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Background: An association between long-term exposure to fine particulate matter (PM2.5) and lung cancer has been established in previous studies. PM2.5 is a complex mixture of chemical components from various sources and little is known about whether certain components contribute specifically to the associated lung cancer risk. The present study builds on recent findings from the “Effects of Low-level Air Pollution: A Study in Europe” (ELAPSE) collaboration and addresses the potential association between specific elemental components of PM2.5 and lung cancer incidence. Methods: We pooled seven cohorts from across Europe and assigned exposure estimates for eight components of PM2.5 representing non-tail pipe emissions (copper (Cu), iron (Fe), and zinc (Zn)), long-range transport (sulfur (S)), oil burning/industry emissions (nickel (Ni), vanadium (V)), crustal material (silicon (Si)), and biomass burning (potassium (K)) to cohort participants’ baseline residential address based on 100 m by 100 m grids from newly developed hybrid models combining air pollution monitoring, land use data, satellite observations, and dispersion model estimates. We applied stratified Cox proportional hazards models, adjusting for potential confounders (age, sex, calendar year, marital status, smoking, body mass index, employment status, and neighborhood-level socio-economic status). Results: The pooled study population comprised 306,550 individuals with 3916 incident lung cancer events during 5,541,672 person-years of follow-up. We observed a positive association between exposure to all eight components and lung cancer incidence, with adjusted HRs of 1.10 (95% CI 1.05, 1.16) per 50 ng/m3 PM2.5 K, 1.09 (95% CI 1.02, 1.15) per 1 ng/m3 PM2.5 Ni, 1.22 (95% CI 1.11, 1.35) per 200 ng/m3 PM2.5 S, and 1.07 (95% CI 1.02, 1.12) per 200 ng/m3 PM2.5 V. Effect estimates were largely unaffected by adjustment for nitrogen dioxide (NO2). After adjustment for PM2.5 mass, effect estimates of K, Ni, S, and V were slightly attenuated, whereas effect estimates of Cu, Si, Fe, and Zn became null or negative. Conclusions: Our results point towards an increased risk of lung cancer in connection with sources of combustion particles from oil and biomass burning and secondary inorganic aerosols rather than non-exhaust traffic emissions. Specific limit values or guidelines targeting these specific PM2.5 components may prove helpful in future lung cancer prevention strategies. © 2020 Elsevier Inc.

Pancreatic cancer (PC) is a highly fatal cancer with currently limited opportunities for early detection and effective treatment. Modifiable factors may offer pathways for primary prevention. In this study, the association between the Healthy Lifestyle Index (HLI) and PC risk was examined. Within the European Prospective Investigation into Cancer and Nutrition cohort, 1113 incident PC (57% women) were diagnosed from 400,577 participants followed-up for 15 years (median). HLI scores combined smoking, alcohol intake, dietary exposure, physical activity and, in turn, overall and central adiposity using BMI (HLIBMI) and waist-to-hip ratio (WHR, HLIWHR), respectively. High values of HLI indicate adherence to healthy behaviors. Cox proportional hazard models with age as primary time variable were used to estimate PC hazard ratios (HR) and 95% confidence intervals (CI). Sensitivity analyses were performed by excluding, in turn, each factor from the HLI score. Population attributable fractions (PAF) were estimated assuming participants’ shift to healthier lifestyles. The HRs for a one-standard deviation increment of HLIBMI and HLIWHR were 0.84 (95% CI: 0.79, 0.89; ptrend = 4.3e−09) and 0.77 (0.72, 0.82; ptrend = 1.7e−15), respectively. Exclusions of smoking from HLIWHR resulted in HRs of 0.88 (0.82, 0.94; ptrend = 4.9e−04). The overall PAF estimate was 19% (95% CI: 11%, 26%), and 14% (6%, 21%) when smoking was removed from the score. Adherence to a healthy lifestyle was inversely associated with PC risk, beyond the beneficial role of smoking avoidance. Public health measures targeting compliance with healthy lifestyles may have an impact on PC incidence. © 2019, Springer Nature B.V.

Background: Bile acids have been proposed to promote colon carcinogenesis. However, there are limited prospective data on circulating bile acid levels and colon cancer risk in humans. Methods: Associations between prediagnostic plasma levels of 17 primary, secondary, and tertiary bile acid metabolites (conjugated and unconjugated) and colon cancer risk were evaluated in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Bile acid levels were quantified by tandem mass spectrometry in samples from 569 incident colon cancer cases and 569 matched controls. Multivariable logistic regression analyses were used to estimate odds ratios (ORs) for colon cancer risk across quartiles of bile acid concentrations. Results: Positive associations were observed between colon cancer risk and plasma levels of seven conjugated bile acid metabolites: the primary bile acids glycocholic acid (ORquartile 4 vs quartile 1= 2.22, 95% confidence interval [CI] = 1.52 to 3.26), taurocholic acid (OR = 1.78, 95% CI = 1.23 to 2.58), glycochenodeoxycholic acid (OR = 1.68, 95% CI = 1.13 to 2.48), taurochenodeoxycholic acid (OR = 1.62, 95% CI = 1.11 to 2.36), and glycohyocholic acid (OR = 1.65, 95% CI = 1.13 to 2.40), and the secondary bile acids glycodeoxycholic acid (OR = 1.68, 95% CI = 1.12 to 2.54) and taurodeoxycholic acid (OR = 1.54, 95% CI = 1.02 to 2.31). By contrast, unconjugated bile acids and tertiary bile acids were not associated with risk. Conclusions: This prospective study showed that prediagnostic levels of certain conjugated primary and secondary bile acids were positively associated with risk of colon cancer. Our findings support experimental data to suggest that a high bile acid load is colon cancer promotive. © 2020 The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Background: Urothelial carcinoma is the predominant (95%) bladder cancer subtype in industrialized nations. Animal and epidemiologic human studies suggest that hormonal factors may influence urothelial carcinoma risk. Methods: We used an analytic cohort of 333,919 women from the European Prospective Investigation into Cancer and Nutrition Cohort. Associations between hormonal factors and incident urothelial carcinoma (overall and by tumor grade, tumor aggressiveness, and non–muscle-invasive urothelial carcinoma) risk were evaluated using Cox proportional hazards models. Results: During a mean of 15 years of follow-up, 529 women developed urothelial carcinoma. In a model including number of full-term pregnancies (FTP), menopausal status, and menopausal hormone therapy (MHT), number of FTP was inversely associated with urothelial carcinoma risk (HR≥5vs1 ¼ 0.48; 0.25–0.90; Ptrend in parous women ¼ 0.010) and MHT use (compared with nonuse) was positively associated with urothelial carcinoma risk (HR ¼ 1.27; 1.03–1.57), but no dose response by years of MHT use was observed. No modification of HRs by smoking status was observed. Finally, sensitivity analyses in never smokers showed similar HR patterns for the number of FTP, while no association between MHT use and urothelial carcinoma risk was observed. Association between MHT use and urothelial carcinoma risk remained significant only in current smokers. No heterogeneity of the risk estimations in the final model was observed by tumor aggressiveness or by tumor grade. A positive association between MTH use and non–muscle-invasive urothelial carcinoma risk was observed. Conclusions: Our results support that increasing the number of FTP may reduce urothelial carcinoma risk. Impact: More detailed studies on parity are needed to understand the possible effects of perinatal hormone changes in urothelial cells. © 2020 American Association for Cancer Research.

Several studies have reported associations of hypertension with cancer, but not all results were conclusive. We examined the association of systolic (SBP) and diastolic (DBP) blood pressure with the development of incident cancer at all anatomical sites in the European Prospective Investigation into Cancer and Nutrition (EPIC). Hazard ratios (HRs) (95% confidence intervals) were estimated using multivariable Cox proportional hazards models, stratified by EPIC-participating center and age at recruitment, and adjusted for sex, education, smoking, body mass index, physical activity, diabetes and dietary (in women also reproductive) factors. The study included 307,318 men and women, with an average follow-up of 13.7 (standard deviation 4.4) years and 39,298 incident cancers. We confirmed the expected positive association with renal cell carcinoma: HR = 1.12 (1.08–1.17) per 10 mm Hg higher SBP and HR = 1.23 (1.14–1.32) for DBP. We additionally found positive associations for esophageal squamous cell carcinoma (SCC): HR = 1.16 (1.07–1.26) (SBP), HR = 1.31 (1.13–1.51) (DBP), weaker for head and neck cancers: HR = 1.08 (1.04–1.12) (SBP), HR = 1.09 (1.01–1.17) (DBP) and, similarly, for skin SCC, colon cancer, postmenopausal breast cancer and uterine adenocarcinoma (AC), but not for esophageal AC, lung SCC, lung AC or uterine endometroid cancer. We observed weak inverse associations of SBP with cervical SCC: HR = 0.91 (0.82–1.00) and lymphomas: HR = 0.97 (0.93–1.00). There were no consistent associations with cancers in other locations. Our results are largely compatible with published studies and support weak associations of blood pressure with cancers in specific locations and morphologies. © 2019 UICC

Background: There is a lack of prospective data on the potential association of Fusobacterium nucleatum (F. nucleatum) and colorectal cancer risk. In this study, we assessed whether antibody responses to F. nucleatum are associated with colorectal cancer risk in prediagnostic serum samples in the European Prospective Investigation into Nutrition and Cancer (EPIC) cohort. Methods: We applied a multiplex serology assay to simultaneously measure antibody responses to 11 F. nucleatum antigens in prediagnostic serum samples from 485 colorectal cancer cases and 485 matched controls. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CI). Results: We observed neither a statistically significant colorectal cancer risk association for antibodies to individual F. nucleatum proteins nor for combined positivity to any of the 11 proteins (OR, 0.81; 95% CI, 0.62–1.06). Conclusions: Antibody responses to F. nucleatum proteins in prediagnostic serum samples from a subset of colorectal cancer cases and matched controls within the EPIC study were not associated with colorectal cancer risk. Impact: Our findings in prospectively ascertained serum samples contradict the existing literature on the association of F. nucleatum with colorectal cancer risk. Future prospective studies, specifically detecting F. nucleatum in stool or tissue biopsies, are needed to complement our findings. © 2019 American Association for Cancer Research.

Background: Except for a documented increase in osteoprotegerin (OPG) concentrations with older age, data on determinants of soluble Receptor Activator of Nuclear Factor kB (sRANKL) and OPG concentrations in women are limited. We evaluated reproductive and lifestyle factors as potential sources of variation in circulating sRANKL and OPG concentrations in pre- and postmenopausal women. Methods: This study includes 2,016 controls [n = 1,552 (76%) postmenopausal, n = 757 (38%) using postmenopausal hormone therapy (PMH)] from a breast cancer case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Serum sRANKL was measured using an ELISA and serum OPG using an electrochemiluminescent assay. Generalized linear models were used to evaluate associations between these analytes and reproductive and lifestyle factors. Results: Older age at blood collection was associated with lower sRANKL concentrations in postmenopausal women (Ptrend < 0.03) and higher OPG concentrations in all women (Ptrend < 0.01). Longer duration of oral contraceptive use among premenopausal women and postmenopausal PMH users was associated with higher OPG (Ptrend < 0.04). In postmenopausal non-PMH users, sRANKL concentrations were lower with longer duration of oral contraceptive use and current (vs. never) smoking (P < 0.01). sRANKL concentrations were higher among women with higher BMI (Ptrend < 0.01). The evaluated factors accounted for 12% of the variation in sRANKL concentrations and 21% of the variation in OPG concentrations. Conclusions: Circulating sRANKL and OPG concentrations are minimally impacted by hormone-related factors in pre- and postmenopausal women. Impact: This study suggests circulating concentrations of sRANKL and OPG are unlikely to be strongly modified by hormone-related reproductive and lifestyle factors. © 2019 American Association for Cancer Research.

Background: Metabolomics is a promising molecular tool to identify novel etiologic pathways leading to cancer. Using a targeted approach, we prospectively investigated the associations between metabolite concentrations in plasma and breast cancer risk. Methods: A nested case-control study was established within the European Prospective Investigation into Cancer cohort, which included 1624 first primary incident invasive breast cancer cases (with known estrogen and progesterone receptor and HER2 status) and 1624 matched controls. Metabolites (n = 127, acylcarnitines, amino acids, biogenic amines, glycerophospholipids, hexose, sphingolipids) were measured by mass spectrometry in pre-diagnostic plasma samples and tested for associations with breast cancer incidence using multivariable conditional logistic regression. Results: Among women not using hormones at baseline (n = 2248), and after control for multiple tests, concentrations of arginine (odds ratio [OR] per SD = 0.79, 95% confidence interval [CI] = 0.70-0.90), asparagine (OR = 0.83 (0.74-0.92)), and phosphatidylcholines (PCs) ae C36:3 (OR = 0.83 (0.76-0.90)), aa C36:3 (OR = 0.84 (0.77-0.93)), ae C34:2 (OR = 0.85 (0.78-0.94)), ae C36:2 (OR = 0.85 (0.78-0.88)), and ae C38:2 (OR = 0.84 (0.76-0.93)) were inversely associated with breast cancer risk, while the acylcarnitine C2 (OR = 1.23 (1.11-1.35)) was positively associated with disease risk. In the overall population, C2 (OR = 1.15 (1.06-1.24)) and PC ae C36:3 (OR = 0.88 (0.82-0.95)) were associated with risk of breast cancer, and these relationships did not differ by breast cancer subtype, age at diagnosis, fasting status, menopausal status, or adiposity. Conclusions: These findings point to potentially novel pathways and biomarkers of breast cancer development. Results warrant replication in other epidemiological studies. © 2019 The Author(s).

Background: Even though in situ breast cancer (BCIS) accounts for a large proportion of the breast cancers diagnosed, few studies have investigated potential risk factors for BCIS. Their results suggest that some established risk factors for invasive breast cancer have a similar impact on BCIS risk, but large population-based studies on lifestyle factors and BCIS risk are lacking. Thus, we investigated the association between lifestyle and BCIS risk within the European Prospective Investigation into Cancer and Nutrition cohort. Methods: Lifestyle was operationalized by a score reflecting the adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations. The recommendations utilized in these analyses were the ones pertinent to healthy body weight, physical activity, consumption of plant-based foods, energy-dense foods, red and processed meat, and sugary drinks and alcohol, as well as the recommendation on breastfeeding. Cox proportional hazards regression was used to assess the association between lifestyle score and BCIS risk. The results were presented as hazard ratios (HR) and corresponding 95% confidence intervals (CI). Results: After an overall median follow-up time of 14.9 years, 1277 BCIS cases were diagnosed. Greater adherence to the WCRF/AICR cancer prevention recommendations was not associated with BCIS risk (HR = 0.98, 95% CI 0.93-1.03; per one unit of increase; multivariable model). An inverse association between the lifestyle score and BCIS risk was observed in study centers, where participants were recruited mainly via mammographic screening and attended additional screening throughout follow-up (HR = 0.85, 95% CI 0.73-0.99), but not in the remaining ones (HR = 0.99, 95% CI 0.94-1.05). Conclusions: While we did not observe an overall association between lifestyle and BCIS risk, our results indicate that lifestyle is associated with BCIS risk among women recruited via screening programs and with regular screening participation. This suggests that a true inverse association between lifestyle habits and BCIS risk in the overall cohort may have been masked by a lack of information on screening attendance. The potential inverse association between lifestyle and BCIS risk in our analyses is consistent with the inverse associations between lifestyle scores and breast cancer risk reported from previous studies. © 2019 The Author(s).

Background: Receptor activator of nuclear factor kappa-B (RANK)-signaling is involved in tumor growth and spread in experimental models. Binding of RANK ligand (RANKL) to RANK activates signaling, which is inhibited by osteoprotegerin (OPG). We have previously shown that circulating soluble RANKL (sRANKL) and OPG are associated with breast cancer risk. Here we extend these findings to provide the first data on pre-diagnosis concentrations of sRANKL and OPG and risk of breast cancer-specific and overall mortality after a breast cancer diagnosis. Methods: Two thousand six pre- and postmenopausal women with incident invasive breast cancer (1620 (81%) with ER+ disease) participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort were followed-up for mortality. Pre-diagnosis concentrations of sRANKL and OPG were quantified in baseline serum samples using an enzyme-linked immunosorbent assay and electrochemiluminescent assay, respectively. Hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer-specific and overall mortality were calculated using Cox proportional hazards regression models. Results: Especially in women with ER+ disease, higher circulating OPG concentrations were associated with higher risk of breast cancer-specific (quintile 5 vs 1 HR 1.77 [CI 1.03, 3.04]; ptrend 0.10) and overall mortality (q5 vs 1 HR 1.39 [CI 0.94, 2.05]; ptrend 0.02). sRANKL and the sRANKL/OPG ratio were not associated with mortality following a breast cancer diagnosis. Conclusions: High pre-diagnosis endogenous concentrations of OPG, the decoy receptor for RANKL, were associated with increased risk of death after a breast cancer diagnosis, especially in those with ER+ disease. These results need to be confirmed in well-characterized patient cohorts. © 2018 The Author(s).

Receptor activator of nuclear factor-kappa B (RANK)-RANK ligand (RANKL) signaling promotes mammary tumor development in experimental models. Circulating concentrations of soluble RANKL (sRANKL) may influence breast cancer risk via activation of RANK signaling; this may be modulated by osteoprotegerin (OPG), the decoy receptor for RANKL. sRANKL and breast cancer risk by hormone receptor subtype has not previously been investigated. A case-control study was nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. This study included 1, 976 incident invasive breast cancer cases [estrogen receptor positive (ER+), n=1, 598], matched 1:1 to controls. Women were pre- or postmenopausal at blood collection. Serum sRANKL was quantified using an ELISA, serum OPG using an electrochemiluminescent assay. Risk ratios (RR) and95% confidence intervals (95% CI) were calculated using conditional logistic regression. Associations between sRANKL and breast cancer risk differed by tumor hormone receptor status (Phet = 0.05). Higher concentrations of sRANKL were positively associated with risk of ER+ breast cancer [5th vs. 1st quintile RR 1.28 (95% CI, 1.01-1.63); Ptrend=0.20], but not ER-disease. For both ER+and estrogen and progesterone receptor positive (ER+PR+) breast cancer, results considering the sRANKL/OPG ratio were similar to those for sRANKL; we observed a suggestive inverse association between the ratio and ER-PR-disease [5th vs. 1st quintile RR = 0.60 (0.31-1.14); Ptrend=0.03]. This study provides the first largescale prospective data on circulating sRANKLand breast cancer. We observed limited evidence for an association between sRANKLand breast cancer risk. Cancer Prev Res; 10(9); 525-34. © 2017 American Association for Cancer Research.

Epidemiological studies have reported inconsistent findings for the association between B vitamins and breast cancer (BC) risk. We investigated the relationship between biomarkers of folate and vitamin B12 and the risk of BC in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Plasma concentrations of folate and vitamin B12 were determined in 2,491 BC cases individually matched to 2,521 controls among women who provided baseline blood samples. Multivariable logistic regression models were used to estimate odds ratios by quartiles of either plasma B vitamin. Subgroup analyses by menopausal status, hormone receptor status of breast tumors (estrogen receptor [ER], progesterone receptor [PR] and human epidermal growth factor receptor 2 [HER2]), alcohol intake and MTHFR polymorphisms (677C > T and 1298A > C) were also performed. Plasma levels of folate and vitamin B12 were not significantly associated with the overall risk of BC or by hormone receptor status. A marginally positive association was found between vitamin B12 status and BC risk in women consuming above the median level of alcohol (ORQ4-Q1 = 1.26; 95% CI 1.00–1.58; Ptrend = 0.05). Vitamin B12 status was also positively associated with BC risk in women with plasma folate levels below the median value (ORQ4-Q1 = 1.29; 95% CI 1.02–1.62; Ptrend = 0.03). Overall, folate and vitamin B12 status was not clearly associated with BC risk in this prospective cohort study. However, potential interactions between vitamin B12 and alcohol or folate on the risk of BC deserve further investigation. © 2016 UICC

In this study, the relation between fruit and vegetable consumption and mortality was investigated within the European Prospective Investigation Into Cancer and Nutrition. Survival analyses were performed, including 451,151 participants from 10 European countries, recruited between 1992 and 2000 and followed until 2010. Hazard ratios, rate advancement periods, and preventable proportions to respectively compare risk of death between quartiles of consumption, to estimate the period by which the risk of death was postponed among high consumers, and to estimate proportions of deaths that could be prevented if all participants would shift their consumption 1 quartile upward. Consumption of fruits and vegetables was inversely associated with all-cause mortality (for the highest quartile, hazard ratio = 0.90, 95% confidence interval (CI): 0.86, 0.94), with a rate advancement period of 1.12 years (95% CI: 0.70, 1.54), and with a preventable proportion of 2.95%. This association was driven mainly by cardiovascular disease mortality (for the highest quartile, hazard ratio = 0.85, 95% CI: 0.77, 0.93). Stronger inverse associations were observed for participants with high alcohol consumption or high body mass index and suggested in smokers. Inverse associations were stronger for raw than for cooked vegetable consumption. These results support the evidence that fruit and vegetable consumption is associated with a lower risk of death. In this study, the relation between fruit and vegetable consumption and mortality was investigated within the European Prospective Investigation Into Cancer and Nutrition. Survival analyses were performed, including 451,151 participants from 10 European countries, recruited between 1992 and 2000 and followed until 2010. Hazard ratios, rate advancement periods, and preventable proportions to respectively compare risk of death between quartiles of consumption, to estimate the period by which the risk of death was postponed among high consumers, and to estimate proportions of deaths that could be prevented if all participants would shift their consumption 1 quartile upward. Consumption of fruits and vegetables was inversely associated with all-cause mortality (for the highest quartile, hazard ratio = 0.90, 95% confidence interval (CI): 0.86, 0.94), with a rate advancement period of 1.12 years (95% CI: 0.70, 1.54), and with a preventable proportion of 2.95%. This association was driven mainly by cardiovascular disease mortality (for the highest quartile, hazard ratio = 0.85, 95% CI: 0.77, 0.93). Stronger inverse associations were observed for participants with high alcohol consumption or high body mass index and suggested in smokers. Inverse associations were stronger for raw than for cooked vegetable consumption. These results support the evidence that fruit and vegetable consumption is associated with a lower risk of death.