Publications by authors named "Dimitrios Trichopoulos"

393 Publications

Blood pressure and risk of cancer in the European Prospective Investigation into Cancer and Nutrition.

Int J Cancer 2020 05 20;146(10):2680-2693. Epub 2019 Aug 20.

Public Health Division of Gipuzkoa, BioDonostia Research Institute, San Sebastian, Spain.

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.
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http://dx.doi.org/10.1002/ijc.32576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115826PMC
May 2020

One-carbon metabolism biomarkers and risk of urothelial cell carcinoma in the European prospective investigation into cancer and nutrition.

Int J Cancer 2019 11 13;145(9):2349-2359. Epub 2019 Feb 13.

Department of Translational Medicine, Division of Clinical Chemistry, Lund University, Malmö, Sweden.

Published associations between dietary folate and bladder cancer risk are inconsistent. Biomarkers may provide more accurate measures of nutrient status. This nested case-control analysis within the European Prospective Investigation into Cancer and Nutrition (EPIC) investigated associations between pre-diagnostic serum folate, homocysteine, vitamins B6 and B12 and the risk of urothelial cell carcinomas of the bladder (UCC). A total of 824 patients with newly diagnosed UCC were matched with 824 cohort members. Serum folate, homocysteine, and vitamins B6 and B12 were measured. Odds ratios (OR) and 95% confidence intervals (CI) for total, aggressive, and non-aggressive UCC were estimated using conditional logistic regression with adjustment for smoking status, smoking duration and intensity, and other potential confounders. Additionally, statistical interaction with smoking status was assessed. A halving in serum folate concentrations was moderately associated with risk of UCC (OR: 1.18; 95% CI: 0.98-1.43), in particular aggressive UCC (OR: 1.34; 95% CI: 1.02-1.75; p-heterogeneity = 0.19). Compared to never smokers in the highest quartile of folate concentrations, this association seemed only apparent among current smokers in the lowest quartile of folate concentrations (OR: 6.26; 95% CI: 3.62-10.81, p-interaction = 0.07). Dietary folate was not associated with aggressive UCC (OR: 1.26; 95% CI: 0.81-1.95; p-heterogeneity = 0.14). No association was observed between serum homocysteine, vitamins B6 and B12 and risk of UCC. This study suggests that lower serum folate concentrations are associated with increased UCC risk, in particular aggressive UCC. Residual confounding by smoking cannot be ruled out and these findings require confirmation in future studies with multiple measurements.
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http://dx.doi.org/10.1002/ijc.32165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899898PMC
November 2019

Coffee and tea consumption and risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition.

Int J Cancer 2019 01 16;144(2):240-250. Epub 2018 Nov 16.

Cancer Risk Factors and Life-Style Epidemiology Unit, Cancer Research and Prevention Institute-ISPO, Florence, Italy.

The epidemiological evidence regarding the association of coffee and tea consumption with prostate cancer risk is inconclusive, and few cohort studies have assessed these associations by disease stage and grade. We examined the associations of coffee (total, caffeinated and decaffeinated) and tea intake with prostate cancer risk in the European Prospective Investigation into Cancer and Nutrition. Among 142,196 men, 7,036 incident prostate cancer cases were diagnosed over 14 years of follow-up. Data on coffee and tea consumption were collected through validated country-specific food questionnaires at baseline. We used Cox proportional hazards regression models to compute hazard ratios (HRs) and 95% confidence intervals (CI). Models were stratified by center and age, and adjusted for anthropometric, lifestyle and dietary factors. Median coffee and tea intake were 375 and 106 mL/day, respectively, but large variations existed by country. Comparing the highest (median of 855 mL/day) versus lowest (median of 103 mL/day) consumers of coffee and tea (450 vs. 12 mL/day) the HRs were 1.02 (95% CI, 0.94-1.09) and 0.98 (95% CI, 0.90-1.07) for risk of total prostate cancer and 0.97 (95% CI, 0.79-1.21) and 0.89 (95% CI, 0.70-1.13) for risk of fatal disease, respectively. No evidence of association was seen for consumption of total, caffeinated or decaffeinated coffee or tea and risk of total prostate cancer or cancer by stage, grade or fatality in this large cohort. Further investigations are needed to clarify whether an association exists by different preparations or by concentrations and constituents of these beverages.
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http://dx.doi.org/10.1002/ijc.31634DOI Listing
January 2019

Burden of hip fracture using disability-adjusted life-years: a pooled analysis of prospective cohorts in the CHANCES consortium.

Lancet Public Health 2017 05 11;2(5):e239-e246. Epub 2017 Apr 11.

Hellenic Health Foundation, Athens, Greece; WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.

Background: No studies have estimated disability-adjusted life-years (DALYs) lost due to hip fractures using real-life follow-up cohort data. We aimed to quantify the burden of disease due to incident hip fracture using DALYs in prospective cohorts in the CHANCES consortium, and to calculate population attributable fractions based on DALYs for specific risk factors.

Methods: We used data from six cohorts of participants aged 50 years or older at recruitment to calculate DALYs. We applied disability weights proposed by the National Osteoporosis Foundation and did a series of sensitivity analyses to examine the robustness of DALY estimates. We calculated population attributable fractions for smoking, body-mass index (BMI), physical activity, alcohol intake, type 2 diabetes and parity, use of hormone replacement therapy, and oral contraceptives in women. We calculated summary risk estimates across cohorts with pooled analysis and random-effects meta-analysis methods.

Findings: 223 880 men and women were followed up for a mean of 13 years (SD 6). 7724 (3·5%) participants developed an incident hip fracture, of whom 413 (5·3%) died as a result. 5964 DALYs (27 per 1000 individuals) were lost due to hip fractures, 1230 (20·6%) of which were in the group aged 75-79 years. 4150 (69·6%) DALYs were attributed to disability. Current smoking was the risk factor responsible for the greatest hip fracture burden (7·5%, 95% CI 5·2-9·7) followed by physical inactivity (5·5%, 2·1-8·5), history of diabetes (2·8%, 2·1-4·0), and low to average BMI (2·0%, 1·4-2·7), whereas low alcohol consumption (0·01-2·5 g per day) and high BMI had a protective effect.

Interpretation: Hip fracture can lead to a substantial loss of healthy life-years in elderly people. National public health policies should be strengthened to reduce hip fracture incidence and mortality. Primary prevention measures should be strengthened to prevent falls, and reduce smoking and a sedentary lifestyle.

Funding: European Community's Seventh Framework Programme.
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http://dx.doi.org/10.1016/S2468-2667(17)30046-4DOI Listing
May 2017

Self-rated health and all-cause and cause-specific mortality of older adults: Individual data meta-analysis of prospective cohort studies in the CHANCES Consortium.

Maturitas 2017 Sep 17;103:37-44. Epub 2017 Jun 17.

Hellenic Health Foundation, 115 27, Athens, Greece; Department of Epidmiology, Harvard School of Public Health, Boston, MA 02115, USA; Bureau of Epidemiologic Research, Academy of Athens, 115 27Athens, Greece.

Objectives: To evaluate, among the elderly, the association of self-rated health (SRH) with mortality, and to identify determinants of self-rating health as "at-least-good".

Study Design: Individual data on SRH and important covariates were obtained for 424,791 European and United States residents, ≥60 years at recruitment (1982-2008), in eight prospective studies in the Consortium on Health and Ageing: Network of Cohorts in Europe and the United States (CHANCES). In each study, adjusted mortality ratios (hazard ratios, HRs) in relation to SRH were calculated and subsequently combined with random-effect meta-analyses.

Main Outcome Measures: All-cause, cardiovascular and cancer mortality.

Results: Within the median 12.5 years of follow-up, 93,014 (22%) deaths occurred. SRH "fair" or "poor" vs. "at-least-good" was associated with increased mortality: HRs 1.46 (95% CI 1·23-1.74) and 2.31 (1.79-2.99), respectively. These associations were evident: for cardiovascular and, to a lesser extent, cancer mortality, and within-study, within-subgroup analyses. Accounting for lifestyle, sociodemographic, somatometric factors and, subsequently, for medical history explained only a modest amount of the unadjusted associations. Factors favourably associated with SRH were: sex (males), age (younger-old), education (high), marital status (married/cohabiting), physical activity (active), body mass index (non-obese), alcohol consumption (low to moderate) and previous morbidity (absence).

Conclusion: SRH provides a quick and simple tool for assessing health and identifying groups of elders at risk of early mortality that may be useful also in clinical settings. Modifying determinants of favourably rating health, e.g. by increasing physical activity and/or by eliminating obesity, may be important for older adults to "feel healthy" and "be healthy".
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http://dx.doi.org/10.1016/j.maturitas.2017.06.023DOI Listing
September 2017

Coffee Drinking and Mortality in 10 European Countries: A Multinational Cohort Study.

Ann Intern Med 2017 Aug 11;167(4):236-247. Epub 2017 Jul 11.

From International Agency for Research on Cancer, Lyon, France; Imperial College London, London, United Kingdom; Institut Gustave Roussy, Villejuif, France; German Cancer Research Center, Heidelberg, Germany; German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; Danish Cancer Society Research Center, Copenhagen, Denmark; Aarhus University, Aarhus, Denmark; Bispebjerg and Frederiksberg Hospital, Frederiksberg, Denmark; Public Health Directorate, Asturias, Spain; Catalan Institute of Oncology, Barcelona, Spain; Andalusian School of Public Health, Granada, Spain; Public Health Division of Gipuzkoa, Basque Regional Health Department, San Sebastián, Spain; Murcia Regional Health Council, Murcia, Spain; Navarre Public Health Institute, Pamplona, Spain; University of Cambridge and MRC Epidemiology Unit, Cambridge, United Kingdom; University of Oxford, Oxford, United Kingdom; Hellenic Health Foundation, Athens, Greece; Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Cancer Research and Prevention Institute-ISPO, Florence, Italy; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Federico II University, Naples, Italy; "Civic - M.P. Arezzo" Hospital, ASP Ragusa, Ragusa, Italy; National Institute for Public Health and the Environment, Bilthoven, the Netherlands; University Medical Centre, Utrecht, the Netherlands; Malmö University Hospital, Malmö, Sweden; Umeå University, Umeå, Sweden; Swedish University of Agricultural Sciences, Uppsala, Sweden; University of Tromsø, The Arctic University of Norway, Tromsø, Norway; and National Cancer Institute, Bethesda, Maryland.

Background: The relationship between coffee consumption and mortality in diverse European populations with variable coffee preparation methods is unclear.

Objective: To examine whether coffee consumption is associated with all-cause and cause-specific mortality.

Design: Prospective cohort study.

Setting: 10 European countries.

Participants: 521 330 persons enrolled in EPIC (European Prospective Investigation into Cancer and Nutrition).

Measurements: Hazard ratios (HRs) and 95% CIs estimated using multivariable Cox proportional hazards models. The association of coffee consumption with serum biomarkers of liver function, inflammation, and metabolic health was evaluated in the EPIC Biomarkers subcohort (n = 14 800).

Results: During a mean follow-up of 16.4 years, 41 693 deaths occurred. Compared with nonconsumers, participants in the highest quartile of coffee consumption had statistically significantly lower all-cause mortality (men: HR, 0.88 [95% CI, 0.82 to 0.95]; P for trend < 0.001; women: HR, 0.93 [CI, 0.87 to 0.98]; P for trend = 0.009). Inverse associations were also observed for digestive disease mortality for men (HR, 0.41 [CI, 0.32 to 0.54]; P for trend < 0.001) and women (HR, 0.60 [CI, 0.46 to 0.78]; P for trend < 0.001). Among women, there was a statistically significant inverse association of coffee drinking with circulatory disease mortality (HR, 0.78 [CI, 0.68 to 0.90]; P for trend < 0.001) and cerebrovascular disease mortality (HR, 0.70 [CI, 0.55 to 0.90]; P for trend = 0.002) and a positive association with ovarian cancer mortality (HR, 1.31 [CI, 1.07 to 1.61]; P for trend = 0.015). In the EPIC Biomarkers subcohort, higher coffee consumption was associated with lower serum alkaline phosphatase; alanine aminotransferase; aspartate aminotransferase; γ-glutamyltransferase; and, in women, C-reactive protein, lipoprotein(a), and glycated hemoglobin levels.

Limitations: Reverse causality may have biased the findings; however, results did not differ after exclusion of participants who died within 8 years of baseline. Coffee-drinking habits were assessed only once.

Conclusion: Coffee drinking was associated with reduced risk for death from various causes. This relationship did not vary by country.

Primary Funding Source: European Commission Directorate-General for Health and Consumers and International Agency for Research on Cancer.
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http://dx.doi.org/10.7326/M16-2945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788283PMC
August 2017

Fiber intake modulates the association of alcohol intake with breast cancer.

Int J Cancer 2017 Jan;140(2):316-321

Department of Epidemiology, Murcia Regional Health Authority, Murcia, Spain, CIBER Epidemiology and Public Health CIBERESP, Spain.

Alcohol intake has been related to an increased risk of breast cancer (BC) while dietary fiber intake has been inversely associated to BC risk. A beneficial effect of fibers on ethanol carcinogenesis through their impact on estrogen levels is still controversial. We investigated the role of dietary fiber as a modifying factor of the association of alcohol and BC using data from the European Prospective Investigation into Cancer and Nutrition (EPIC). This study included 334,850 women aged 35-70 years at baseline enrolled in the ten countries of the EPIC study and followed up for 11.0 years on average. Information on fiber and alcohol intake at baseline and average lifetime alcohol intake were calculated from country-specific dietary and lifestyle questionnaires. Hazard ratios (HR) of developing invasive BC according to different levels of alcohol and fiber intake were computed. During 3,670,439 person-years, 11,576 incident BC cases were diagnosed. For subjects with low intake of fiber (<18.5 g/day), the risk of BC per 10 g/day of alcohol intake was 1.06 (1.03-1.08) while among subjects with high intake of fiber (>24.2 g/day) the risk of BC was 1.02 (0.99-1.05) (test for interaction p = 0.011). This modulating effect was stronger for fiber from vegetables. Our results suggest that fiber intake may modulate the positive association of alcohol intake and BC. Alcohol is well known to increase the risk for BC, while a fiber-rich diet has the opposite effect. Here the authors find a significant interaction between both lifestyle factors indicating that high fiber intake can ease the adverse effects associated with alcohol consumption. Consequently, women with high alcohol intake and low fiber intake (<18.5 g/day) had the highest risk for BC. Specific benefits were associated with fibers from vegetable, warranting further investigations into specific fiber sources and their mechanistic interactions with alcohol-induced BC risk.
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http://dx.doi.org/10.1002/ijc.30415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198933PMC
January 2017

Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21.

Oncotarget 2016 Oct;7(41):66328-66343

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10 -15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10 -9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10 -8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 ( NR5A2), chr8q24.21 ( MYC) and chr5p15.33 ( CLPTM1L- TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal ( n = 10) and tumor ( n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10 -8). This finding was validated in a second set of paired ( n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10 -4-2.0x10 -3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.
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http://dx.doi.org/10.18632/oncotarget.11041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340084PMC
October 2016

Combined effects of smoking and HPV16 in oropharyngeal cancer.

Int J Epidemiol 2016 06 19;45(3):752-61. Epub 2016 May 19.

Public Health Division of Gipuzkoa, BIODonostia Research Institute, Basque Health Department, San Sebastián, Spain, CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain.

Background: Although smoking and HPV infection are recognized as important risk factors for oropharyngeal cancer, how their joint exposure impacts on oropharyngeal cancer risk is unclear. Specifically, whether smoking confers any additional risk to HPV-positive oropharyngeal cancer is not understood.

Methods: Using HPV serology as a marker of HPV-related cancer, we examined the interaction between smoking and HPV16 in 459 oropharyngeal (and 1445 oral cavity and laryngeal) cancer patients and 3024 control participants from two large European multi-centre studies. Odds ratios and credible intervals [CrI], adjusted for potential confounders, were estimated using Bayesian logistic regression.

Results: Both smoking [odds ratio (OR [CrI]: 6.82 [4.52, 10.29]) and HPV seropositivity (OR [CrI]: 235.69 [99.95, 555.74]) were independently associated with oropharyngeal cancer. The joint association of smoking and HPV seropositivity was consistent with that expected on the additive scale (synergy index [CrI]: 1.32 [0.51, 3.45]), suggesting they act as independent risk factors for oropharyngeal cancer.

Conclusions: Smoking was consistently associated with increase in oropharyngeal cancer risk in models stratified by HPV16 seropositivity. In addition, we report that the prevalence of oropharyngeal cancer increases with smoking for both HPV16-positive and HPV16-negative persons. The impact of smoking on HPV16-positive oropharyngeal cancer highlights the continued need for smoking cessation programmes for primary prevention of head and neck cancer.
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http://dx.doi.org/10.1093/ije/dyw069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841602PMC
June 2016

Burden of Cancer in a Large Consortium of Prospective Cohorts in Europe.

J Natl Cancer Inst 2016 10 6;108(10). Epub 2016 May 6.

Affiliations of authors: Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece (KKT, NP); Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, UK (KKT); Hellenic Health Foundation, Athens, Greece (KKT, DC, CB, PB, DT, AT); World Health Organization Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece (CB, VB, AT); International Agency for Research on Cancer (IARC-WHO), Lyon, France (MJ, HF, IS); UKCRC Centre of Excellence for Public Health, Queens University Belfast, Northern Ireland, UK (FK, MGO, AS); Department of Health Economics and Management, University of Wuppertal, Wuppertal, Germany (AN); Research Centre for Education and the Labour Market, Maastricht University, Maastricht, the Netherlands (AN); Danish Cancer Society Research Center, Copenhagen, Denmark (AT); Julius Center for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, the Netherlands (AMM); Public Health Directorate, Asturias, Spain (JRQ); Department of Pharmacology and Clinical Neurosciences (UPK) and Department of Biobank Research (SE), Umeå University, Umeå, Sweden (UPK); Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (HB), Heidelberg, Germany (HB, BS, JMOM, AKD); Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany (HB); Network Aging Research (NAR), Heidelberg University, Heidelberg, Germany (JMOM); Department of Community Medicine, UiT The Arctic University of Norway, Tromsø, Norway (EBM, IN, GS, TW); Institute for Translational Epidemiology and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY (PB); Department of Epidemiology, Harvard School of Public Health, Boston, MA (DT); Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece (DT).

Background: Disability-adjusted life-years (DALYs) are an indicator of mortality, morbidity, and disability. We calculated DALYs for cancer in middle-aged and older adults participating in the Consortium on Health and Ageing Network of Cohorts in Europe and the United States (CHANCES) consortium.

Methods: A total of 90 199 participants from five European cohorts with 10 455 incident cancers and 4399 deaths were included in this study. DALYs were calculated as the sum of the years of life lost because of premature mortality (YLLs) and the years lost because of disability (YLDs). Population-attributable fractions (PAFs) were also estimated for five cancer risk factors, ie, smoking, adiposity, physical inactivity, alcohol intake, and type II diabetes.

Results: After a median follow-up of 12 years, the total number of DALYs lost from cancer was 34 474 (382 per 1000 individuals) with a similar distribution by sex. Lung cancer was responsible for the largest number of lost DALYs (22.9%), followed by colorectal (15.3%), prostate (10.2%), and breast cancer (8.7%). Mortality (81.6% of DALYs) predominated over disability. Ever cigarette smoking was the risk factor responsible for the greatest total cancer burden (24.0%, 95% confidence interval [CI] = 22.2% to 26.0%), followed by physical inactivity (4.9%, 95% CI = 0.8% to 8.1%) and adiposity (1.8%, 95% CI = 0.2% to 2.8%).

Conclusions: DALYs lost from cancer were substantial in this large European sample of middle-aged and older adults. Even if the burden of disease because of cancer is predominantly caused by mortality, some cancers have sizeable consequences for disability. Smoking remained the predominant risk factor for total cancer burden.
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http://dx.doi.org/10.1093/jnci/djw127DOI Listing
October 2016

Healthy Lifestyle and Risk of Cancer in the European Prospective Investigation Into Cancer and Nutrition Cohort Study.

Medicine (Baltimore) 2016 Apr;95(16):e2850

From the International Agency for Research on Cancer (IARC), Lyon (FM, CB, PF, HF, SR, VC, IR), INSERM, Centre for Research in Epidemiology and Population Health (CESP) (LD), Paris South University, UMRS 1018 (LD), Department of Public Health, Aarhus University, Aarhus, Denmark (CCD, KO), Institute Gustave Roussy (LD), INSERM, Centre for Research in Epidemiology and Population Health (CESP), Villejuif, France (LD), Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School (PL), Bureau of Epidemiologic Research, Academy of Athens (PL, DT), Hellenic Health Foundation, Athens, Greece (DT, AT), Department of Epidemiology, Harvard School of Public Health, Boston, MA (PL, DT), National Institute for Public Health and the Environment (RIVM), Bilthoven (HBBM), Department of Gastroenterology and Hepatology, University Medical Centre (HBBM), Julius Center, University Medical Center Utrecht, Utrecht, The Netherlands (AM, PHP), School of Public Health, Imperial College, London (HBBM, PHP), Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom (RCT), Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia (HBBM), Department of Community Medicine, Faculty of Health Sciences, UiT, The Arctic University of Norway, Tromsø (EW), Department of Research, Cancer Registry of Norway, Oslo, Norway (EW), Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm (EW), Department of Clinical Sciences in Malmö, Lund University, Lund, Sweden (UE, EW), Samfundet Folkhälsan, Helsinki, Finland (EW), CIBER Epidemiology and Public Health (CIBERESP), España (M-JS, CN, EA), Andalusian School of Public Health, University of Granada, Granada (M-JS), Department of Epidemiology, Murcia Regional Health Council (CN), Department of Health and Social Sciences, Universidad de Murcia, Murcia (CN), Navarra Public Health Institute (EA), and Navarra Institute for Health Research (IdiSNA), Pamplona, Spain (EA).

It has been estimated that at least a third of the most common cancers are related to lifestyle and as such are preventable. Key modifiable lifestyle factors have been individually associated with cancer risk; however, less is known about the combined effects of these factors. This study generated a healthy lifestyle index score (HLIS) to investigate the joint effect of modifiable factors on the risk of overall cancers, alcohol-related cancers, tobacco-related cancers, obesity-related cancers, and reproductive-related cancers. The study included 391,608 men and women from the multinational European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. The HLIS was constructed from 5 factors assessed at baseline (diet, physical activity, smoking, alcohol consumption, and anthropometry) by assigning scores of 0 to 4 to categories of each factor, for which higher values indicate healthier behaviors. Hazard ratios (HR) were estimated by Cox proportional regression and population attributable fractions (PAFs) estimated from the adjusted models. There was a 5% lower risk (adjusted HR 0.952, 95% confidence interval (CI): 0.946, 0.958) of all cancers per point score of the index for men and 4% (adjusted HR 0.961, 95% CI: 0.956, 0.966) for women. The fourth versus the second category of the HLIS was associated with a 28% and 24% lower risk for men and women respectively across all cancers, 41% and 33% for alcohol-related, 49% and 46% for tobacco-related, 41% and 26% for obesity-related, and 21% for female reproductive cancers. Findings suggest simple behavior modifications could have a sizeable impact on cancer prevention, especially for men.
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http://dx.doi.org/10.1097/MD.0000000000002850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4845813PMC
April 2016

Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation.

Nat Commun 2016 Apr 7;7:10979. Epub 2016 Apr 7.

Department of Public Health Sciences, Henry Ford Hospital, Detroit, Michigan 48202, USA.

Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.
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http://dx.doi.org/10.1038/ncomms10979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4829663PMC
April 2016

A Nested Case-Control Study of Metabolically Defined Body Size Phenotypes and Risk of Colorectal Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC).

PLoS Med 2016 Apr 5;13(4):e1001988. Epub 2016 Apr 5.

Dipartimento di Medicina Clinica e Sperimentale, Federico II University, Naples, Italy.

Background: Obesity is positively associated with colorectal cancer. Recently, body size subtypes categorised by the prevalence of hyperinsulinaemia have been defined, and metabolically healthy overweight/obese individuals (without hyperinsulinaemia) have been suggested to be at lower risk of cardiovascular disease than their metabolically unhealthy (hyperinsulinaemic) overweight/obese counterparts. Whether similarly variable relationships exist for metabolically defined body size phenotypes and colorectal cancer risk is unknown.

Methods And Findings: The association of metabolically defined body size phenotypes with colorectal cancer was investigated in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Metabolic health/body size phenotypes were defined according to hyperinsulinaemia status using serum concentrations of C-peptide, a marker of insulin secretion. A total of 737 incident colorectal cancer cases and 737 matched controls were divided into tertiles based on the distribution of C-peptide concentration amongst the control population, and participants were classified as metabolically healthy if below the first tertile of C-peptide and metabolically unhealthy if above the first tertile. These metabolic health definitions were then combined with body mass index (BMI) measurements to create four metabolic health/body size phenotype categories: (1) metabolically healthy/normal weight (BMI < 25 kg/m2), (2) metabolically healthy/overweight (BMI ≥ 25 kg/m2), (3) metabolically unhealthy/normal weight (BMI < 25 kg/m2), and (4) metabolically unhealthy/overweight (BMI ≥ 25 kg/m2). Additionally, in separate models, waist circumference measurements (using the International Diabetes Federation cut-points [≥80 cm for women and ≥94 cm for men]) were used (instead of BMI) to create the four metabolic health/body size phenotype categories. Statistical tests used in the analysis were all two-sided, and a p-value of <0.05 was considered statistically significant. In multivariable-adjusted conditional logistic regression models with BMI used to define adiposity, compared with metabolically healthy/normal weight individuals, we observed a higher colorectal cancer risk among metabolically unhealthy/normal weight (odds ratio [OR] = 1.59, 95% CI 1.10-2.28) and metabolically unhealthy/overweight (OR = 1.40, 95% CI 1.01-1.94) participants, but not among metabolically healthy/overweight individuals (OR = 0.96, 95% CI 0.65-1.42). Among the overweight individuals, lower colorectal cancer risk was observed for metabolically healthy/overweight individuals compared with metabolically unhealthy/overweight individuals (OR = 0.69, 95% CI 0.49-0.96). These associations were generally consistent when waist circumference was used as the measure of adiposity. To our knowledge, there is no universally accepted clinical definition for using C-peptide level as an indication of hyperinsulinaemia. Therefore, a possible limitation of our analysis was that the classification of individuals as being hyperinsulinaemic-based on their C-peptide level-was arbitrary. However, when we used quartiles or the median of C-peptide, instead of tertiles, as the cut-point of hyperinsulinaemia, a similar pattern of associations was observed.

Conclusions: These results support the idea that individuals with the metabolically healthy/overweight phenotype (with normal insulin levels) are at lower colorectal cancer risk than those with hyperinsulinaemia. The combination of anthropometric measures with metabolic parameters, such as C-peptide, may be useful for defining strata of the population at greater risk of colorectal cancer.
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http://dx.doi.org/10.1371/journal.pmed.1001988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4821615PMC
April 2016

Cellular immune activity biomarker neopterin is associated hyperlipidemia: results from a large population-based study.

Immun Ageing 2016 25;13. Epub 2016 Feb 25.

Cancer Registry and Histopathology Unit, "Civic - M.P. Arezzo" Hospital, ASP Ragusa, Italy.

Background: Increased serum neopterin had been described in older age two decades ago. Neopterin is a biomarker of systemic adaptive immune activation that could be potentially implicated in metabolic syndrome (MetS). Measurements of waist circumference, triglycerides, high-density lipoprotein cholesterol (HDLC), systolic and diastolic blood pressure, glycated hemoglobin as components of MetS definition, and plasma total neopterin concentrations were performed in 594 participants recruited in the European Prospective Investigation into Cancer and Nutrition (EPIC).

Results: Higher total neopterin concentrations were associated with reduced HDLC (9.7 %, p < 0.01 for men and 9.2 %, p < 0.01 for women), whereas no association was observed with the rest of the MetS components as well as with MetS overall (per 10 nmol/L: OR = 1.42, 95 % CI = 0.85-2.39 for men and OR = 1.38, 95 % CI = 0.79-2.43).

Conclusions: These data suggest that high total neopterin concentrations are cross-sectionally associated with reduced HDLC, but not with overall MetS.
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http://dx.doi.org/10.1186/s12979-016-0059-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4766742PMC
February 2016

Plasma carotenoids, vitamin C, tocopherols, and retinol and the risk of breast cancer in the European Prospective Investigation into Cancer and Nutrition cohort.

Am J Clin Nutr 2016 Feb 20;103(2):454-64. Epub 2016 Jan 20.

Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway;

Background: Carotenoids and vitamin C are thought to be associated with reduced cancer risk because of their antioxidative capacity.

Objective: This study evaluated the associations of plasma carotenoid, retinol, tocopherol, and vitamin C concentrations and risk of breast cancer.

Design: In a nested case-control study within the European Prospective Investigation into Cancer and Nutrition cohort, 1502 female incident breast cancer cases were included, with an oversampling of premenopausal (n = 582) and estrogen receptor-negative (ER-) cases (n = 462). Controls (n = 1502) were individually matched to cases by using incidence density sampling. Prediagnostic samples were analyzed for α-carotene, β-carotene, lycopene, lutein, zeaxanthin, β-cryptoxanthin, retinol, α-tocopherol, γ-tocopherol, and vitamin C. Breast cancer risk was computed according to hormone receptor status and age at diagnosis (proxy for menopausal status) by using conditional logistic regression and was further stratified by smoking status, alcohol consumption, and body mass index (BMI). All statistical tests were 2-sided.

Results: In quintile 5 compared with quintile 1, α-carotene (OR: 0.61; 95% CI: 0.39, 0.98) and β-carotene (OR: 0.41; 95% CI: 0.26, 0.65) were inversely associated with risk of ER- breast tumors. The other analytes were not statistically associated with ER- breast cancer. For estrogen receptor-positive (ER+) tumors, no statistically significant associations were found. The test for heterogeneity between ER- and ER+ tumors was statistically significant only for β-carotene (P-heterogeneity = 0.03). A higher risk of breast cancer was found for retinol in relation to ER-/progesterone receptor-negative tumors (OR: 2.37; 95% CI: 1.20, 4.67; P-heterogeneity with ER+/progesterone receptor positive = 0.06). We observed no statistically significant interaction between smoking, alcohol, or BMI and all investigated plasma analytes (based on tertile distribution).

Conclusion: Our results indicate that higher concentrations of plasma β-carotene and α-carotene are associated with lower breast cancer risk of ER- tumors.
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http://dx.doi.org/10.3945/ajcn.114.101659DOI Listing
February 2016

Prospective association of liver function biomarkers with development of hepatobiliary cancers.

Cancer Epidemiol 2016 Feb 11;40:179-87. Epub 2016 Jan 11.

epartment of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromso, Norway.

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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http://dx.doi.org/10.1016/j.canep.2016.01.002DOI Listing
February 2016

Vegetable and fruit consumption and the risk of hormone receptor-defined breast cancer in the EPIC cohort.

Am J Clin Nutr 2016 Jan 25;103(1):168-77. Epub 2015 Nov 25.

CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Navarre Public Health Institute, Pamplona, Spain;

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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http://dx.doi.org/10.3945/ajcn.114.101436DOI Listing
January 2016

The association of coffee intake with liver cancer risk is mediated by biomarkers of inflammation and hepatocellular injury: data from the European Prospective Investigation into Cancer and Nutrition.

Am J Clin Nutr 2015 Dec 11;102(6):1498-508. Epub 2015 Nov 11.

Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway;

Background: Higher coffee intake has been purportedly related to a lower risk of liver cancer. However, it remains unclear whether this association may be accounted for by specific biological mechanisms.

Objective: We aimed to evaluate the potential mediating roles of inflammatory, metabolic, liver injury, and iron metabolism biomarkers on the association between coffee intake and the primary form of liver cancer-hepatocellular carcinoma (HCC).

Design: We conducted a prospective nested case-control study within the European Prospective Investigation into Cancer and Nutrition among 125 incident HCC cases matched to 250 controls using an incidence-density sampling procedure. The association of coffee intake with HCC risk was evaluated by using multivariable-adjusted conditional logistic regression that accounted for smoking, alcohol consumption, hepatitis infection, and other established liver cancer risk factors. The mediating effects of 21 biomarkers were evaluated on the basis of percentage changes and associated 95% CIs in the estimated regression coefficients of models with and without adjustment for biomarkers individually and in combination.

Results: The multivariable-adjusted RR of having ≥4 cups (600 mL) coffee/d compared with <2 cups (300 mL)/d was 0.25 (95% CI: 0.11, 0.62; P-trend = 0.006). A statistically significant attenuation of the association between coffee intake and HCC risk and thereby suspected mediation was confirmed for the inflammatory biomarker IL-6 and for the biomarkers of hepatocellular injury glutamate dehydrogenase, alanine aminotransferase, aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), and total bilirubin, which-in combination-attenuated the regression coefficients by 72% (95% CI: 7%, 239%). Of the investigated biomarkers, IL-6, AST, and GGT produced the highest change in the regression coefficients: 40%, 56%, and 60%, respectively.

Conclusion: These data suggest that the inverse association of coffee intake with HCC risk was partly accounted for by biomarkers of inflammation and hepatocellular injury.
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http://dx.doi.org/10.3945/ajcn.115.116095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4658462PMC
December 2015

Reproductive factors and risk of mortality in the European Prospective Investigation into Cancer and Nutrition; a cohort study.

BMC Med 2015 Oct 30;13:252. Epub 2015 Oct 30.

CIBER de Epidemiología y Salud Pública (CIBERESP), Melchor Fernández Almagro, 3-5, 28029, Madrid, Spain.

Background: Reproductive events are associated with important physiologic changes, yet little is known about how reproductive factors influence long-term health in women. Our objective was to assess the relation of reproductive characteristics with all-cause and cause-specific mortality risk.

Methods: The analysis was performed within the European Investigation into Cancer and Nutrition prospective cohort study, which enrolled >500,000 women and men from 1992 to 2000, who were residing in a given town/geographic area in 10 European countries. The current analysis included 322,972 eligible women aged 25-70 years with 99 % complete follow-up for vital status. We assessed reproductive characteristics reported at the study baseline including parity, age at the first birth, breastfeeding, infertility, oral contraceptive use, age at menarche and menopause, total ovulatory years, and history of oophorectomy/hysterectomy. Hazard ratios (HRs) and 95 % confidence intervals (CIs) for mortality were determined using Cox proportional hazards regression models adjusted for menopausal status, body mass index, physical activity, education level, and smoking status/intensity and duration.

Results: During a mean follow-up of 12.9 years, 14,383 deaths occurred. The HR (95 % CI) for risk of all-cause mortality was lower in parous versus nulliparous women (0.80; 0.76-0.84), in women who had ever versus never breastfed (0.92; 0.87-0.97), in ever versus never users of oral contraceptives (among non-smokers; 0.90; 0.86-0.95), and in women reporting a later age at menarche (≥15 years versus <12; 0.90; 0.85-0.96; P for trend = 0.038).

Conclusions: Childbirth, breastfeeding, oral contraceptive use, and a later age at menarche were associated with better health outcomes. These findings may contribute to the development of improved strategies to promote better long-term health in women.
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http://dx.doi.org/10.1186/s12916-015-0484-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627614PMC
October 2015

Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for Thirteen Cancer Types.

J Natl Cancer Inst 2015 Dec 12;107(12):djv279. Epub 2015 Oct 12.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD (JNS, OP, SIB, QL, CCA, LTA, JDF, MTL, LM, SAS, PRT, KAM, PR, DA, DB, BAB, AB, LBr, WHC, CCC, JSC, JFFJr, NDF, LEBF, MGC, AMG, RNH, NH, WH, PDI, BTJ, CK, CMK, LML, MSL, LEM, LPO, RSSS, WeiT, MT, CWa, SW, NW, KY, PH, LMM, NEC, NR, DTS, SJC, NC); Information Management Services, Silver Spring, MD (WAW, CG); Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Gaithersburg, MD (MY, ZW, LBu, AH, CLi); Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (IDV, KAB, BMB, CoC, MCB, CF, EG, SL, JP, MSt, DJH); Department of Epidemiology, Harvard School of Public Health, Boston, MA (IDV, OA, KAB, CoC, MCB, EG, RSK, SL, JP, HDS, MSt, DTr, DJH, PK); Ontario Health Study, Toronto, Ontario, Canada (MPP); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (HOA, EWe); Unit of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (AA, MF); UCL Cancer Institute, London, UK (MFA, AMF, DH); Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, UK (MFA, AMF, DH, RT); Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China (SJA, JS, YLW, XCZ); Department of Radiation Sciences, Oncology, Umea University, Umea, Sweden (UA, RH, BSM); Division of Urologic Surgery, Washington University School of Medicine, Saint Louis, MO (GAJr, RGIII); Litwin Centre for Cancer Genetics, University of Toronto, Ontario, Canada (ILA, NG, JSW); Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (ILA, SG, NG, JSW); Hematology Unit, Ospedale Oncologico di Riferimento Regionale A. Businco, Cagliari, Italy (EA); Department of Medicin

Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites.

Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers.

Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl (2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures.

Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
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http://dx.doi.org/10.1093/jnci/djv279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4806328PMC
December 2015

Determinants of the t(14;18) translocation and their role in t(14;18)-positive follicular lymphoma.

Cancer Causes Control 2015 Dec 30;26(12):1845-55. Epub 2015 Sep 30.

Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway.

Purpose: The strong association between t(14;18) translocation and follicular lymphoma (FL) is well known. However, the determinants of this chromosomal aberration and their role in t(14;18) associated FL remain to be established.

Methods: t(14;18) frequency within the B cell lymphoma 2 major breakpoint region was determined for 135 incident FL cases and 251 healthy controls as part of a nested case-control study within the European Prospective Investigation into Cancer cohort. Quantitative real-time PCR was performed in DNA extracted from blood samples taken at recruitment. The relationship between prevalence and frequency of the translocation with baseline anthropometric, lifestyle, and dietary factors in cases and controls was determined. Unconditional logistic regression was used to explore whether the risk of FL associated with these factors differed in t(14;18)(+) as compared to t(14;18)(-) cases.

Results: Among incident FL cases, educational level (χ(2) p = 0.021) and height (χ(2) p = 0.025) were positively associated with t(14;18) prevalence, and cases with high frequencies [t(14;18)(HF)] were significantly taller (t test p value = 0.006). These findings were not replicated in the control population, although there were a number of significant associations with dietary variables. Further analyses revealed that height was a significant risk factor for t(14;18)(+) FL [OR 6.31 (95% CI 2.11, 18.9) in the tallest versus the shortest quartile], but not t(14;18)(-) cases.

Conclusions: These findings suggest a potential role for lifestyle factors in the prevalence and frequency of the t(14;18) translocation. The observation that the etiology of FL may differ by t(14;18) status, particularly with regard to height, supports the subdivision of FL by translocation status.
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http://dx.doi.org/10.1007/s10552-015-0677-2DOI Listing
December 2015

Metabolomic profiles of hepatocellular carcinoma in a European prospective cohort.

BMC Med 2015 Sep 23;13:242. Epub 2015 Sep 23.

Escuela Andaluza de Salud Pública, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain.

Background: Hepatocellular carcinoma (HCC), the most prevalent form of liver cancer, is difficult to diagnose and has limited treatment options with a low survival rate. Aside from a few key risk factors, such as hepatitis, high alcohol consumption, smoking, obesity, and diabetes, there is incomplete etiologic understanding of the disease and little progress in identification of early risk biomarkers.

Methods: To address these aspects, an untargeted nuclear magnetic resonance metabolomic approach was applied to pre-diagnostic serum samples obtained from first incident, primary HCC cases (n = 114) and matched controls (n = 222) identified from amongst the participants of a large European prospective cohort.

Results: A metabolic pattern associated with HCC risk comprised of perturbations in fatty acid oxidation and amino acid, lipid, and carbohydrate metabolism was observed. Sixteen metabolites of either endogenous or exogenous origin were found to be significantly associated with HCC risk. The influence of hepatitis infection and potential liver damage was assessed, and further analyses were made to distinguish patterns of early or later diagnosis.

Conclusion: Our results show clear metabolic alterations from early stages of HCC development with application for better etiologic understanding, prevention, and early detection of this increasingly common cancer.
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http://dx.doi.org/10.1186/s12916-015-0462-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4581424PMC
September 2015

Polyphenol metabolome in human urine and its association with intake of polyphenol-rich foods across European countries.

Am J Clin Nutr 2015 Oct 12;102(4):905-13. Epub 2015 Aug 12.

International Agency for Research on Cancer, Lyon, France;

Background: An improved understanding of the contribution of the diet to health and disease risks requires accurate assessments of dietary exposure in nutritional epidemiologic studies. The use of dietary biomarkers may improve the accuracy of estimates.

Objective: We applied a metabolomic approach in a large cohort study to identify novel biomarkers of intake for a selection of polyphenol-containing foods. The large chemical diversity of polyphenols and their wide distribution over many foods make them ideal biomarker candidates for such foods.

Design: Metabolic profiles were measured with the use of high-resolution mass spectrometry in 24-h urine samples from 481 subjects from the large European Prospective Investigation on Cancer and Nutrition cohort. Peak intensities were correlated to acute and habitual dietary intakes of 6 polyphenol-rich foods (coffee, tea, red wine, citrus fruit, apples and pears, and chocolate products) measured with the use of 24-h dietary recalls and food-frequency questionnaires, respectively.

Results: Correlation (r > 0.3, P < 0.01 after correction for multiple testing) and discriminant [pcorr (1) > 0.3, VIP > 1.5] analyses showed that >2000 mass spectral features from urine metabolic profiles were significantly associated with the consumption of the 6 selected foods. More than 80 polyphenol metabolites associated with the consumption of the selected foods could be identified, and large differences in their concentrations reflecting individual food intakes were observed within and between 4 European countries. Receiver operating characteristic curves showed that 5 polyphenol metabolites, which are characteristic of 5 of the 6 selected foods, had a high predicting ability of food intake.

Conclusion: Highly diverse food-derived metabolites (the so-called food metabolome) can be characterized in human biospecimens through this powerful metabolomic approach and screened to identify novel biomarkers for dietary exposures, which are ultimately essential to better understand the role of the diet in the cause of chronic diseases.
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http://dx.doi.org/10.3945/ajcn.114.101881DOI Listing
October 2015

ABO blood group alleles and prostate cancer risk: Results from the breast and prostate cancer cohort consortium (BPC3).

Prostate 2015 Nov 13;75(15):1677-81. Epub 2015 Aug 13.

International Agency for Research on Cancer, Lyon, France.

Background: ABO blood group has been associated with risk of cancers of the pancreas, stomach, ovary, kidney, and skin, but has not been evaluated in relation to risk of aggressive prostate cancer.

Methods: We used three single nucleotide polymorphisms (SNPs) (rs8176746, rs505922, and rs8176704) to determine ABO genotype in 2,774 aggressive prostate cancer cases and 4,443 controls from the Breast and Prostate Cancer Cohort Consortium (BPC3). Unconditional logistic regression was used to calculate age and study-adjusted odds ratios and 95% confidence intervals for the association between blood type, genotype, and risk of aggressive prostate cancer (Gleason score ≥8 or locally advanced/metastatic disease (stage T3/T4/N1/M1).

Results: We found no association between ABO blood type and risk of aggressive prostate cancer (Type A: OR = 0.97, 95%CI = 0.87-1.08; Type B: OR = 0.92, 95%CI =n0.77-1.09; Type AB: OR = 1.25, 95%CI = 0.98-1.59, compared to Type O, respectively). Similarly, there was no association between "dose" of A or B alleles and aggressive prostate cancer risk.

Conclusions: ABO blood type was not associated with risk of aggressive prostate cancer.
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http://dx.doi.org/10.1002/pros.23035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4578997PMC
November 2015

Prenatal Maternal Physical Activity and Stem Cells in Umbilical Cord Blood.

Med Sci Sports Exerc 2016 Jan;48(1):82-9

1Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA; 2Department of Obstetrics and Gynecology, Tufts Medical Center, Boston, MA; 3Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical School and UMass Memorial Health Care, Worcester, MA; 4Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; 5Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA; and 6Department of Hygiene, Epidemiology, and Medical Statistics, University of Athens, Athens, GREECE.

Purpose: Early life processes, through influence on fetal stem cells, affect postnatal and adult health outcomes. This study examines the effects of physical activity before and during pregnancy on stem cell counts in umbilical cord blood.

Methods: We isolated mononuclear cells from umbilical cord blood samples from 373 singleton full-term pregnancies and quantified hematopoietic (CD34(+), CD34(+)CD38(-), and CD34(+) c-kit(+)), endothelial (CD34(+)CD133(+), CD34(+)CD133(+)VEGFR2(+), CD34(+)VEGFR2(+), and CD133(+)VEGFR2(+)), and putative breast (EpCAM(+), EpCAM(+)CD49f(+), EpCAM(+)CD49f(+)CD117(+), CD49f(+)CD24(+), CD24(+)CD29(+), and CD24(+)CD29(+)CD49f(+)) stem/progenitor cell subpopulations by flow cytometry. Information on physical activities before and during pregnancy was obtained from questionnaires. Weekly energy expenditure was estimated based on metabolic equivalent task values.

Results: Prepregnancy vigorous exercise was associated positively with levels of endothelial CD34(+)CD133(+), CD34(+)CD133(+)VEGFR2(+), CD34(+)VEGFR2(+), and CD133(+)VEGFR2(+ )progenitor cell populations (P = 0.02, P = 0.01, P = 0.001, and P = 0.003, respectively); positive associations were observed in samples from the first births and those from the second or later births. Prepregnancy moderate and light exercises and light exercise during the first trimester were not significantly associated with any stem/progenitor cell population. Light exercise during the second trimester was positively associated with CD34(+)VEGFR2(+) endothelial progenitor cells (P = 0.03). In addition, levels of EpCAM(+)CD49f(+) and CD49f(+)CD24(+) breast stem cells were significantly lower among pregnant women who engaged in vigorous/moderate exercise during pregnancy (P = 0.05 and P = 0.02, respectively).

Conclusions: Vigorous exercise before pregnancy increases the number of endothelial progenitor cells in umbilical cord blood and thus could potentially enhance endothelial function and improve cardiovascular fitness in the offspring. Findings of lower levels of putative breast stem cell subpopulations could have implications on exercise and breast cancer prevention. Prenatal effects of exercise on fetal stem cells warrant further studies.
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http://dx.doi.org/10.1249/MSS.0000000000000731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4681599PMC
January 2016

Genetic risk variants associated with in situ breast cancer.

Breast Cancer Res 2015 Jun 13;17:82. Epub 2015 Jun 13.

Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.

Introduction: Breast cancer in situ (BCIS) diagnoses, a precursor lesion for invasive breast cancer, comprise about 20 % of all breast cancers (BC) in countries with screening programs. Family history of BC is considered one of the strongest risk factors for BCIS.

Methods: To evaluate the association of BC susceptibility loci with BCIS risk, we genotyped 39 single nucleotide polymorphisms (SNPs), associated with risk of invasive BC, in 1317 BCIS cases, 10,645 invasive BC cases, and 14,006 healthy controls in the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3). Using unconditional logistic regression models adjusted for age and study, we estimated the association of SNPs with BCIS using two different comparison groups: healthy controls and invasive BC subjects to investigate whether BCIS and BC share a common genetic profile.

Results: We found that five SNPs (CDKN2BAS-rs1011970, FGFR2-rs3750817, FGFR2-rs2981582, TNRC9-rs3803662, 5p12-rs10941679) were significantly associated with BCIS risk (P value adjusted for multiple comparisons <0.0016). Comparing invasive BC and BCIS, the largest difference was for CDKN2BAS-rs1011970, which showed a positive association with BCIS (OR = 1.24, 95 % CI: 1.11-1.38, P = 1.27 x 10(-4)) and no association with invasive BC (OR = 1.03, 95 % CI: 0.99-1.07, P = 0.06), with a P value for case-case comparison of 0.006. Subgroup analyses investigating associations with ductal carcinoma in situ (DCIS) found similar associations, albeit less significant (OR = 1.25, 95 % CI: 1.09-1.42, P = 1.07 x 10(-3)). Additional risk analyses showed significant associations with invasive disease at the 0.05 level for 28 of the alleles and the OR estimates were consistent with those reported by other studies.

Conclusions: Our study adds to the knowledge that several of the known BC susceptibility loci are risk factors for both BCIS and invasive BC, with the possible exception of rs1011970, a putatively functional SNP situated in the CDKN2BAS gene that may be a specific BCIS susceptibility locus.
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http://dx.doi.org/10.1186/s13058-015-0596-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4487950PMC
June 2015

Size at birth and risk of breast cancer: update from a prospective population-based study.

Eur J Epidemiol 2015 Jun 31;30(6):485-92. Epub 2015 May 31.

Department of Public Health and General Practice, Norwegian University of Science and Technology, Trondheim, Norway.

Birth size variables (birth weight, birth length and head circumference) have been reported to be positively associated with adult breast cancer risk, whereas a possible association of placental weight has not been adequately studied. It has also been suggested that maternal height may modify the association of birth size with adult breast cancer risk, but this has not been studied in detail. We updated a long-term follow-up of 22,931 Norwegian women (average of 51 years of follow up during which 870 women were diagnosed with breast cancer) and assessed placental weight in relation to breast cancer risk, in addition to providing updated analyses on breast cancer risk in relation to birth weight, birth length and head circumference. Placental weight was not associated with risk for breast cancer in adulthood, but there was a positive association of breast cancer risk with birth length (HR 1.13, 95% CI 1.05-1.21, per 2 cm increment), though not with birth weight (HR 1.02, 95% CI 0.95-1.10 per 0.5 kg increment). For birth length, the graded increase in risk was particularly strong among women whose mothers were relatively tall (p for trend, 0.001), compared to the trend among women whose mothers were relatively short (p for trend, 0.221). The results showed a robust and positive association of birth length with breast cancer risk, and may be especially strong in women whose mothers were relatively tall. We found no association of placental weight with risk for breast cancer.
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http://dx.doi.org/10.1007/s10654-015-0045-2DOI Listing
June 2015

Circulating prolactin and in situ breast cancer risk in the European EPIC cohort: a case-control study.

Breast Cancer Res 2015 Mar 31;17:49. Epub 2015 Mar 31.

Department of Radiation Sciences, University of Umeå, Umeå, Sweden.

Introduction: The relationship between circulating prolactin and invasive breast cancer has been investigated previously, but the association between prolactin levels and in situ breast cancer risk has received less attention.

Methods: We analysed the relationship between pre-diagnostic prolactin levels and the risk of in situ breast cancer overall, and by menopausal status and use of postmenopausal hormone therapy (HT) at blood donation. Conditional logistic regression was used to assess this association in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, including 307 in situ breast cancer cases and their matched control subjects.

Results: We found a significant positive association between higher circulating prolactin levels and risk of in situ breast cancer among all women [pre-and postmenopausal combined, ORlog2=1.35 (95% CI 1.04-1.76), Ptrend=0.03]. No statistically significant heterogeneity was found between prolactin levels and in situ cancer risk by menopausal status (Phet=0.98) or baseline HT use (Phet=0.20), although the observed association was more pronounced among postmenopausal women using HT compared to non-users (Ptrend=0.06 vs Ptrend=0.35). In subgroup analyses, the observed positive association was strongest in women diagnosed with in situ breast tumors<4 years compared to ≥4 years after blood donation (Ptrend=0.01 vs Ptrend=0.63; Phet=0.04) and among nulliparous women compared to parous women (Ptrend=0.03 vs Ptrend=0.15; Phet=0.07).

Conclusions: Our data extends prior research linking prolactin and invasive breast cancer to the outcome of in situ breast tumours and shows that higher circulating prolactin is associated with increased risk of in situ breast cancer.
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http://dx.doi.org/10.1186/s13058-015-0563-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413538PMC
March 2015

Alcohol consumption and the risk of renal cancers in the European prospective investigation into cancer and nutrition (EPIC).

Int J Cancer 2015 Oct 28;137(8):1953-66. Epub 2015 Apr 28.

Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain.

Epidemiologic studies have reported that moderate alcohol consumption is inversely associated with the risk of renal cancer. However, there is no information available on the associations in renal cancer subsites. From 1992 through to 2010, 477,325 men and women in the European Prospective Investigation into Cancer and Nutrition cohort were followed for incident renal cancers (n = 931). Baseline and lifetime alcohol consumption was assessed by country-specific, validated dietary questionnaires. Information on past alcohol consumption was collected by lifestyle questionnaires. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from Cox proportional hazard models. In multivariate analysis, total alcohol consumption at baseline was inversely associated with renal cancer; the HR and 95% CI for the increasing categories of total alcohol consumption at recruitment versus the light drinkers category were 0.78 (0.62-0.99), 0.82 (0.64-1.04), 0.70 (0.55-0.90), 0.91 (0.63-1.30), respectively, (ptrend  = 0.001). A similar relationship was observed for average lifetime alcohol consumption and for all renal cancer subsites combined or for renal parenchyma subsite. The trend was not observed in hypertensive individuals and not significant in smokers. In conclusion, moderate alcohol consumption was associated with a decreased risk of renal cancer.
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http://dx.doi.org/10.1002/ijc.29559DOI Listing
October 2015
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