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Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study.

ABSTRACT: INTRODUCTION:Several common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in the Breast Cancer Association Consortium. METHODS:We evaluated two-way interactions between each of age at menarche, ever having had a live birth, number of live births, age at first birth and body mass index (BMI) and each of 12 single nucleotide polymorphisms (SNPs) (10q26-rs2981582 (FGFR2), 8q24-rs13281615, 11p15-rs3817198 (LSP1), 5q11-rs889312 (MAP3K1), 16q12-rs3803662 (TOX3), 2q35-rs13387042, 5p12-rs10941679 (MRPS30), 17q23-rs6504950 (COX11), 3p24-rs4973768 (SLC4A7), CASP8-rs17468277, TGFB1-rs1982073 and ESR1-rs3020314). Interactions were tested for by fitting logistic regression models including per-allele and linear trend main effects for SNPs and risk factors, respectively, and single-parameter interaction terms for linear departure from independent multiplicative effects. RESULTS:These analyses were applied to data for up to 26,349 invasive breast cancer cases and up to 32,208 controls from 21 case-control studies. No statistical evidence of interaction was observed beyond that expected by chance. Analyses were repeated using data from 11 population-based studies, and results were very similar. CONCLUSIONS:The relative risks for breast cancer associated with the common susceptibility variants identified to date do not appear to vary across women with different reproductive histories or body mass index (BMI). The assumption of multiplicative combined effects for these established genetic and other risk factors in risk prediction models appears justified.

SUBMITTER: Milne RL

PROVIDER: S-EPMC3046455 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study.

Milne Roger L RL Gaudet Mia M MM Spurdle Amanda B AB Fasching Peter A PA Couch Fergus J FJ Benítez Javier J Arias Pérez José Ignacio JI Zamora M Pilar MP Malats Núria N Dos Santos Silva Isabel I Gibson Lorna J LJ Fletcher Olivia O Johnson Nichola N Anton-Culver Hoda H Ziogas Argyrios A Figueroa Jonine J Brinton Louise L Sherman Mark E ME Lissowska Jolanta J Hopper John L JL Dite Gillian S GS Apicella Carmel C Southey Melissa C MC Sigurdson Alice J AJ Linet Martha S MS Schonfeld Sara J SJ Freedman D Michal DM Mannermaa Arto A Kosma Veli-Matti VM Kataja Vesa V Auvinen Päivi P Andrulis Irene L IL Glendon Gord G Knight Julia A JA Weerasooriya Nayana N Cox Angela A Reed Malcolm Wr MW Cross Simon S SS Dunning Alison M AM Ahmed Shahana S Shah Mitul M Brauch Hiltrud H Ko Yon-Dschun YD Brüning Thomas T Lambrechts Diether D Reumers Joke J Smeets Ann A Wang-Gohrke Shan S Hall Per P Czene Kamila K Liu Jianjun J Irwanto Astrid K AK Chenevix-Trench Georgia G Holland Helene H Giles Graham G GG Baglietto Laura L Severi Gianluca G Bojensen Stig E SE Nordestgaard Børge G BG Flyger Henrik H John Esther M EM West Dee W DW Whittemore Alice S AS Vachon Celine C Olson Janet E JE Fredericksen Zachary Z Kosel Matthew M Hein Rebecca R Vrieling Alina A Flesch-Janys Dieter D Heinz Judith J Beckmann Matthias W MW Heusinger Katharina K Ekici Arif B AB Haeberle Lothar L Humphreys Manjeet K MK Morrison Jonathan J Easton Doug F DF Pharoah Paul D PD García-Closas Montserrat M Goode Ellen L EL Chang-Claude Jenny J

Breast cancer research : BCR 20101231 6

<h4>Introduction</h4>Several common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in the Breast Cancer Association Consortium.<h4>Methods</h4>We evaluated two-way interactions between each of age at menarche, ever having had a live birth, number of live births, age at ...[more]

PMID: 21194473

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Project description:Importance:First-degree family history is a strong risk factor for breast cancer, but controversy exists about the magnitude of the association among older women. Objective:To determine whether first-degree family history is associated with increased risk of breast cancer among older women, and identify whether the association varies by breast density. Design, Setting, and Participants:Prospective cohort study between 1996 and 2012 from 7 Breast Cancer Surveillance Consortium (BCSC) registries located in New Hampshire, North Carolina, San Francisco Bay area, western Washington state, New Mexico, Colorado, and Vermont. During a mean (SD) follow-up of 6.3 (3.2) years, 10?929 invasive breast cancers were diagnosed in a cohort of 403?268 women 65 years and older with data from 472?220 mammography examinations. We estimated the 5-year cumulative incidence of invasive breast cancer by first-degree family history, breast density, and age groups. Cox proportional hazards models were fit to estimate the association of first-degree family history with risk of invasive breast cancer (after adjustment for breast density, BCSC registry, race/ethnicity, body mass index, postmenopausal hormone therapy use, and benign breast disease for age groups 65 to 74 years and 75 years and older, separately). Data analyses were performed between June 2016 and June 2017. Exposure:First-degree family history of breast cancer. Main Outcomes and Measures:Incident breast cancer. Results:In 403 268 women 65 years and older, first-degree family history was associated with an increased risk of breast cancer among women ages 65 to 74 years (hazard ratio [HR],?1.48; 95% CI, 1.35-1.61) and 75 years and older (HR, 1.44; 95% CI, 1.28-1.62). Estimates were similar for women 65 to 74 years with first-degree relative's diagnosis age younger than 50 years (HR, 1.47; 95% CI, 1.25-1.73) vs 50 years and older (HR, 1.33; 95% CI, 1.17-1.51) and for women ages 75 years and older with the relative's diagnosis age younger than 50 years (HR, 1.31; 95% CI, 1.05-1.63) vs 50 years and older (HR, 1.55; 95% CI, 1.33-1.81). Among women ages 65 to 74 years, the risk associated with first-degree family history was highest among those with fatty breasts (HR, 1.67; 95% CI, 1.27-2.21), whereas in women 75 years and older the risk associated with family history was highest among those with dense breasts (HR, 1.55; 95% CI, 1.29-1.87). Conclusions and Relevance:First-degree family history was associated with increased risk of invasive breast cancer in all subgroups of older women irrespective of a relative's age at diagnosis.

Project description:BackgroundWe investigated the associations of reproductive factors with the percentage of epithelium, stroma, and fat tissue in benign breast biopsy samples.MethodsThis study included 983 cancer-free women with biopsy-confirmed benign breast disease (BBD) within the Nurses' Health Study and Nurses' Health Study II cohorts. The percentage of each tissue type (epithelium, stroma, and fat) was measured on whole-section images with a deep-learning technique. All tissue measures were log-transformed in all the analyses to improve normality. The data on reproductive variables and other breast cancer risk factors were obtained from biennial questionnaires. Generalized linear regression was used to examine the associations of reproductive factors with the percentage of tissue types, while adjusting for known breast cancer risk factors.ResultsAs compared to parous women, nulliparous women had a smaller percentage of epithelium (β = - 0.26, 95% confidence interval [CI] - 0.41, - 0.11) and fat (β = - 0.34, 95% CI - 0.54, - 0.13) and a greater percentage of stroma (β = 0.04, 95% CI 0.01, 0.08). Among parous women, the number of children was inversely associated with the percentage of stroma (β per child = - 0.01, 95% CI - 0.02, - 0.00). The duration of breastfeeding of ≥ 24 months was associated with a reduced proportion of fat (β = - 0.30, 95% CI - 0.54, - 0.06; p-trend = 0.04). In a separate analysis restricted to premenopausal women, older age at first birth was associated with a greater proportion of epithelium and a smaller proportion of stroma.ConclusionsOur findings suggest that being nulliparous as well as having a fewer number of children (both positively associated with breast cancer risk) is associated with a smaller proportion of epithelium and a greater proportion of stroma, potentially suggesting the importance of epithelial-stromal interactions. Future studies are warranted to confirm our findings and to elucidate the underlying biological mechanisms.

Project description:Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 × 10(-6)], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 × 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 × 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 × 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 × 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.

Project description:BackgroundMany epidemiologic studies have analyzed the relations of individual foods and nutrients and breast cancer risk with inconsistent results. Few studies have examined recommendation-based dietary indices and breast cancer risk.ObjectiveThe aim of this study was to determine associations between recommendation-based dietary index scores and incident invasive breast cancer.MethodsThe Sister Study is a prospective cohort of 50,884 US women (baseline: 2003-2009) who had a sister with breast cancer but no prior breast cancer themselves. We created scores for the Dietary Approaches to Stop Hypertension (DASH) diet, Alternative Mediterranean Diet (AMED), and Alternative Healthy Eating Index-2010 (AHEI-2010) from dietary intakes estimated by a baseline-validated Block food-frequency questionnaire (FFQ). We used Cox regression to estimate multivariable-adjusted HRs and 95% CIs for total invasive breast cancer risk and by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status.ResultsWe documented 1,700 invasive breast cancer cases through 2015 (mean follow-up, 7.6 y). Individuals in the highest quartile of DASH scores had a lower risk of invasive breast cancer compared with those in the lowest quartile (HR: 0.78; 95% CI: 0.67, 0.90; P-trend = 0.001), with stronger associations for ER- (HR: 0.61; 95% CI: 0.40, 0.94; P-trend = 0.006) as well as ER-/PR- and ER-/PR-/HER2- subtypes. AHEI-2010 (HR for highest compared with lowest quartile: 0.90; 95% CI: 0.78, 1.03; P-trend = 0.15) and AMED (HR for highest compared with lowest quartile: 0.90; 95% CI: 0.77, 1.06; P-trend = 0.07) were weakly and nonsignificantly associated with breast cancer risk, but after excluding alcohol, AHEI-2010 was inversely associated with risk of ER-/PR- (HR: 0.64; 95% CI: 0.42, 0.98; P-trend = 0.04) and ER-/PR-/HER2- subtypes. We did not observe any significant interactions by menopausal status or other participant characteristics.ConclusionsDASH scores were inversely associated with breast cancer risk; DASH and AHEI-2010 scores excluding alcohol were particularly inversely associated with risk of ER-/PR- and ER-/PR-/HER2- breast cancers. This trial was registered at clinicaltrials.gov as NCT00047970.

Project description: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.

Dataset Information

Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study.

Publications

Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study.

Similar Datasets

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