Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants (CCVs) in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium, and enriched genomic features to determine variants with high posterior probabilities (HPPs) of being causal.Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of potentially causal variants, using gene expression (eQTL), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways, were over-represented among the 178 highest confidence target genes.
BackgroundGenome-wide average DNA methylation (GWAM) and epigenetic age acceleration have been suggested to predict breast cancer risk. We aimed to investigate the relationships between these putative risk-predicting measures and environmental breast cancer risk factors. MethodsUsing the Illumina HumanMethylation450K assay methylation data, we calculated GWAM and epigenetic age acceleration for 132 female twin pairs and their 215 sisters. Linear regression was used to estimate associations between these risk-predicting measures and multiple breast cancer risk factors.Within-pair analysis was performed for the 132 twin pairs. ResultsGWAM was negatively associated with number of live births, and positively with age at first live birth (both P<0.05). Epigenetic age acceleration was positively associated with body mass index (BMI), smoking, alcohol drinking and age at menarche, and negatively with age at first live birth (all P<0.05), and the associations with BMI, alcohol drinking and age at first live birth remained in the within-pair analysis. ConclusionsThis exploratory study shows that lifestyle and hormone-related breast cancer risk factors are associated with DNA methylation-based measures that could predict breast cancer risk. The associations of epigenetic age acceleration with BMI, alcohol drinking and age at first live birth are unlikely to be due to familial confounding.
Background: Benign breast disease (BBD) is one of the strongest risk factors for breast cancer but it is unclear whether the strength of the association with BBD and breast cancers varies by breast cancer family history. Few studies of BBD enrich specifically for putative genetic factors by over-sampling based on family history let alone evaluate potential interactions with measures of underlying familial risk. The aim of this study was to evaluate how risk associated with BBD is modified by underlying familial risk so as to guide clinical management and risk assessment of women with BBD. Methods: Using a prospective family study cohort of 17,154 women unaffected with breast cancer at baseline and followed by questionnaire at regular intervals, we examined the association between BBD and breast cancer risk using Cox Proportional Hazards models. We classified women as having BBD if they reported at baseline having been told by a doctor that they had BBD, such as a non-cancerous cyst or breast lump. We did not have information on histologic sub-type. We confirmed self-reported diagnosis of BBD with pathology reports in a subset of the New York cohort and found high agreement between self-reported and pathologically confirmed BBD (93.5%). We assessed multiplicative and additive interactions with underlying familial risk profile (FRP) defined as either fixed-time horizon of 1-year, or total lifetime risk, estimated from the Breast Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) model. Results: During 176,756 person-years of follow-up (mean 10.2, maximum 23.7 years), we observed 968 incident breast cancers cases with an average age at diagnosis of 55.8 years and average age at enrollment into the cohort of 46.8 years. At baseline, 4,704 (27%) women reported having a previous diagnosis of BBD. Compared to women with no history of BBD, breast cancer risk was increased in women of all ages (HR: 1.37, 95% CI: 1.19,1.56), and in women up to age 45 years (using attained age models) (HR: 1.40, 95% CI: 1.01,1.93). In terms of recency of BBD, we found that the increased risk associated with BBD remained 21 years or more after the initial BBD diagnosis (HR: 1.37, 95% CI: 1.11, 1.68). We found no evidence for multiplicative interactions with FRP, which implies that the increase in absolute risk associated with BBD depends on a woman's FRP (Table 1). Conclusions: Women with a history of BBD have an increased risk of breast cancer that multiplies their underlying familial risk (FRP). These results could prove to be valuable for risk counseling and clinical management. Table 1: Cumulative Incidence of Breast Cancer to age 45, 55, and 65 by BBD and underlying FRP as measured by 10-year BOADICEA score.AgeNo BBD, <3.4 %BBD, <3.4%No BBD, ≥3.4%BBD, ≥3.4%454.6 (3.8, 5.6)6.1(4.7, 8.0)12.1 (10.2, 14.5)16.1 (13.1, 19.7)557.4 (6.3, 8.7)9.8 (7.5, 12.8)19.1 (16.6, 22.0)25.0 (21.7, 28.9)659.7 (8.2, 11.5)12.8 (9.9, 16.5)24.5 (21.8, 27.6)31.8 (28.3, 35.7) Citation Format: Zeinomar N, Phillips KA, Liao Y, MacInnis RJ, Dite GS, Daly MB, John EM, Andrulis IL, Buys SS, Hopper JL, Terry MB. Benign breast disease and breast cancer risk across the spectrum of familial risk using a prospective family study cohort (ProF-SC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-09-04.
This abstract was withdrawn by the authors. Citation Format: Kehm RD, Phillips K-A, Daly MB, Andrulis IL, Liao Y, Ma X, Zeinomar N, MacInnis RJ, Dite GS, John EM, Buys SS, Milne RL, Hopper JL, Terry MB. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD6-05.
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