| 1. |
- Couch, Fergus J., et al.
(author)
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Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer
- 2016
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In: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 7:11375, s. 1-13
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Journal article (peer-reviewed)abstract
- Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 x 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for similar to 11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.
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| 2. |
- Merritt, Melissa A., et al.
(author)
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Nutrient-wide association study of 57 foods/nutrients and epithelial ovarian cancer in the European Prospective Investigation into Cancer and Nutrition study and the Netherlands Cohort Study
- 2016
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In: American Journal of Clinical Nutrition. - : Elsevier BV. - 0002-9165 .- 1938-3207. ; 103:1, s. 161-167
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Journal article (peer-reviewed)abstract
- Background: Studies of the role of dietary factors in epithelial ovarian cancer (EOC) development have been limited, and no specific dietary factors have been consistently associated with EOC risk.Objective: We used a nutrient-wide association study approach to systematically test the association between dietary factors and invasive EOC risk while accounting for multiple hypothesis testing by using the false discovery rate and evaluated the findings in an independent cohort.Design: We assessed dietary intake amounts of 28 foods/food groups and 29 nutrients estimated by using dietary questionnaires in the EPIC (European Prospective Investigation into Cancer and Nutrition) study (n = 1095 cases). We selected 4 foods/nutrients that were statistically significantly associated with EOC risk when comparing the extreme quartiles of intake in the EPIC study (false discovery rate = 0.43) and evaluated these factors in the NLCS (Netherlands Cohort Study; n = 383 cases). Cox regression models were used to estimate HRs and 95% CIs.Results: None of the 4 dietary factors that were associated with EOC risk in the EPIC study (cholesterol, polyunsaturated and saturated fat, and bananas) were statistically significantly associated with EOC risk in the NLCS; however, in meta-analysis of the EPIC study and the NLCS, we observed a higher risk of EOC with a high than with a low intake of saturated fat (quartile 4 compared with quartile 1; overall HR: 1.21; 95% CI: 1.04, 1.41).Conclusion: In the meta-analysis of both studies, there was a higher risk of EOC with a high than with a low intake of saturated fat.
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| 3. |
- Kong, So Yeon, et al.
(author)
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Serum Endotoxins and Flagellin and Risk of Colorectal Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) Cohort
- 2016
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In: Cancer Epidemiology, Biomarkers and Prevention. - 1055-9965 .- 1538-7755. ; 25:2, s. 291-301
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Journal article (peer-reviewed)abstract
- Background: Chronic inflammation and oxidative stress are thought to be involved in colorectal cancer development. These processes may contribute to leakage of bacterial products, such as lipopolysaccharide (LPS) and flagellin, across the gut barrier. The objective of this study, nested within a prospective cohort, was to examine associations between circulating LPS and flagellin serum antibody levels and colorectal cancer risk. Methods: A total of 1,065 incident colorectal cancer cases (colon, n = 667; rectal, n = 398) were matched (1:1) to control subjects. Serum flagellin-and LPS-specific IgA and IgG levels were quantitated by ELISA. Multivariable conditional logistic regression models were used to calculate ORs and 95% confidence intervals (CI), adjusting for multiple relevant confouding factors. Results: Overall, elevated anti-LPS and anti-flagellin biomarker levels were not associated with colorectal cancer risk. After testing potential interactions by various factors relevant for colorectal cancer risk and anti-LPS and anti-flagellin, sex was identified as a statistically significant interaction factor (P-interaction < 0.05 for all the biomarkers). Analyses stratified by sex showed a statistically significant positive colorectal cancer risk association for men (fully-adjusted OR for highest vs. lowest quartile for total anti-LPS + flagellin, 1.66; 95% CI, 1.10-2.51; P-trend, 0.049), whereas a borderline statistically significant inverse association was observed for women (fully-adjusted OR, 0.70; 95% CI, 0.47-1.02; P-trend, 0.18). Conclusion: In this prospective study on European populations, we found bacterial exposure levels to be positively associated to colorectal cancer risk among men, whereas in women, a possible inverse association may exist. Impact: Further studies are warranted to better clarify these preliminary observations. (C) 2016 AACR.
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| 4. |
- Emaus, Marleen J., et al.
(author)
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Vegetable and fruit consumption and the risk of hormone receptor-defined breast cancer in the EPIC cohort
- 2016
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In: American Journal of Clinical Nutrition. - : Elsevier BV. - 0002-9165 .- 1938-3207. ; 103:1, s. 168-177
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Journal article (peer-reviewed)abstract
- Background: The recent literature indicates that a high vegetable intake and not a high fruit intake could be associated with decreased steroid hormone receptor–negative breast cancer risk.Objective: This study aimed to investigate the association between vegetable and fruit intake and steroid hormone receptor–defined breast cancer risk.Design: A total of 335,054 female participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort were included in this study (mean ± SD age: 50.8 ± 9.8 y). Vegetable and fruit intake was measured by country-specific questionnaires filled out at recruitment between 1992 and 2000 with the use of standardized procedures. Cox proportional hazards models were stratified by age at recruitment and study center and were adjusted for breast cancer risk factors.Results: After a median follow-up of 11.5 y (IQR: 10.1–12.3 y), 10,197 incident invasive breast cancers were diagnosed [3479 estrogen and progesterone receptor positive (ER+PR+); 1021 ER and PR negative (ER−PR−)]. Compared with the lowest quintile, the highest quintile of vegetable intake was associated with a lower risk of overall breast cancer (HRquintile 5–quintile 1: 0.87; 95% CI: 0.80, 0.94). Although the inverse association was most apparent for ER−PR− breast cancer (ER−PR−: HRquintile 5–quintile 1: 0.74; 95% CI: 0.57, 0.96; P-trend = 0.03; ER+PR+: HRquintile 5–quintile 1: 0.91; 95% CI: 0.79, 1.05; P-trend = 0.14), the test for heterogeneity by hormone receptor status was not significant (P-heterogeneity = 0.09). Fruit intake was not significantly associated with total and hormone receptor–defined breast cancer risk.Conclusion: This study supports evidence that a high vegetable intake is associated with lower (mainly hormone receptor–negative) breast cancer risk.
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| 5. |
- Hughes, David J., et al.
(author)
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Prediagnostic selenium status and hepatobiliary cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort
- 2016
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In: American Journal of Clinical Nutrition. - : Elsevier BV. - 0002-9165 .- 1938-3207. ; 104:2, s. 406-414
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Journal article (peer-reviewed)abstract
- Background: Selenium status is suboptimal in many Europeans and may be a risk factor for the development of various cancers, including those of the liver and biliary tract.Objective: We wished to examine whether selenium status in advance of cancer onset is associated with hepatobiliary cancers in the EPIC (European Prospective Investigation into Cancer and Nutrition) study.Design: We assessed prediagnostic selenium status by measuring serum concentrations of selenium and selenoprotein P (SePP; the major circulating selenium transfer protein) and examined the association with hepatocellular carcinoma (HCC; n = 121), gallbladder and biliary tract cancers (GBTCs; n = 100), and intrahepatic bile duct cancer (IHBC; n = 40) risk in a nested case-control design within the EPIC study. Selenium was measured by total reflection X-ray fluorescence, and SePP was determined by a colorimetric sandwich ELISA. Multivariable ORs and 95% CIs were calculated by using conditional logistic regression.Results: HCC and GBTC cases, but not IHBC cases, showed significantly lower circulating selenium and SePP concentrations than their matched controls. Higher circulating selenium was associated with a significantly lower HCC risk (OR per 20-mg/L increase: 0.41; 95% CI: 0.23, 0.72) but not with the risk of GBTC or IHBC. Similarly, higher SePP concentrations were associated with lowered HCC risk only in both the categorical and continuous analyses (HCC: P-trend <= 0.0001; OR per 1.5-mg/L increase: 0.37; 95% CI: 0.21, 0.63).Conclusion: These findings from a large prospective cohort provide evidence that suboptimal selenium status in Europeans may be associated with an appreciably increased risk of HCC development.
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| 6. |
- Terry, Kathryn L., et al.
(author)
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A Prospective Evaluation of Early Detection Biomarkers for Ovarian Cancer in the European EPIC Cohort
- 2016
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In: Clinical Cancer Research. - : American Association for Cancer Research. - 1078-0432 .- 1557-3265. ; 22:18, s. 4664-4675
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Journal article (peer-reviewed)abstract
- Purpose: About 60% of ovarian cancers are diagnosed at late stage, when 5-year survival is less than 30% in contrast to 90% for local disease. This has prompted search for early detection biomarkers. For initial testing, specimens taken months or years before ovarian cancer diagnosis are the best source of information to evaluate earlydetection biomarkers. Here we evaluate the most promising ovarian cancer screening biomarkers in prospectively collected samples from the European Prospective Investigation into Cancer and Nutrition study. Experimental Design: We measured CA125, HE4, CA72.4, and CA15.3 in 810 invasive epithelial ovarian cancer cases and 1,939 controls. We calculated the sensitivity at 95% and 98% specificity as well as area under the receiver operator curve (C-statistic) for each marker individually and in combination. In addition, we evaluated marker performance by stage at diagnosis and time between blood draw and diagnosis. Results: We observed the best discrimination between cases and controls within 6 months of diagnosis for CA125 (C-statistic = 0.92), then HE4 (0.84), CA72.4 (0.77), and CA15.3 (0.73). Marker performance declined with longer time between blood draw and diagnosis and for earlier staged disease. However, assessment of discriminatory ability at early stage was limited by small numbers. Combinations of markers performed modestly, but significantly better than any single marker. Conclusions: CA125 remains the single best marker for the early detection of invasive epithelial ovarian cancer, but can be slightly improved by combining with other markers. Identifying novel markers for ovarian cancer will require studies including larger numbers of early-stage cases.
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| 7. |
- Lu, Yunxia, et al.
(author)
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Comparison of abdominal adiposity and overall obesity in relation to risk of small intestinal cancer in a European Prospective Cohort
- 2016
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In: Cancer Causes and Control. - : Springer Science and Business Media LLC. - 0957-5243 .- 1573-7225. ; 27:7, s. 919-927
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Journal article (peer-reviewed)abstract
- BACKGROUND: The etiology of small intestinal cancer (SIC) is largely unknown, and there are very few epidemiological studies published to date. No studies have investigated abdominal adiposity in relation to SIC.METHODS: We investigated overall obesity and abdominal adiposity in relation to SIC in the European Prospective Investigation into Cancer and Nutrition (EPIC), a large prospective cohort of approximately half a million men and women from ten European countries. Overall obesity and abdominal obesity were assessed by body mass index (BMI), waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR). Multivariate Cox proportional hazards regression modeling was performed to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs). Stratified analyses were conducted by sex, BMI, and smoking status.RESULTS: During an average of 13.9 years of follow-up, 131 incident cases of SIC (including 41 adenocarcinomas, 44 malignant carcinoid tumors, 15 sarcomas and 10 lymphomas, and 21 unknown histology) were identified. WC was positively associated with SIC in a crude model that also included BMI (HR per 5-cm increase = 1.20, 95 % CI 1.04, 1.39), but this association attenuated in the multivariable model (HR 1.18, 95 % CI 0.98, 1.42). However, the association between WC and SIC was strengthened when the analysis was restricted to adenocarcinoma of the small intestine (multivariable HR adjusted for BMI = 1.56, 95 % CI 1.11, 2.17). There were no other significant associations.CONCLUSION: WC, rather than BMI, may be positively associated with adenocarcinomas but not carcinoid tumors of the small intestine.IMPACT: Abdominal obesity is a potential risk factor for adenocarcinoma in the small intestine.
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| 8. |
- Roura, Esther, et al.
(author)
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The Influence of Hormonal Factors on the Risk of Developing Cervical Cancer and Pre-Cancer: Results from the EPIC Cohort
- 2016
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:1
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Journal article (peer-reviewed)abstract
- In addition to HPV, high parity and hormonal contraceptives have been associated with cervical cancer (CC). However, most of the evidence comes from retrospective case-control studies. The aim of this study is to prospectively evaluate associations between hormonal factors and risk of developing cervical intraepithelial neoplasia grade 3 (CIN3)/carcinoma in situ (CIS) and invasive cervical cancer (ICC).
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| 9. |
- Stepien, Magdalena, et al.
(author)
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Prospective association of liver function biomarkers with development of hepatobiliary cancers
- 2016
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In: Cancer Epidemiology. - : Elsevier. - 1877-7821 .- 1877-783X. ; 40, s. 179-187
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Journal article (peer-reviewed)abstract
- Introduction: Serum liver biomarkers (gamma-glutamyl transferase, GGT; alanine aminotransferase, ALT; aspartate aminotransferase, AST; alkaline phosphatase, ALP; total bilirubin) are used as indicators of liver disease, but there is currently little data on their prospective association with risk of hepatobiliary cancers. Methods: A nested-case control study was conducted within the prospective EPIC cohort (>520,000 participants, 10 European countries). After a mean 7.5 mean years of follow-up, 121 hepatocellular carcinoma (HCC), 34 intrahepatic bile duct (IHBC) and 131 gallbladder and biliary tract (GBTC) cases were identified and matched to 2 controls each. Circulating biomarkers were measured in serum taken at recruitment into the cohort, prior to cancer diagnosis. Multivariable adjusted conditional logistic regression was used to calculate odds ratios and 95% confidence intervals (OR; 95% CI). Results: In multivariable models, 1SD increase of each log-transformed biomarker was positively associated with HCC risk (OR(GGT) = 4.23, 95% CI: 2.72-6.59; OR(ALP) = 3.43, 95% CI: 2.31-5.10; OR(AST) = 3.00, 95% CI: 2.04-4.42; OR(ALT) = 2.69, 95% CI: 1.89-3.84; OR(Bilirubin) = 2.25, 95% CI: 1.58-3.20). Each liver enzyme (OR(GGT) = 4.98; 95% CI: 1.75-14.17; OR(AST) = 3.10, 95% CI: 1.04-9.30; OR(ALT) = 2.86, 95% CI: 1.26-6.48, OR(ALP) = 2.31, 95% CI: 1.10-4.86) but not bilirubin (OR(Bilirubin) = 1.46,95% CI: 0.85-2.51) showed a significant association with IHBC. Only ALP was significantly associated with GBTC risk (OR (ALP) = 1.59, 95% CI: 1.20-2.09). Conclusion: This study shows positive associations between circulating liver biomarkers in sera collected prior to cancer diagnoses and the risks of developing HCC or IHBC, but not GBTC.
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| 10. |
- Stepien, Magdalena, et al.
(author)
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Alteration of amino acid and biogenic amine metabolism in hepatobiliary cancers : findings from a prospective cohort study
- 2016
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In: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 138:2, s. 348-360
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Journal article (peer-reviewed)abstract
- Perturbations in levels of amino acids (AA) and their derivatives are observed in hepatocellular carcinoma (HCC). Yet, it is unclear whether these alterations precede or are a consequence of the disease, nor whether they pertain to anatomically related cancers of the intrahepatic bile duct (IHBC), and gallbladder and extrahepatic biliary tract (GBTC). Circulating standard AA, biogenic amines and hexoses were measured (Biocrates AbsoluteIDQ-p180Kit) in a case-control study nested within a large prospective cohort (147 HCC, 43 IHBC and 134 GBTC cases). Liver function and hepatitis status biomarkers were determined separately. Multivariable conditional logistic regression was used to calculate odds ratios and 95% confidence intervals (OR; 95%CI) for log-transformed standardised (mean = 0, SD = 1) serum metabolite levels and relevant ratios in relation to HCC, IHBC or GBTC risk. Fourteen metabolites were significantly associated with HCC risk, of which seven metabolites and four ratios were the strongest predictors in continuous models. Leucine, lysine, glutamine and the ratio of branched chain to aromatic AA (Fischer's ratio) were inversely, while phenylalanine, tyrosine and their ratio, glutamate, glutamate/glutamine ratio, kynurenine and its ratio to tryptophan were positively associated with HCC risk. Confounding by hepatitis status and liver enzyme levels was observed. For the other cancers no significant associations were observed. In conclusion, imbalances of specific AA and biogenic amines may be involved in HCC development.
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