Although there is some evidence suggesting that olive oil could reduce breast cancer (BC) risk, the epidemiological data are still relatively limited, not entirely consistent and mainly based on ...case–control studies. Therefore, we prospectively assessed the association between olive oil and BC risk in postmenopausal women from the Mediterranean cohorts within the European Prospective Investigation into Cancer and Nutrition. The analysis included 62,284 postmenopausal women recruited from Spain, Italy and Greece who had complete dietary data (collected from validated country‐specific dietary questionnaires). The risk of BC (overall and by hormone receptor subtypes) was assessed using hazards ratios (HRs) obtained from Cox proportional hazards regression, while adjusting for known BC risk factors. After a mean follow‐up of 9 years, 1,256 women were diagnosed with a primary incident invasive BC. The multivariate HRs for BC risk by olive oil intake (highest vs. lowest tertile of g/day/2,000 kcal) were 1.07 (95% CI = 0.91–1.25) in the adjusted model, 1.06 (95% CI = 0.91–1.24) in the model additionally adjusted for reproductive‐related factors and 1.10 (95% CI = 0.92–1.31) for the model additionally adjusted for dietary factors. There was no association between olive oil and risk of estrogen or progesterone receptor‐positive tumors, but a suggestion of a negative association with estrogens and progesterone receptor‐negative tumors. The results from our prospective study showed that olive oil consumption during adult life was not associated with the risk of BC. However, larger prospective studies are still needed to explore possible differences related to hormone receptor status.
Fetuin-A, a hepatic-origin protein, is strongly positively associated with risk of type 2 diabetes in human observational studies, but it is unknown whether this association is causal. We aimed to ...study the potential causal relation of circulating fetuin-A to risk of type 2 diabetes in a Mendelian randomization study with single nucleotide polymorphisms located in the fetuin-A-encoding
gene. We used data from eight European countries of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study including 10,020 incident cases. Plasma fetuin-A concentration was measured in a subset of 965 subcohort participants and 654 case subjects. A genetic score of the
single nucleotide polymorphisms was strongly associated with fetuin-A (28% explained variation). Using the genetic score as instrumental variable of fetuin-A, we observed no significant association of a 50 µg/mL higher fetuin-A concentration with diabetes risk (hazard ratio 1.02 95% CI 0.97, 1.07). Combining our results with those from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium (12,171 case subjects) also did not suggest a clear significant relation of fetuin-A with diabetes risk. In conclusion, although there is mechanistic evidence for an effect of fetuin-A on insulin sensitivity and secretion, this study does not support a strong, relevant relationship between circulating fetuin-A and diabetes risk in the general population.
The associations of individual dietary fatty acids with prostate cancer risk have not been examined comprehensively. We examined the prospective association of individual dietary fatty acids with ...prostate cancer risk overall, by tumor subtypes, and prostate cancer death. 142,239 men from the European Prospective Investigation into Cancer and Nutrition who were free from cancer at recruitment were included. Dietary intakes of individual fatty acids were estimated using center‐specific validated dietary questionnaires at baseline and calibrated with 24‐h recalls. Multivariable Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). After an average follow‐up of 13.9 years, 7,036 prostate cancer cases and 936 prostate cancer deaths were ascertained. Intakes of individual fatty acids were not related to overall prostate cancer risk. There was evidence of heterogeneity in the association of some short chain saturated fatty acids with prostate cancer risk by tumor stage (pheterogeneity < 0.015), with a positive association with risk of advanced stage disease for butyric acid (4:0; HR1SD = 1.08; 95%CI = 1.01–1.15; p‐trend = 0.026). There were no associations with fatal prostate cancer, with the exception of a slightly higher risk for those who consumed more eicosenoic acid (22:1n‐9c; HR1SD = 1.05; 1.00–1.11; p‐trend = 0.048) and eicosapentaenoic acid (20:5n‐3c; HR1SD = 1.07; 1.00–1.14; p‐trend = 0.045). There was no evidence that dietary intakes of individual fatty acids were associated with overall prostate cancer risk. However, a higher intake of butyric acid might be associated with a higher risk of advanced, whereas intakes of eicosenoic and eicosapentaenoic acids might be positively associated with fatal prostate cancer risk.
What's new?
Are individual dietary fatty acids associated with prostate cancer development and progression? In this large, prospective study, the authors found that for prostate cancer overall, the answer is no. However, a higher intake of butyric acid may be associated with an increased risk of advanced‐stage prostate cancer, and higher intakes of eicosenoic and eicosapentaenoic acids may be positively associated with risk of lethal prostate cancer.
Overexpression of the receptor for advanced glycation end-product (RAGE) has been associated with chronic inflammation, which in turn has been associated with increased colorectal cancer risk. ...Soluble RAGE (sRAGE) competes with RAGE to bind its ligands, thus potentially preventing RAGE-induced inflammation.
To investigate whether sRAGE and related genetic variants are associated with colorectal cancer risk, we conducted a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC). Plasma sRAGE concentrations were measured by ELISA in 1,361 colorectal cancer matched case-control sets. Twenty-four SNPs encoded in the genes associated with sRAGE concentrations were available for 1,985 colorectal cancer cases and 2,220 controls. Multivariable adjusted ORs and 95% confidence intervals (CIs) were computed using conditional and unconditional logistic regression for colorectal cancer risk and circulating sRAGE and SNPs, respectively.
Higher sRAGE concentrations were inversely associated with colorectal cancer (OR
, 0.77; 95% CI, 0.59-1.00). Sex-specific analyses revealed that the observed inverse risk association was restricted to men (OR
, 0.63; 95% CI, 0.42-0.94), whereas no association was observed in women (OR
, 1.00; 95% CI, 0.68-1.48;
for sex = 0.006). Participants carrying minor allele of rs653765 (promoter region of
) had lower colorectal cancer risk (C vs. T, OR, 0.90; 95% CI, 0.82-0.99).
Prediagnostic sRAGE concentrations were inversely associated with colorectal cancer risk in men, but not in women. An SNP located within
gene, pertaining to RAGE shedding, was associated with colorectal cancer risk.
Further studies are needed to confirm our observed sex difference in the association and better explore the potential involvement of genetic variants of sRAGE in colorectal cancer development.
Anthocyanidins are bioactive flavonoids with potential health-promoting effects. These may vary among single anthocyanidins considering differences in their bioavailability and some of the mechanisms ...involved. The aim of the present study was to estimate the dietary intake of anthocyanidins, their food sources and the lifestyle factors (sex, age, BMI, smoking status, educational level and physisical activity) involved among twenty-seven centres in ten European countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Anthocyanidin intake and their food sources for 36 037 subjects, aged between 35 and 74 years, in twenty-seven redefined centres were obtained using standardised 24 h dietary recall software (EPIC-SOFT). An ad hoc food composition database on anthocyanidins (cyanidin, delphinidin, malvidin, pelargonidin, peonidin, petunidin) was compiled using data from the US Department of Agriculture and Phenol-Explorer databases and was expanded by adding recipes, estimated values and cooking factors. For men, the total anthocyanidin mean intake ranged from 19·83 (se 1·53) mg/d (Bilthoven, The Netherlands) to 64·88 (se 1·86) mg/d (Turin, Italy), whereas for women the range was 18·73 (se 2·80) mg/d (Granada, Spain) to 44·08 (se 2·45) mg/d (Turin, Italy). A clear south to north gradient intake was observed. Cyanidins and malvidins were the main anthocynidin contributors depending on the region and sex. Anthocyanidin intake was higher in non-obese older females, non-smokers, and increased with educational level and physical activity. The major food sources were fruits, wine, non-alcoholic beverages and some vegetables. The present study shows differences in both total and individual anthocyanidin intakes and various lifestyle factors throughout Europe, with some geographical variability in their food sources.
Circulating hormone concentrations are associated with breast cancer risk, with well-established associations for postmenopausal women. Biomarkers may represent minimally invasive measures to improve ...risk prediction models.
We evaluated improvements in discrimination gained by adding serum biomarker concentrations to risk estimates derived from risk prediction models developed by Gail and colleagues and Pfeiffer and colleagues using a nested case-control study within the EPIC cohort, including 1,217 breast cancer cases and 1,976 matched controls. Participants were pre- or postmenopausal at blood collection. Circulating sex steroids, prolactin, insulin-like growth factor (IGF) I, IGF-binding protein 3, and sex hormone-binding globulin (SHBG) were evaluated using backward elimination separately in women pre- and postmenopausal at blood collection. Improvement in discrimination was evaluated as the change in concordance statistic (C-statistic) from a modified Gail or Pfeiffer risk score alone versus models, including the biomarkers and risk score. Internal validation with bootstrapping (1,000-fold) was used to adjust for overfitting.
Among women postmenopausal at blood collection, estradiol, testosterone, and SHBG were selected into the prediction models. For breast cancer overall, model discrimination after including biomarkers was 5.3 percentage points higher than the modified Gail model alone, and 3.4 percentage points higher than the Pfeiffer model alone, after accounting for overfitting. Discrimination was more markedly improved for estrogen receptor-positive disease (percentage point change in C-statistic: 7.2, Gail; 4.8, Pfeiffer). We observed no improvement in discrimination among women premenopausal at blood collection.
Integration of hormone measurements in clinical risk prediction models may represent a strategy to improve breast cancer risk stratification.
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General obesity, as reflected by BMI, is an established risk factor for esophageal adenocarcinoma (EAC), a suspected risk factor for gastric cardia adenocarcinoma (GCC) and appears unrelated to ...gastric non‐cardia adenocarcinoma (GNCC). How abdominal obesity, as commonly measured by waist circumference (WC), relates to these cancers remains largely unexplored. Using measured anthropometric data from 391,456 individuals from the European Prospective Investigation into Cancer and Nutrition (EPIC) study and 11 years of follow‐up, we comprehensively assessed the association of anthropometric measures with risk of EAC, GCC and GNCC using multivariable proportional hazards regression. One hundred twenty‐four incident EAC, 193 GCC and 224 GNCC were accrued. After mutual adjustment, BMI was unrelated to EAC, while WC showed a strong positive association (highest vs. lowest quintile HR = 1.19; 95% CI, 0.63–2.22 and HR = 3.76; 1.72–8.22, respectively). Hip circumference (HC) was inversely related to EAC after controlling for WC, while WC remained positively associated (HR = 0.35; 0.18–0.68, and HR=4.10; 1.94‐8.63, respectively). BMI was not associated with GCC or GNCC. WC was related to higher risks of GCC after adjustment for BMI and more strongly after adjustment for HC (highest vs. lowest quintile HR = 1.91; 1.09–3.37, and HR = 2.23; 1.28–3.90, respectively). Our study demonstrates that abdominal, rather than general, obesity is an indisputable risk factor for EAC and also provides evidence for a protective effect of gluteofemoral (subcutaneous) adipose tissue in EAC. Our study further shows that general obesity is not a risk factor for GCC and GNCC, while the role of abdominal obesity in GCC needs further investigation.
What's new?
While mainly general obesity, as measured by body mass index, has been investigated in relation to gastric and esophageal cancer, the effect of a large waist on these cancer sites is unknown. In this article, the authors report results of extensive analysis of measured anthropometry, including measures of general (BMI) and abdominal obesity (waist circumference), collected by the European Prospective Investigation into Cancer and Nutrition (EPIC). They show that general obesity is not a risk factor for esophageal and gastric cancer, while waist circumference strongly increases risk of esophageal cancer and may potentially be related to gastric cardia cancer.
A number of biomarkers of inflammatory and metabolic pathways are individually related to higher risk of colorectal cancer (CRC); however, the association between biomarker patterns and CRC incidence ...has not been previously evaluated. Our study investigates the association of biomarker patterns with CRC in a prospective nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC). During median follow-up time of 7.0 (3.7-9.4) years, 1,260 incident CRC cases occurred and were matched to 1,260 controls using risk-set sampling. Pre-diagnostic measurements of C-peptide, glycated hemoglobin, triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), C-reactive protein (CRP), reactive oxygen metabolites (ROM), insulin-like growth factor 1, adiponectin, leptin and soluble leptin receptor (sOB-R) were used to derive biomarker patterns from principal component analysis (PCA). The relation with CRC incidence was assessed using conditional logistic regression models. We identified four biomarker patterns 'HDL-C/Adiponectin fractions', 'ROM/CRP', 'TG/C-peptide' and 'leptin/sOB-R' to explain 60 % of the overall biomarker variance. In multivariable-adjusted logistic regression, the 'HDL-C/Adiponectin fractions', 'ROM/CRP' and 'leptin/sOB-R' patterns were associated with CRC risk for the highest quartile vs the lowest, incidence rate ratio (IRR) = 0.69, 95 % CI 0.51-0.93, P-trend = 0.01; IRR = 1.70, 95 % CI 1.30-2.23, P-trend = 0.002; and IRR = 0.79, 95 % CI 0.58-1.07; P-trend = 0.05, respectively. In contrast, the 'TG/C-peptide' pattern was not associated with CRC risk (IRR = 0.75, 95 % CI 0.56-1.00, P-trend = 0.24). After cases within the first 2 follow-up years were excluded, the 'ROM/CRP' pattern was no longer associated with CRC risk, suggesting potential influence of preclinical disease on these associations. By application of PCA, the study identified 'HDL-C/Adiponectin fractions', 'ROM/CRP' and 'leptin/sOB-R' as biomarker patterns representing potentially important pathways for CRC development.
Cancer of unknown primary site (CUP) may be called an “orphan” disease, as it is diagnosed when metastases are detected while the primary tumor typically remains undetected, and because little ...research has been done on its primary causes. So far, few epidemiological studies, if any, have addressed possible risk factors for CUP. We analyzed data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (N = 476,940). During prospective follow‐up, a total of 651 cases of incident cases of CUP were detected (ICD‐O‐2 code C809). Proportional hazards models were conducted to examine the associations of lifetime history of smoking habits, alcohol consumption, levels of education and anthropometric indices of adiposity with risk of being diagnosed with CUP. Risk of being diagnosed with CUP was strongly related to smoking, with a relative risk of 3.66 95% C.I., 2.24–5.97 for current, heavy smokers (26+ cigarettes/day) compared to never smokers (adjusted for alcohol consumption, body mass index, waist circumference and level of education) and a relative risk of 5.12 3.09–8.47 for cases with CUP who died within 12 months. For alcohol consumption and level of education, weaker associations were observed but attenuated and no longer statistically significant after adjusting for smoking and indices of obesity. Finally, risk of CUP was increased by approximately 30 per cent for subjects in the highest versus lowest quartiles of waist circumference. Our analyses provide further documentation, in addition to autopsy studies, that a substantial proportion of cancers of unknown primary site may have their origin in smoking‐related tumors, in particular.
What's new?
When cancer appears as metastatic disease but no primary tumor can be observed, it's called “cancer of unknown primary site.” Little is known about the risk factors for this type of cancer. This study analyzed data from a European cohort and discovered a strong association between smoking and these cancers. Other risk factors they identified were drinking alcohol and being fat. This is the first epidemiological study of these type of cancers, and it strengthens the observations from autopsy studies that many of these cancers of unknown primary site stem from smoking‐related tumors.
General obesity has been positively associated with risk of liver and probably with biliary tract cancer, but little is known about abdominal obesity or weight gain during adulthood. We used ...multivariable Cox proportional hazard models to investigate associations between weight, body mass index, waist and hip circumference, waist‐to‐hip and waist‐to‐height ratio (WHtR), weight change during adulthood and risk of hepatocellular carcinoma (HCC), intrahepatic (IBDC) and extrahepatic bile duct system cancer EBDSC including gallbladder cancer (GBC) among 359,525 men and women in the European Prospective Investigation into Cancer and Nutrition study. Hepatitis B and C virus status was measured in a nested case–control subset. During a mean follow‐up of 8.6 years, 177 cases of HCC, 58 cases of IBDC and 210 cases of EBDSC, including 76 cases of GBC, occurred. All anthropometric measures were positively associated with risk of HCC and GBC. WHtR showed the strongest association with HCC relative risk (RR) comparing extreme tertiles 3.51, 95% confidence interval (95% CI): 2.09–5.87; ptrend < 0.0001 and with GBC (RR: 1.56, 95% CI: 1.12–2.16 for an increment of one unit in WHtR). Weight gain during adulthood was also positively associated with HCC when comparing extreme tertiles (RR: 2.48, 95% CI: 1.49–4.13; <0.001). No statistically significant association was observed between obesity and risk of IBDC and EBDSC. Our results provide evidence of an association between obesity, particularly abdominal obesity, and risk of HCC and GBC. Our findings support public health recommendations to reduce the prevalence of obesity and weight gain in adulthood for HCC and GBC prevention in Western populations.
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