| 1. |
- Shu, Xiang, et al.
(författare)
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Associations of obesity and circulating insulin and glucose with breast cancer risk : a Mendelian randomization analysis
- 2019
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Ingår i: International Journal of Epidemiology. - : OXFORD UNIV PRESS. - 0300-5771 .- 1464-3685. ; 48:3, s. 795-806
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Tidskriftsartikel (refereegranskat)abstract
- Background: 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. Methods: 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 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium. Results: 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 x 10(-4)], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p = 4.02 x 10(-4)), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p = 5.05 x 10(-19)) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p = 9.22 x 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 2h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer. Conclusions: 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.
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| 2. |
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| 3. |
- Dixon-Suen, Suzanne C, et al.
(författare)
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Physical activity, sedentary time and breast cancer risk : a Mendelian randomisation study
- 2022
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Ingår i: British Journal of Sports Medicine. - : BMJ Publishing Group Ltd. - 0306-3674 .- 1473-0480. ; 56:20, s. 1157-1170
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics.METHODS: We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity.RESULTS: Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger).CONCLUSION: Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women.
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| 4. |
- Kapoor, Pooja Middha, et al.
(författare)
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Combined associations of a polygenic risk score and classical risk factors with breast cancer risk
- 2021
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 113:3, s. 329-337
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Tidskriftsartikel (refereegranskat)abstract
- We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.
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| 5. |
- Middha, Pooja K., et al.
(författare)
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A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry
- 2023
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Ingår i: Breast Cancer Research. - : BioMed Central (BMC). - 1465-5411 .- 1465-542X. ; 25:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Genome-wide studies of gene-environment interactions (GxE) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide GxE analysis of similar to 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer. Methods Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene-environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs. Results Assuming a 1 x 10(-5) prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability < 15%, we identified two independent SNP-risk factor pairs: rs80018847(9p13)-LINGO2 and adult height in association with overall breast cancer risk (ORint = 0.94, 95% CI 0.92-0.96), and rs4770552(13q12)-SPATA13 and age at menarche for ER + breast cancer risk (ORint = 0.91, 95% CI 0.88-0.94). Conclusions Overall, the contribution of GxE interactions to the heritability of breast cancer is very small. At the population level, multiplicative GxE interactions do not make an important contribution to risk prediction in breast cancer.
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| 6. |
- Mueller, Stefanie H., et al.
(författare)
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Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry
- 2023
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Ingår i: Genome Medicine. - : BioMed Central (BMC). - 1756-994X. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Background: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes.Methods: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry.Results: In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 x 10(-6)) and AC058822.1 (P = 1.47 x 10(-4)), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C.Conclusions: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 x 10(-5)), demonstrating the importance of diversifying study cohorts.
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| 7. |
- Clendenen, Tess V., et al.
(författare)
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Breast Cancer Risk Factors and Circulating Anti-Müllerian Hormone Concentration in Healthy Premenopausal Women
- 2021
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : Oxford University Press. - 0021-972X .- 1945-7197. ; 106:11, s. E4542-E4553
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Tidskriftsartikel (refereegranskat)abstract
- Context: We previously reported that anti-Müllerian hormone (AMH), a marker of ovarian reserve, is positively associated with breast cancer risk, consistent with other studies.Objective: This study assessed whether risk factors for breast cancer are correlates of AMH concentration.Methods: This cross-sectional study included 3831 healthy premenopausal women (aged 21-57, 87% aged 35-49) from 10 cohort studies among the general population.Results: Adjusting for age and cohort, AMH positively associated with age at menarche (P < 0.0001) and parity (P = 0.0008) and inversely associated with hysterectomy/partial oophorectomy (P = 0.0008). Compared with women of normal weight, AMH was lower (relative geometric mean difference 27%, P < 0.0001) among women who were obese. Current oral contraceptive (OC) use and current/former smoking were associated with lower AMH concentration than never use (40% and 12% lower, respectively, P < 0.0001). We observed higher AMH concentrations among women who had had a benign breast biopsy (15% higher, P = 0.03), a surrogate for benign breast disease, an association that has not been reported. In analyses stratified by age (<40 vs ≥40), associations of AMH with body mass index and OCs were similar in younger and older women, while associations with the other factors (menarche, parity, hysterectomy/partial oophorectomy, smoking, and benign breast biopsy) were limited to women ≥40 (P-interaction < 0.05).Conclusion: This is the largest study of AMH and breast cancer risk factors among women from the general population (not presenting with infertility), and it suggests that most associations are limited to women over 40, who are approaching menopause and whose AMH concentration is declining.
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| 8. |
- Clendenen, Tess V., et al.
(författare)
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Breast cancer risk prediction in women aged 35-50 years : impact of including sex hormone concentrations in the Gail model
- 2019
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Ingår i: Breast Cancer Research. - : BioMed Central. - 1465-5411 .- 1465-542X. ; 21
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Tidskriftsartikel (refereegranskat)abstract
- Background: Models that accurately predict risk of breast cancer are needed to help younger women make decisions about when to begin screening. Premenopausal concentrations of circulating anti-Mullerian hormone (AMH), a biomarker of ovarian reserve, and testosterone have been positively associated with breast cancer risk in prospective studies. We assessed whether adding AMH and/or testosterone to the Gail model improves its prediction performance for women aged 35-50.Methods: In a nested case-control study including ten prospective cohorts (1762 invasive cases/1890 matched controls) with pre-diagnostic serum/plasma samples, we estimated relative risks (RR) for the biomarkers and Gail risk factors using conditional logistic regression and random-effects meta-analysis. Absolute risk models were developed using these RR estimates, attributable risk fractions calculated using the distributions of the risk factors in the cases from the consortium, and population-based incidence and mortality rates. The area under the receiver operating characteristic curve (AUC) was used to compare the discriminatory accuracy of the models with and without biomarkers.Results: The AUC for invasive breast cancer including only the Gail risk factor variables was 55.3 (95% CI 53.4, 57.1). The AUC increased moderately with the addition of AMH (AUC 57.6, 95% CI 55.7, 59.5), testosterone (AUC 56.2, 95% CI 54.4, 58.1), or both (AUC 58.1, 95% CI 56.2, 59.9). The largest AUC improvement (4.0) was among women without a family history of breast cancer.Conclusions: AMH and testosterone moderately increase the discriminatory accuracy of the Gail model among women aged 35-50. We observed the largest AUC increase for women without a family history of breast cancer, the group that would benefit most from improved risk prediction because early screening is already recommended for women with a family history.
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| 9. |
- Ge, Wenzhen, et al.
(författare)
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Circulating anti-Müllerian hormone and breast cancer risk : a study in ten prospective cohorts
- 2018
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Ingår i: International Journal of Cancer. - Hoboken : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 142:11, s. 2215-2226
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Tidskriftsartikel (refereegranskat)abstract
- A strong positive association has been observed between circulating anti‐Müllerian hormone (AMH), a biomarker of ovarian reserve, and breast cancer risk in three prospective studies. Confirming this association is important because of the paucity of biomarkers of breast cancer risk in premenopausal women. We conducted a consortium study including ten prospective cohorts that had collected blood from premenopausal women. A nested case–control design was implemented within each cohort. A total of 2,835 invasive (80%) and in situ (20%) breast cancer cases were individually matched to controls (n = 3,122) on age at blood donation. AMH was measured using a high sensitivity enzyme‐linked immunoabsorbent assay. Conditional logistic regression was applied to the aggregated dataset. There was a statistically significant trend of increasing breast cancer risk with increasing AMH concentration (ptrend across quartiles <0.0001) after adjusting for breast cancer risk factors. The odds ratio (OR) for breast cancer in the top vs. bottom quartile of AMH was 1.60 (95% CI = 1.31–1.94). Though the test for interaction was not statistically significant (pinteraction = 0.15), the trend was statistically significant only for tumors positive for both estrogen receptor (ER) and progesterone receptor (PR): ER+/PR+: ORQ4–Q1 = 1.96, 95% CI = 1.46–2.64, ptrend <0.0001; ER+/PR−: ORQ4–Q1 = 0.82, 95% CI = 0.40–1.68, ptrend = 0.51; ER−/PR+: ORQ4–Q1 = 3.23, 95% CI = 0.48–21.9, ptrend = 0.26; ER−/PR−: ORQ4–Q1 = 1.15, 95% CI = 0.63–2.09, ptrend = 0.60. The association was observed for both pre‐ (ORQ4–Q1= 1.35, 95% CI = 1.05–1.73) and post‐menopausal (ORQ4–Q1 = 1.61, 95% CI = 1.03–2.53) breast cancer (pinteraction = 0.34). In this large consortium study, we confirmed that AMH is associated with breast cancer risk, with a 60% increase in risk for women in the top vs. bottom quartile of AMH.What's new? To make informed decisions about screening and prevention, women need tools to accurately assess their breast cancer risk. Young women have few predictive biomarkers to look to; estrogen and progesterone are only weakly predictive before menopause. Anti-Müllerian hormone (AMH), which strongly correlates with age at menopause, may also correlate with breast cancer risk, according to some previous data. Here, the authors test this correlation by conducting nested case-control studies within ten different cohorts. They found that breast cancer risk increased along with increasing AMH concentration, confirming this hormone as a possible biomarker for breast cancer.
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| 10. |
- Nichols, Hazel B, et al.
(författare)
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Breast Cancer Risk After Recent Childbirth : A Pooled Analysis of 15 Prospective Studies
- 2019
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Ingår i: Annals of Internal Medicine. - : American College of Physicians. - 0003-4819 .- 1539-3704. ; 170:1, s. 22-30
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Tidskriftsartikel (refereegranskat)abstract
- Background: Parity is widely recognized as protective for breast cancer, but breast cancer risk may be increased shortly after childbirth. Whether this risk varies with breastfeeding, family history of breast cancer, or specific tumor subtype has rarely been evaluated.Objective: To characterize breast cancer risk in relation to recent childbirth.Design: Pooled analysis of individual-level data from 15 prospective cohort studies.Setting: The international Premenopausal Breast Cancer Collaborative Group.Participants: Women younger than 55 years.Measurements: During 9.6 million person-years of follow-up, 18 826 incident cases of breast cancer were diagnosed. Hazard ratios (HRs) and 95% CIs for breast cancer were calculated using Cox proportional hazards regression.Results: Compared with nulliparous women, parous women had an HR for breast cancer that peaked about 5 years after birth (HR, 1.80 [95% CI, 1.63 to 1.99]) before decreasing to 0.77 (CI, 0.67 to 0.88) after 34 years. The association crossed over from positive to negative about 24 years after birth. The overall pattern was driven by estrogen receptor (ER)-positive breast cancer; no crossover was seen for ER-negative cancer. Increases in breast cancer risk after childbirth were pronounced when combined with a family history of breast cancer and were greater for women who were older at first birth or who had more births. Breastfeeding did not modify overall risk patterns.Limitations: Breast cancer diagnoses during pregnancy were not uniformly distinguishable from early postpartum diagnoses. Data on human epidermal growth factor receptor 2 (HER2) oncogene overexpression were limited.Conclusion: Compared with nulliparous women, parous women have an increased risk for breast cancer for more than 20 years after childbirth. Health care providers should consider recent childbirth a risk factor for breast cancer in young women.Primary Funding Source: The Avon Foundation, the National Institute of Environmental Health Sciences, Breast Cancer Now and the UK National Health Service, and the Institute of Cancer Research.
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