age at starting smoking (P = 0.003) and starting smoking relative to age at menarche (P = 0.0001).Conclusions: Smoking was associated with a modest but significantly increased risk of breast cancer, particularly among women who started smoking at adolescent or peri-menarcheal ages. The relative risk of breast cancer associated with smoking was greater for women with a family history of the disease. [ABSTRACT FROM AUTHOR]

Background: An earlier age at onset of breast development and longer time between pubertal stages has been implicated in breast cancer risk. It is not clear whether associations of breast cancer risk with puberty or predictors of onset of puberty, such as weight and height, are mediated via mammographic density, an important risk factor for breast cancer.Methods: We investigated whether childhood body size and pubertal timing and tempo, collected by questionnaire, are associated with percentage and absolute area mammographic density at ages 47-73 years in 1105 women recruited to a prospective study.Results: After controlling for adult adiposity, weight at ages 7 and 11 years was strongly significantly inversely associated with percentage and absolute dense area (p trend <0.001), and positively associated with absolute non-dense area. Greater height at age 7, but not age 11, was associated with lower percentage density (p trend = 0.016). Later age at menarche and age at when regular periods were established was associated with increased density, but additional adjustment for childhood weight attenuated the association. A longer interval between thelarche and menarche, and between thelarche and regular periods, was associated with increased dense area, even after adjusting for childhood weight (p trend = 0.013 and 0.028, respectively), and was independent of age at pubertal onset.Conclusions: Greater prepubertal weight and earlier pubertal onset are associated with lower adult breast density, but age at pubertal onset does not appear to have an independent effect on adult density after controlling for childhood adiposity. A possible effect of pubertal tempo on density needs further investigation. [ABSTRACT FROM AUTHOR]

Background: Women diagnosed with breast cancer frequently attribute their cancer to psychological stress, but scientific evidence is inconclusive. We investigated whether experienced frequency of stress and adverse life events affect subsequent breast cancer risk.Methods: Breast cancer incidence was analysed with respect to stress variables collected at enrolment in a prospective cohort study of 106,000 women in the United Kingdom, with 1783 incident breast cancer cases. Relative risks (RR) were obtained as hazard ratios using Cox proportional hazards models.Results: There was no association of breast cancer risk overall with experienced frequency of stress. Risk was reduced for death of a close relative during the 5 years preceding study entry (RR = 0.87, 95 % confidence interval (CI): 0.78-0.97), but not for death of a spouse/partner or close friend, personal illness/injury, or divorce/separation. There was a positive association of divorce with oestrogen-receptor-negative (RR = 1.54, 95 % CI: 1.01-2.34), but not with oestrogen-receptor-positive breast cancer. Risk was raised in women who were under age 20 at the death of their mother (RR = 1.31, 95 % CI: 1.02-1.67), but not of their father, and the effect was attenuated after excluding mothers with breast or ovarian cancer (RR = 1.17, 95 % CI: 0.85-1.61).Conclusions: This large prospective study did not show consistent evidence for an association of breast cancer risk with perceived stress levels or adverse life events in the preceding 5 years, or loss of parents during childhood and adolescence. [ABSTRACT FROM AUTHOR]

Background: Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer. It is often associated with invasive ductal carcinoma (IDC), and is considered to be a non-obligate precursor of IDC. It is not clear to what extent these two forms of cancer share low-risk susceptibility loci, or whether there are differences in the strength of association for shared loci.Methods: To identify genetic polymorphisms that predispose to DCIS, we pooled data from 38 studies comprising 5,067 cases of DCIS, 24,584 cases of IDC and 37,467 controls, all genotyped using the iCOGS chip.Results: Most (67 %) of the 76 known breast cancer predisposition loci showed an association with DCIS in the same direction as previously reported for invasive breast cancer. Case-only analysis showed no evidence for differences between associations for IDC and DCIS after considering multiple testing. Analysis by estrogen receptor (ER) status confirmed that loci associated with ER positive IDC were also associated with ER positive DCIS. Analysis of DCIS by grade suggested that two independent SNPs at 11q13.3 near CCND1 were specific to low/intermediate grade DCIS (rs75915166, rs554219). These associations with grade remained after adjusting for ER status and were also found in IDC. We found no novel DCIS-specific loci at a genome wide significance level of P < 5.0x10(-8).Conclusion: In conclusion, this study provides the strongest evidence to date of a shared genetic susceptibility for IDC and DCIS. Studies with larger numbers of DCIS are needed to determine if IDC or DCIS specific loci exist. [ABSTRACT FROM AUTHOR]

Introduction We 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. Methods We 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. Results We 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 (Ptrend = 0.02). There was no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche in controls (Ptrend = 0.005) but not cases (Ptrend = 0.97). Consequently the association between rs10235235 and breast cancer risk differed according to age at menarche (Phet = 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 (ORhet = 0.84, 95% CI 0.75, 0.94; ORhom = 0.81, 95% CI 0.51, 1.30; Ptrend = 0.002) but not for those who had their menarche age ⩽11 years (ORhet = 1.06, 95% CI 0.95, 1.19, ORhom = 1.07, 95% CI 0.67, 1.72; Ptrend = 0.29). Conclusions To 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. [ABSTRACT FROM AUTHOR]

Background: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. Method We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Results: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06–1.12; P = 3 × 10-9), rs805510 (OR = 1.08, 95 % CI = 1.04–1.12, P = 2 × 10-5), and rs1871152 (OR = 1.04, 95 % CI = 1.02–1.06; P = 2 × 10-4) identified in the general populations, and rs113824616 (P = 7 × 10-5) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. Conclusion: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk. Electronic supplementary material The online version of this article (doi:10.1186/s13058-016-0718-0) contains supplementary material, which is available to authorized users.