Person:

Eliassen, A

Empirical prediction models that weight food frequency questionnaire (FFQ) food items by their relation to nutrient biomarker concentrations may estimate nutrient exposure better than nutrient intakes derived from food composition databases. Carotenoids may especially benefit because contributing foods vary in bioavailability and assessment validity. Our objective was to develop empirical prediction models for the major plasma carotenoids and total carotenoids and evaluate their validity compared with dietary intakes calculated from standard food composition tables. 4180 nonsmoking women in the Nurses’ Health Study (NHS) blood subcohort with previously measured plasma carotenoids were randomly divided into training (n = 2787) and testing (n = 1393) subsets. Empirical prediction models were developed in the training subset by stepwise selection from foods contributing ≥0.5% to intake of the relevant carotenoid. Spearman correlations between predicted and measured plasma concentrations were compared to Spearman correlations between dietary intake and measured plasma concentrations for each carotenoid. Three to 12 foods were selected for the α-carotene, β-carotene, β-cryptoxanthin, lutein/zeaxanthin, lycopene, and total carotenoids prediction models. In the testing subset, Spearman correlations with measured plasma concentrations for the calculated dietary intakes and predicted plasma concentrations, respectively, were 0.31 and 0.37 for α-carotene, 0.29 and 0.31 for β-carotene, 0.36 and 0.41 for β-cryptoxanthin, 0.28 and 0.31 for lutein/zeaxanthin, 0.22 and 0.23 for lycopene, and 0.22 and 0.27 for total carotenoids. Empirical prediction models may modestly improve assessment of some carotenoids, particularly α-carotene and β-cryptoxanthin.

Objective: To investigate the association between dietary protein sources in early adulthood and risk of breast cancer. Design: Prospective cohort study. Setting: Health professionals in the United States. Participants: 88 803 premenopausal women from the Nurses’ Health Study II who completed a questionnaire on diet in 1991. Main outcome measure Incident cases of invasive breast carcinoma, identified through self report and confirmed by pathology report. Results: We documented 2830 cases of breast cancer during 20 years of follow-up. Higher intake of total red meat was associated with an increased risk of breast cancer overall (relative risk 1.22, 95% confidence interval 1.06 to 1.40; Ptrend=0.01, for highest fifth v lowest fifth of intake). However, higher intakes of poultry, fish, eggs, legumes, and nuts were not related to breast cancer overall. When the association was evaluated by menopausal status, higher intake of poultry was associated with a lower risk of breast cancer in postmenopausal women (0.73, 0.58 to 0.91; Ptrend=0.02, for highest fifth v lowest fifth of intake) but not in premenopausal women (0.93, 0.78 to 1.11; Ptrend=0.60, for highest fifth v lowest fifth of intake). In estimating the effects of exchanging different protein sources, substituting one serving/day of legumes for one serving/day of red meat was associated with a 15% lower risk of breast cancer among all women (0.85, 0.73 to 0.98) and a 19% lower risk among premenopausal women (0.81, 0.66 to 0.99). Also, substituting one serving/day of poultry for one serving/day of red meat was associated with a 17% lower risk of breast cancer overall (0.83, 0.72 to 0.96) and a 24% lower risk of postmenopausal breast cancer (0.76, 0.59 to 0.99). Furthermore, substituting one serving/day of combined legumes, nuts, poultry, and fish for one serving/day of red meat was associated with a 14% lower risk of breast cancer overall (0.86, 0.78 to 0.94) and premenopausal breast cancer (0.86, 0.76 to 0.98). Conclusion: Higher red meat intake in early adulthood may be a risk factor for breast cancer, and replacing red meat with a combination of legumes, poultry, nuts and fish may reduce the risk of breast cancer.

Introduction: Prior research supports an association between endogenous sex steroids and breast cancer among postmenopausal women; the association is less clear among premenopausal women. Methods: We evaluated the associations between estrogens, androgens, progesterone and sex hormone binding globulin (SHBG) and breast cancer in a nested case-control study in the Nurses' Health Study II. Between 1996 and 1999, 29,611 participants provided blood samples; 18,521 provided samples timed in early follicular and mid-luteal phases of the menstrual cycle. A total of 634 women, premenopausal at blood collection, developed breast cancer between 1999 and 2009 and were matched to 1,264 controls (514 cases and 1,030 controls with timed samples). We used conditional logistic regression controlling for breast cancer risk factors for overall analyses; unconditional logistic regression additionally controlling for matching factors was used for subgroup analyses. Results: In analyses of premenopausal estrogens including breast cancers diagnosed both before and after menopause, there was no association between follicular estradiol, estrone and free estradiol and risk of either total or invasive breast cancer. Luteal estradiol was positively associated with estrogen receptor positive (ER+)/progesterone receptor positive (PR+) cancers (5th vs. 1st quintile odds ratio (OR): 1.7 (95% confidence interval (CI): 1.0 to 2.9), Ptrend = 0.02). Luteal estrone, free estradiol and progesterone were not associated with risk. Androgens were suggestively or significantly associated with risk when the sample was restricted to invasive tumors (for example, testosterone: OR: 1.4 (1.0 to 2.0), Ptrend = 0.23) and ER+/PR+ disease (testosterone: OR: 1.7 (1.1 to 2.6) Ptrend = 0.10; dehydroepiandrosterone sulfate (DHEAS) OR: 1.3 (0.8 to 2.0) Ptrend = 0.05). SHBG was not associated with breast cancer risk. The results varied by menopausal status at diagnosis, with follicular estradiol suggestively positively associated with breast cancers in women premenopausal at diagnosis (OR: 1.1 (0.9 to 1.3) and significantly inversely associated with postmenopausal disease (OR: 0.6 (0.4 to 0.9); Pheterogeneity < 0.01). Conclusions: Androgens were associated with modestly increased risk of breast cancer in this population, with stronger associations for invasive and ER+/PR+ disease. Luteal phase estradiol levels were suggestively associated with ER+/PR+ tumors but no other strong associations were observed with estrogens. Associations with follicular phase estrogens may vary by menopausal status at diagnosis, but case numbers were limited. Additional studies to confirm the role of premenopausal hormones in the etiology of both premenopausal and postmenopausal breast cancer are needed.

Background: Primary prevention of cardiovascular disease (CVD) focuses on treatment of risk factors, including hypercholesterolemia, hypertension, and type 2 diabetes mellitus. We investigated whether a healthy diet in adolescence prevents development of clinical risk factors or incidence of CVD in adulthood. Methods and Results: We examined the time to the first development of ≥1 clinical risk factor (hypercholesterolemia, hypertension, or type 2 diabetes mellitus) or CVD in relation to a high school Alternative Healthy Eating Index (HS‐AHEI) within the Nurses’ Health Study II. Among those who completed a food frequency questionnaire about their high school diet and adult diet (mean age 42 years), 27 406 women free of clinical risk factors and 42 112 women free of CVD in 1998 were followed to June 2011. Hazard ratios (HRs) and 95% CIs were adjusted for potential confounders in high school and adulthood. We documented 11 542 first diagnoses of clinical risk factors and 423 CVD events. The HS‐AHEI was associated with a lower rate of risk factors (HR highest versus lowest quintiles 0.82; 95% CI, 0.77–0.87 [P trend <0.001]), was inversely associated with risk of developing ≥1 clinical risk factor in women with a low, medium, and high AHEI score during adulthood (HR high HS‐AHEI/high adult AHEI versus low/low 0.79 [95% CI, 0.74–0.85]), but was not statistically significantly associated with incident CVD. Conclusions: A healthy diet during adolescence is associated with lower risk of developing CVD risk factors. As diet tracks throughout life, and adult diet prevents CVD, healthy dietary habits that begin early are important for primordial prevention of CVD.

Obesity is well established as a cause of postmenopausal breast cancer incidence and mortality. In contrast, adiposity in early life reduces breast cancer incidence. However, whether short-term weight change influences breast cancer risk is not well known. We followed a cohort of 77,232 women from 1980 to 2006 (1,445,578 person-years), with routinely updated risk factor information, documenting 4196 incident cases of invasive breast cancer. ER and PR status were obtained from pathology reports and medical records yielding a total of 2033 ER+/PR+ tumors, 595 ER−/PR− tumors, 512 ER+/PR− tumors. The log incidence breast cancer model was used to assess the association of short-term weight gain (over past 4 years) while controlling for average BMI before and after menopause. Short-term weight change was significantly associated with breast cancer risk (RR 1.20; 95 % CI 1.09–1.33) for a 4-year weight gain of ≥15 lbs versus no change (≤5 lbs) (P_trend < 0.001). The association was stronger for premenopausal women (RR 1.38; 95 % CI 1.13–1.69) (P_trend = 0.004) than for postmenopausal women (RR 1.10; 95 % CI 0.97–1.25) (P_trend = 0.063). Short-term weight gain during premenopause had a stronger association for ER+/PR− (RR per 25 lb weight gain = 2.19; 95 % CI 1.33–3.61, P = 0.002) and ER−/PR− breast cancer (RR per 25 lb weight gain = 1.61; 95 % CI 1.09–2.38, P = 0.016) than for ER+/PR+ breast cancer (RR per 25 lb weight gain = 1.13; 95 % CI 0.89–1.43, P = 0.32). There are deleterious effects of short-term weight gain, particularly during pre-menopause, even after controlling for average BMI before and after menopause. The association was stronger for ER+/PR− and ER−/PR− than for ER+/PR+ breast cancer. Electronic supplementary material The online version of this article (doi:10.1007/s10549-015-3344-0) contains supplementary material, which is available to authorized users.

Healthy diets may lower oxidative stress and risk of chronic diseases. However, no previous studies examined associations between diet and fluorescent oxidation products (FlOP), a global marker of oxidative stress. We evaluated associations between healthy eating patterns (Alternative Healthy Eating Index (AHEI), Dietary Approach to Stop Hypertension (DASH), and Alternate Mediterranean Diet (aMED)) and FlOP, measured at three excitation/emission wavelengths (FlOP_360, FlOP_320, FlOP_400) from 2021 blood samples collected from 1688 women within the Nurses’ Health Study. AHEI, DASH, and aMED scores were significantly positively associated with FlOP_360 and FlOP_320 concentrations (p-trend ≤ 0.04), but not associated with FlOP_400. Among specific food groups that contribute to these diet scores, significantly positive associations were observed with legumes and vegetables for FlOP_360, vegetables and fruits for FlOP_320, and legumes and alcohol for FlOP_400. Inverse associations were observed with nuts, sweets or desserts, and olive oil for FlOP_360, nuts for FlOP_320 and sweets or desserts for FlOP_400 (all p-trend ≤ 0.05). However, FlOP variation due to diet was small compared to overall FlOP variation. In conclusion, AHEI, DASH, and aMED scores were unexpectedly positively, but weakly, associated with FlOP_360 and FlOP_320. However, these findings should be interpreted cautiously as the determinants of FlOP concentrations are not fully understood.

Studies have suggested that hormone receptor and Ki67 expression in normal breast tissue are associated with subsequent breast cancer risk. We examined the associations of breast cancer risk factors with estrogen receptor (ER), progesterone receptor (PR), insulin-like growth factor-1 receptor (IGF-1R), and Ki67 expression in normal breast tissue. This analysis included 388 women with benign breast disease (ages 17–67 years) in the Nurses’ Health Studies. Immunohistochemical staining was performed on tissue microarrays constructed from benign biopsies containing normal breast epithelium and scored as the percentage of epithelial cells that were positively stained. Ordinal logistic regression (outcomes in tertiles), adjusting for age and potential confounders, was performed to estimate odds ratios (OR) and 95% confidence intervals (CI) for the associations with risk factors. Alcohol consumption was positively associated (≥2.5 vs.<0.4 drink/wk: OR = 2.69, 95% CI = 1.26–5.75, p-trend = 0.008) and breastfeeding was inversely associated (≥6 months vs. never: OR = 0.11, 95% CI = 0.04–0.35, p-trend = 0.0003) with ER expression. Height (≥66 vs.<64 inches: OR = 2.50, 95% CI = 1.34–4.67, p-trend = 0.005) and BMI at age 18 (≥22 vs.<20 kg/m2: OR = 2.33, 95% CI = 1.18–4.62, p-trend = 0.01) were positively associated with PR expression. Body size at age 5–10 years was inversely associated with Ki67 (Level ≥ 2.5 vs. 1: OR = 0.55, 95% CI = 0.30–1.01, p-trend = 0.03). Premenopausal BMI (≥25 vs.<20 kg/m2) was positively associated with cytoplasmic IGF-1R (OR = 5.06, 95% CI = 1.17–21.8, p-trend = 0.04). Our data suggest that anthropometrics, breastfeeding, and alcohol intake may influence the molecular characteristics of normal breast tissue, elucidating the mechanisms by which these risk factors operate. However, larger studies are required to confirm these results.

Breast cancer risk is influenced by rare coding variants in susceptibility genes such as BRCA1 and many common, mainly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. We report results from a genome-wide association study (GWAS) of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry1. We identified 65 new loci associated with overall breast cancer at p<5x10-8. The majority of credible risk SNPs in the new loci fall in distal regulatory elements, and by integrating in-silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all SNPs in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the utility of genetic risk scores for individualized screening and prevention.

Breast cancer risk is influenced by rare coding variants in susceptibility genes such as BRCA1 and many common, mainly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. We report results from a genome-wide association study (GWAS) of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry1. We identified 65 new loci associated with overall breast cancer at p<5x10-8. The majority of credible risk SNPs in the new loci fall in distal regulatory elements, and by integrating in-silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all SNPs in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the utility of genetic risk scores for individualized screening and prevention.

Breast cancer risk variants identified in genome-wide association studies explain only a small fraction of familial relative risk, and genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82×10−6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony forming efficiency. Our study provides new insights into breast cancer genetics and biology.