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  • 1. Baumeister, Sebastian E.
    et al.
    Schlesinger, Sabrina
    Aleksandrova, Krasimira
    Jochem, Carmen
    Jenab, Mazda
    Gunter, Marc J.
    Overvad, Kim
    Tjonneland, Anne
    Boutron-Ruault, Marie-Christine
    Carbonnel, Franck
    Fournier, Agnes
    Kuehn, Tilman
    Kaaks, Rudolf
    Pischon, Tobias
    Boeing, Heiner
    Trichopoulou, Antonia
    Bamia, Christina
    La Vecchia, Carlo
    Masala, Giovanna
    Panico, Salvatore
    Fasanelli, Francesca
    Tumino, Rosario
    Grioni, Sara
    de Mesquita, Bas Bueno
    Vermeulen, Roel
    May, Anne M.
    Borch, Kristin B.
    Oyeyemi, Sunday O.
    Ardanaz, Eva
    Rodriguez-Barranco, Miguel
    Chirlaque Lopez, Maria Dolores
    Felez-Nobrega, Mireia
    Sonestedt, Emily
    Ohlsson, Bodil
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Werner, Mårten
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Perez-Cornago, Aurora
    Ferrari, Pietro
    Stepien, Magdalena
    Freisling, Heinz
    Tsilidis, Konstantinos K.
    Ward, Heather
    Riboli, Elio
    Weiderpass, Elisabete
    Leitzmann, Michael F.
    Association between physical activity and risk of hepatobiliary cancers: A multinational cohort study2019In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 70, no 5, p. 885-892Article in journal (Refereed)
    Abstract [en]

    Background & Aims: To date, evidence on the association between physical activity and risk of hepatobiliary cancers has been inconclusive. We examined this association in the European Prospective Investigation into Cancer and Nutrition cohort (EPIC).

    Methods: We identified 275 hepatocellular carcinoma (HCC) cases, 93 intrahepatic bile duct cancers (IHBCs), and 164 non-gallbladder extrahepatic bile duct cancers (NGBCs) among 467,336 EPIC participants (median follow-up 14.9 years). We estimated cause-specific hazard ratios (HRs) for total physical activity and vigorous physical activity and performed mediation analysis and secondary analyses to assess robustness to confounding (e.g. due to hepatitis virus infection).

    Results: In the EPIC cohort, the multivariable-adjusted HR of HCC was 0.55 (95% CI 0.38–0.80) comparing active and inactive individuals. Regarding vigorous physical activity, for those reporting >2 hours/week compared to those with no vigorous activity, the HR for HCC was 0.50 (95% CI 0.33–0.76). Estimates were similar in sensitivity analyses for confounding. Total and vigorous physical activity were unrelated to IHBC and NGBC. In mediation analysis, waist circumference explained about 40% and body mass index 30% of the overall association of total physical activity and HCC.

    Conclusions: These findings suggest an inverse association between physical activity and risk of HCC, which is potentially mediated by obesity.

    Lay summary: In a pan-European study of 467,336 men and women, we found that physical activity is associated with a reduced risk of developing liver cancers over the next decade. This risk was independent of other liver cancer risk factors, and did not vary by age, gender, smoking status, body weight, and alcohol consumption.

  • 2. Butt, Julia
    et al.
    Jenab, Mazda
    Pawlita, Michael
    Overvad, Kim
    Tjonneland, Anne
    Olsen, Anja
    Boutron-Ruault, Marie-Christine
    Carbonnel, Franck
    Mancini, Francesca Romana
    Kaaks, Rudolf
    Kühn, Tilman
    Boeing, Heiner
    Trichopoulou, Antonia
    Karakatsani, Anna
    Palli, Domenico
    Pala, Valeria Maria
    Tumino, Rosario
    Sacerdote, Carlotta
    Panico, Salvatore
    Bueno-de-Mesquita, Bas
    van Gils, Carla H.
    Vermeulen, Roel C. H.
    Weiderpass, Elisabete
    Quiros, Jose Ramon
    Duell, Eric Jeffrey
    Sanchez, Maria-Jose
    Dorronsoro, Miren
    Maria Huerta, Jose
    Ardanaz, Eva
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Harlid, Sophia
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Perez-Cornago, Aurora
    Gunter, Marc J.
    Murphy, Neil
    Freisling, Heinz
    Aune, Dagfinn
    Waterboer, Tim
    Hughes, David J.
    Antibody Responses to Fusobacterium nucleatum Proteins in Prediagnostic Blood Samples are not Associated with Risk of Developing Colorectal Cancer2019In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 28, no 9, p. 1552-1555Article in journal (Refereed)
    Abstract [en]

    Background: There is a lack of prospective data on the potential association of Fusobacterium nucleatum (F. nucleatum) and colorectal cancer risk. In this study, we assessed whether antibody responses to F. nucleatum are associated with colorectal cancer risk in prediagnostic serum samples in the European Prospective Investigation into Nutrition and Cancer (EPIC) cohort.

    Methods: We applied a multiplex serology assay to simultaneously measure antibody responses to 11 F. nucleatum antigens in prediagnostic serum samples from 485 colorectal cancer cases and 485 matched controls. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CI).

    Results: We observed neither a statistically significant colorectal cancer risk association for antibodies to individual F. nucleatum proteins nor for combined positivity to any of the 11 proteins (OR, 0.81; 95% CI, 0.62–1.06).

    Conclusions: Antibody responses to F. nucleatum proteins in prediagnostic serum samples from a subset of colorectal cancer cases and matched controls within the EPIC study were not associated with colorectal cancer risk.

    Impact: Our findings in prospectively ascertained serum samples contradict the existing literature on the association of F. nucleatum with colorectal cancer risk. Future prospective studies, specifically detecting F. nucleatum in stool or tissue biopsies, are needed to complement our findings.

  • 3. Cramer, Daniel W.
    et al.
    Fichorova, Raina N.
    Terry, Kathryn L.
    Yamamoto, Hidemi
    Vitonis, Allison F.
    Ardanaz, Eva
    Aune, Dagfinn
    Boeing, Heiner
    Brändstedt, Jenny
    Boutron-Ruault, Marie-Christine
    Chirlaque, Maria-Dolores
    Dorronsoro, Miren
    Dossus, Laure
    Duell, Eric J.
    Gram, Inger T.
    Gunter, Marc
    Hansen, Louise
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Johnson, Theron
    Khaw, Kay-Tee
    Krogh, Vittorio
    Kvaskoff, Marina
    Mattiello, Amalie
    Matullo, Giuseppe
    Merritt, Melissa A.
    Nodin, Björn
    Orfanos, Philippos
    Onland-Moret, N. Charlotte
    Palli, Domenico
    Peppa, Eleni
    Quirós, J. Ramón
    Sánchez-Perez, Maria-Jose
    Severi, Gianluca
    Tjønneland, Anne
    Travis, Ruth C.
    Trichopoulou, Antonia
    Tumino, Rosario
    Weiderpass, Elisabete
    Fortner, Renée T.
    Kaaks, Rudolf
    Anti-CA15.3 and Anti-CA125 Antibodies and Ovarian Cancer Risk: Results from the EPIC Cohort2018In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 27, no 7, p. 790-804Article in journal (Refereed)
    Abstract [en]

    Background: Neoplastic and non-neoplastic events may raise levels of mucins, CA15.3, and CA125, and generate antibodies against them, but their impact on epithelial ovarian cancer (FOC) risk has not been fully defined.

    Methods: CA15.3, CA125, and IgC1 antibodies against them were measured in 806 women who developed FAN; and 1,927 matched controls from the European Prospective Investigation of Nutrition and Cancer. Associations between epidemiologic factors and anti-mucin antibodies were evaluated using generalized linear models; EOC risks associated with anti-mucin antibodies, by themselves or in combination with respective antigens, were evaluated using conditional logistic regression.

    Results: In controls, lower antibodies against both mucins were associated with current smoking; and, in postmenopausal women, higher levels with longer oral contraceptive use and later-age-at and shorter-interval-since last birth. Lower antiCA15.3 antibodies were associated with higher body mass and, in premenopausal women, more ovulatory cycles. Higher anti-CA15.3 and anti-CA In antibodies were associated with higher risk for mutinous IOC occurring >= 3 years from enrollment. Long-term risk for serous EOC was reduced in women with low CA125 and high anti-CA125 antibodies relative to women with low concentrations of both.

    Conclusions: We found general support for the hypothesis that anti-mucin antibody levels correlate with risk factors for EOC Antibodies alone or in combinations with their antigen may predict longer term risk of specific EOC types.

    Impact: Anti-CA125 and anti-CA15.3 antibodies alone or in perspective of antigens may be informative in the pathogenesis of EOC subtypes, but less useful for informing risk for all EOC.

  • 4. Murphy, Neil
    et al.
    Ward, Heather A.
    Jenab, Mazda
    Rothwell, Joseph A.
    Boutron-Ruault, Marie-Christine
    Carbonnel, Franck
    Kvaskoff, Marina
    Kaaks, Rudolf
    Kühn, Tilman
    Boeing, Heiner
    Aleksandrova, Krasimira
    Weiderpass, Elisabete
    Skeie, Guri
    Borch, Kristin Benjaminsen
    Tjønneland, Anne
    Kyrø, Cecilie
    Overvad, Kim
    Dahm, Christina C.
    Jakszyn, Paula
    Sánchez, Maria-Jose
    Gil, Leire
    Huerta, José M.
    Barricarte, Aurelio
    Ramón Quirós, J.
    Khaw, Kay-Tee
    Wareham, Nick
    Bradbury, Kathryn E.
    Trichopoulou, Antonia
    La Vecchia, Carlo
    Karakatsani, Anna
    Palli, Domenico
    Grioni, Sara
    Tumino, Rosario
    Fasanelli, Francesca
    Panico, Salvatore
    Bueno-de-Mesquita, Bas
    Peeters, Petra H.
    Gylling, Björn
    Myte, Robin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Jirström, Karin
    Berntsson, Jonna
    Xue, Xiaonan
    Riboli, Elio
    Cross, Amanda J.
    Gunter, Marc J.
    Heterogeneity of Colorectal Cancer Risk Factors by Anatomical Subsite in 10 European Countries: A Multinational Cohort Study2019In: Clinical Gastroenterology and Hepatology, ISSN 1542-3565, E-ISSN 1542-7714, Vol. 17, no 7, p. 1323-1331Article in journal (Refereed)
    Abstract [en]

    Background & Aims: Colorectal cancer located at different anatomical subsites may have distinct etiologies and risk factors. Previous studies that have examined this hypothesis have yielded inconsistent results, possibly because most studies have been of insufficient size to identify heterogeneous associations with precision.

    Methods: In the European Prospective Investigation into Cancer and Nutrition study, we used multivariable joint Cox proportional hazards models, which accounted for tumorsat different anatomical sites (proximal colon, distal colon, and rectum) as competing risks, to examine the relationships between 14 established/suspected lifestyle, anthropometric, and reproductive/menstrual risk factors with colorectal cancer risk. Heterogeneity across sites was tested using Wald tests.

    Results: After a median of 14.9 years of follow-up of 521,330 men and women, 6291 colorectal cancer cases occurred. Physical activity was related inversely to proximal colon and distal colon cancer, but not to rectal cancer (P heterogeneity = .03). Height was associated positively with proximal and distal colon cancer only, but not rectal cancer (P heterogeneity = .0001). For men, but not women, heterogeneous relationships were observed for body mass index (P heterogeneity = .008) and waist circumference (P heterogeneity = .03), with weaker positive associations found for rectal cancer, compared with proximal and distal colon cancer. Current smoking was associated with a greater risk of rectal and proximal colon cancer, but not distal colon cancer (P heterogeneity = .05). No heterogeneity by anatomical site was found for alcohol consumption, diabetes, nonsteroidal anti-inflammatory drug use, and reproductive/menstrual factors.

    Conclusions: The relationships between physical activity, anthropometry, and smoking with colorectal cancer risk differed by subsite, supporting the hypothesis that tumors in different anatomical regions may have distinct etiologies.

  • 5. Obon-Santacana, Mireia
    et al.
    Lujan-Barroso, Leila
    Freisling, Heinz
    Naudin, Sabine
    Boutron-Ruault, Marie-Christine
    Mancini, Francesca Romana
    Rebours, Vinciane
    Kuehn, Tilman
    Katzke, Verena
    Boeing, Heiner
    Tjonneland, Anne
    Olsen, Anja
    Overvad, Kim
    Lasheras, Cristina
    Rodriguez-Barranco, Miguel
    Amiano, Pilar
    Santiuste, Carmen
    Ardanaz, Eva
    Khaw, Kay-Thee
    Wareham, Nicholas J.
    Schmidt, Julie A.
    Aune, Dagfinn
    Trichopoulou, Antonia
    Thriskos, Paschalis
    Peppa, Eleni
    Masala, Giovanna
    Grioni, Sara
    Tumino, Rosario
    Panico, Salvatore
    Bueno-de-Mesquita, Bas
    Sciannameo, Veronica
    Vermeulen, Roel
    Sonestedt, Emily
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Weiderpass, Elisabete
    Skeie, Guri
    Gonzalez, Carlos A.
    Riboli, Elio
    Duell, Eric J.
    Consumption of nuts and seeds and pancreatic ductal adenocarcinoma risk in the European Prospective Investigation into Cancer and Nutrition2020In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 146, no 1, p. 76-84Article in journal (Refereed)
    Abstract [en]

    Four epidemiologic studies have assessed the association between nut intake and pancreatic cancer risk with contradictory results. The present study aims to investigate the relation between nut intake (including seeds) and pancreatic ductal adenocarcinoma (PDAC) risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Cox proportional hazards models were used to estimate hazards ratio (HR) and 95% confidence intervals (95% CI) for nut intake and PDAC risk. Information on intake of nuts was obtained from the EPIC country-specific dietary questionnaires. After a mean follow-up of 14 years, 476,160 participants were eligible for the present study and included 1,283 PDAC cases. No association was observed between consumption of nuts and PDAC risk (highest intake vs nonconsumers: HR, 0.89; 95% CI, 0.72-1.10; p-trend = 0.70). Furthermore, no evidence for effect-measure modification was observed when different subgroups were analyzed. Overall, in EPIC, the highest intake of nuts was not statistically significantly associated with PDAC risk.

  • 6. Park, Jin Young
    et al.
    Bueno-de-Mesquita, H. Bas
    Ferrari, Pietro
    Weiderpass, Elisabete
    de Batlle, Jordi
    Tjonneland, Anne
    Kyro, Cecilie
    Rebours, Vinciane
    Boutron-Ruault, Marie-Christine
    Mancini, Francesca Romana
    Katzke, Verena
    Kuehn, Tilman
    Boeing, Heiner
    Trichopoulou, Antonia
    La Vecchia, Carlo
    Kritikou, Maria
    Masala, Giovanna
    Pala, Valeria
    Tumino, Rosario
    Panico, Salvatore
    Peeters, Petra H.
    Skeie, Guri
    Merino, Susana
    Duell, Eric J.
    Rodriguez-Barranco, Miguel
    Dorronsoro, Miren
    Chirlaque, Maria-Dolores
    Ardanaz, Eva
    Gylling, Björn
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Schneede, Jörn
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Ericson, Ulrika
    Sternby, Hanna
    Khaw, Kay-Tee
    Bradbury, Kathryn E.
    Huybrechts, Inge
    Aune, Dagfinn
    Vineis, Paolo
    Slimani, Nadia
    Dietary folate intake and pancreatic cancer risk: Results from the European prospective investigation into cancer and nutrition2019In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 144, no 7, p. 1511-1521Article in journal (Refereed)
    Abstract [en]

    Pancreatic cancer (PC) has an exceptionally low survival rate and primary prevention strategies are limited. Folate plays an important role in one-carbon metabolism and has been associated with the risk of several cancers, but not consistently with PC risk. We aimed to investigate the association between dietary folate intake and PC risk, using the standardised folate database across 10 European countries. A total of 477,206 participants were followed up for 11 years, during which 865 incident primary PC cases were recorded. Folate intake was energy-adjusted using the residual method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. In multivariable analyses stratified by age, sex, study centre and adjusted for energy intake, smoking status, BMI, educational level, diabetes status, supplement use and dietary fibre intake, we found no significant association between folate intake and PC risk: the HR of PC risk for those in the highest quartile of folate intake (>= 353 mu g/day) compared to the lowest (<241 mu g/day) was 0.81 (95% CI: 0.51, 1.31; p(trend) = 0.38). In current smokers, a positive trend was observed in PC risk across folate quartiles [HR = 4.42 (95% CI: 1.05, 18.62) for >= 353 mu g/day vs. <241 mu g/day, p(trend) = 0.01]. Nonetheless, there was no significant interaction between smoking and dietary folate intake (p(interaction) = 0.99). We found no association between dietary folate intake and PC risk in this large European study.

  • 7. Schmit, Stephanie L.
    et al.
    Edlund, Christopher K.
    Schumacher, Fredrick R.
    Gong, Jian
    Harrison, Tabitha A.
    Huyghe, Jeroen R.
    Qu, Chenxu
    Melas, Marilena
    Van den Berg, David J.
    Wang, Hansong
    Tring, Stephanie
    Plummer, Sarah J.
    Albanes, Demetrius
    Alonso, M. Henar
    Amos, Christopher I.
    Anton, Kristen
    Aragaki, Aaron K.
    Arndt, Volker
    Barry, Elizabeth L.
    Berndt, Sonja I.
    Bezieau, Stephane
    Bien, Stephanie
    Bloomer, Amanda
    Boehm, Juergen
    Boutron-Ruault, Marie-Christine
    Brenner, Hermann
    Brezina, Stefanie
    Buchanan, Daniel D.
    Butterbach, Katja
    Caan, Bette J.
    Campbell, Peter T.
    Carlson, Christopher S.
    Castelao, Jose E.
    Chan, Andrew T.
    Chang-Claude, Jenny
    Chanock, Stephen J.
    Cheng, Iona
    Cheng, Ya-Wen
    Chin, Lee Soo
    Church, James M.
    Church, Timothy
    Coetzee, Gerhard A.
    Cotterchio, Michelle
    Correa, Marcia Cruz
    Curtis, Keith R.
    Duggan, David
    Easton, Douglas F.
    English, Dallas
    Feskens, Edith J. M.
    Fischer, Rocky
    FitzGerald, Liesel M.
    Fortini, Barbara K.
    Fritsche, Lars G.
    Fuchs, Charles S.
    Gago-Dominguez, Manuela
    Gala, Manish
    Gallinger, Steven J.
    Gauderman, W. James
    Giles, Graham G.
    Giovannucci, Edward L.
    Gogarten, Stephanie M.
    Gonzalez-Villalpando, Clicerio
    Gonzalez-Villalpando, Elena M.
    Grady, William M.
    Greenson, Joel K.
    Gsur, Andrea
    Gunter, Marc
    Haiman, Christopher A.
    Hampe, Jochen
    Harlid, Sophia
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Harju, John F.
    Hayes, Richard B.
    Hofer, Philipp
    Hoffmeister, Michael
    Hopper, John L.
    Huang, Shu-Chen
    Huerta, Jose Maria
    Hudson, Thomas J.
    Hunter, David J.
    Idos, Gregory E.
    Iwasaki, Motoki
    Jackson, Rebecca D.
    Jacobs, Eric J.
    Jee, Sun Ha
    Jenkins, Mark A.
    Jia, Wei-Hua
    Jiao, Shuo
    Joshi, Amit D.
    Kolonel, Laurence N.
    Kono, Suminori
    Kooperberg, Charles
    Krogh, Vittorio
    Kuehn, Tilman
    Kury, Sebastien
    LaCroix, Andrea
    Laurie, Cecelia A.
    Lejbkowicz, Flavio
    Lemire, Mathieu
    Lenz, Heinz-Josef
    Levine, David
    Li, Christopher I.
    Li, Li
    Lieb, Wolfgang
    Lin, Yi
    Lindor, Noralane M.
    Liu, Yun-Ru
    Loupakis, Fotios
    Lu, Yingchang
    Luh, Frank
    Ma, Jing
    Mancao, Christoph
    Manion, Frank J.
    Markowitz, Sanford D.
    Martin, Vicente
    Matsuda, Koichi
    Matsuo, Keitaro
    McDonnell, Kevin J.
    McNeil, Caroline E.
    Milne, Roger
    Molina, Antonio J.
    Mukherjee, Bhramar
    Murphy, Neil
    Newcomb, Polly A.
    Offit, Kenneth
    Omichessan, Hanane
    Palli, Domenico
    Cotore, Jesus P. Paredes
    Perez-Mayoral, Julyann
    Pharoah, Paul D.
    Potter, John D.
    Qu, Conghui
    Raskin, Leon
    Rennert, Gad
    Rennert, Hedy S.
    Riggs, Bridget M.
    Schafmayer, Clemens
    Schoen, Robert E.
    Sellers, Thomas A.
    Seminara, Daniela
    Severi, Gianluca
    Shi, Wei
    Shibata, David
    Shu, Xiao-Ou
    Siegel, Erin M.
    Slattery, Martha L.
    Southey, Melissa
    Stadler, Zsofia K.
    Stern, Mariana C.
    Stintzing, Sebastian
    Taverna, Darin
    Thibodeau, Stephen N.
    Thomas, Duncan C.
    Trichopoulou, Antonia
    Tsugane, Shoichiro
    Ulrich, Cornelia M.
    van Duijnhoven, Franzel J. B.
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Vijai, Joseph
    Virtamo, Jarmo
    Weinstein, Stephanie J.
    White, Emily
    Win, Aung Ko
    Wolk, Alicja
    Woods, Michael
    Wu, Anna H.
    Wu, Kana
    Xiang, Yong-Bing
    Yen, Yun
    Zanke, Brent W.
    Zeng, Yi-Xin
    Zhang, Ben
    Zubair, Niha
    Kweon, Sun-Seog
    Figueiredo, Jane C.
    Zheng, Wei
    Le Marchand, Loic
    Lindblom, Annika
    Moreno, Victor
    Peters, Ulrike
    Casey, Graham
    Hsu, Li
    Conti, David V.
    Gruber, Stephen B.
    Novel Common Genetic Susceptibility Loci for Colorectal Cancer2019In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 111, no 2, p. 146-157Article in journal (Refereed)
    Abstract [en]

    Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5x10(-8)) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.

    Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5x10(-8)) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.

    Results: The discovery GWAS identified 11 variants associated with CRC at P < 5x10(-8), of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.

    Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

  • 8. Solans, Marta
    et al.
    Benavente, Yolanda
    Saez, Marc
    Agudo, Antonio
    Naudin, Sabine
    Hosnijeh, Fatemeh Saberi
    Noh, Hwayoung
    Freisling, Heinz
    Ferrari, Pietro
    Besson, Caroline
    Mahamat-Saleh, Yahya
    Boutron-Ruault, Marie-Christine
    Kühn, Tilman
    Kaaks, Rudolf
    Boeing, Heiner
    Lasheras, Cristina
    Rodríguez-Barranco, Miguel
    Amiano, Pilar
    Maria Huerta, Jose
    Barricarte, Aurelio
    Schmidt, Julie A.
    Vineis, Paolo
    Riboli, Elio
    Trichopoulou, Antonia
    Bamia, Christina
    Peppa, Eleni
    Masala, Giovanna
    Agnoli, Claudia
    Tumino, Rosario
    Sacerdote, Carlotta
    Panico, Salvatore
    Skeie, Guri
    Weiderpass, Elisabete
    Jerkeman, Mats
    Ericson, Ulrika
    Späth, Florentin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Nilsson, Lena Maria
    Umeå University, Arctic Research Centre at Umeå University. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Dahm, Christina C.
    Overvad, Kim
    Bolvig, Anne Katrine
    Tjønneland, Anne
    de Sanjose, Silvia
    Buckland, Genevieve
    Vermeulen, Roel
    Nieters, Alexandra
    Casabonne, Delphine
    Adherence to the mediterranean diet and lymphoma risk in the european prospective investigation into cancer and nutrition2019In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 145, no 1, p. 122-131Article in journal (Refereed)
    Abstract [en]

    There is a growing evidence of the protective role of the Mediterranean diet (MD) on cancer. However, no prospective study has yet investigated its influence on lymphoma. We evaluated the association between adherence to the MD and risk of lymphoma and its subtypes in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The analysis included 476,160 participants, recruited from 10 European countries between 1991 and 2001. Adherence to the MD was estimated through the adapted relative MD (arMED) score excluding alcohol. Cox proportional hazards regression models were used while adjusting for potential confounders. During an average follow-up of 13.9 years, 3,136 lymphomas (135 Hodgkin lymphoma [HL], 2,606 non-HL and 395 lymphoma not otherwise specified) were identified. Overall, a 1-unit increase in the arMED score was associated with a 2% lower risk of lymphoma (95% CI: 0.97; 1.00, p-trend = 0.03) while a statistically nonsignificant inverse association between a high versus low arMED score and risk of lymphoma was observed (hazard ratio [HR]: 0.91 [95% CI 0.80; 1.03], p-trend = 0.12). Analyses by lymphoma subtype did not reveal any statistically significant associations. Albeit with small numbers of cases (N = 135), a suggestive inverse association was found for HL (HR 1-unit increase = 0.93 [95% CI: 0.86; 1.01], p-trend = 0.07). However, the study may have lacked statistical power to detect small effect sizes for lymphoma subtype. Our findings suggest that an increasing arMED score was inversely related to the risk of overall lymphoma in EPIC but not by subtypes. Further large prospective studies are warranted to confirm these findings.

  • 9. Vrieling, Alina
    et al.
    Bueno-De-Mesquita, H. Bas
    Ros, Martine M.
    Kampman, Ellen
    Aben, Katja K.
    Buchner, Frederike L.
    Jansen, Eugene H.
    Roswall, Nina
    Tjonneland, Anne
    Boutron-Ruault, Marie-Christine
    Cadeau, Claire
    Chang-Claude, Jenny
    Kaaks, Rudolf
    Weikert, Steffen
    Boeing, Heiner
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Sieri, Sabina
    Palli, Domenico
    Panico, Salvatore
    Peeters, Petra H.
    Weiderpass, Elisabete
    Skeie, Guri
    Jakszyn, Paula
    Chirlaque, Maria-Dolores
    Ardanaz, Eva
    Sanchez, Maria-Jose
    Ehrnstrom, Roy
    Malm, Johan
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Khaw, Kay-Tee
    Wareham, Nick J.
    Brennan, Paul
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. Genetic Epidemiology Group, International Agency for Research on Cancer (IARC), Lyon, France.
    Riboli, Elio
    Kiemeney, Lambertus A.
    One-carbon metabolism biomarkers and risk of urothelial cell carcinoma in the European prospective investigation into cancer and nutrition2019In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 145, no 9, p. 2349-2359Article in journal (Refereed)
    Abstract [en]

    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.

  • 10. Ward, Heather A.
    et al.
    Murphy, Neil
    Weiderpass, Elisabete
    Leitzmann, Michael F.
    Aglago, Elom
    Gunter, Marc J.
    Freisling, Heinz
    Jenab, Mazda
    Boutron-Ruault, Marie-Christine
    Severi, Gianluca
    Carbonnel, Franck
    Kuehn, Tilman
    Kaaks, Rudolf
    Boeing, Heiner
    Tjonneland, Anne
    Olsen, Anja
    Overvad, Kim
    Merino, Susana
    Zamora-Ros, Raul
    Rodriguez-Barranco, Miguel
    Dorronsoro, Miren
    Chirlaque, Maria-Dolores
    Barricarte, Aurelio
    Perez-Cornago, Aurora
    Trichopoulou, Antonia
    Bamia, Christina
    Lagiou, Pagona
    Masala, Giovanna
    Grioni, Sara
    Tumino, Rosario
    Sacerdote, Carlotta
    Mattiello, Amalia
    Bueno-de-Mesquita, Bas
    Vermeulen, Roel
    Van Gils, Carla
    Nyström, Hanna
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Rutegård, Martin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Aune, Dagfinn
    Riboli, Elio
    Cross, Amanda J.
    Gallstones and incident colorectal cancer in a large pan-European cohort study2019In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 145, no 6, p. 1510-1516Article in journal (Refereed)
    Abstract [en]

    Gallstones, a common gastrointestinal condition, can lead to several digestive complications and can result in inflammation. Risk factors for gallstones include obesity, diabetes, smoking and physical inactivity, all of which are known risk factors for colorectal cancer (CRC), as is inflammation. However, it is unclear whether gallstones are a risk factor for CRC. We examined the association between history of gallstones and CRC in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, a prospective cohort of over half a million participants from ten European countries. History of gallstones was assessed at baseline using a self‐reported questionnaire. The analytic cohort included 334,986 participants; a history of gallstones was reported by 3,917 men and 19,836 women, and incident CRC was diagnosed among 1,832 men and 2,178 women (mean follow‐up: 13.6 years). Hazard ratios (HR) and 95% confidence intervals (CI) for the association between gallstones and CRC were estimated using Cox proportional hazards regression models, stratified by sex, study centre and age at recruitment. The models were adjusted for body mass index, diabetes, alcohol intake and physical activity. A positive, marginally significant association was detected between gallstones and CRC among women in multivariable analyses (HR = 1.14, 95%CI 0.99–1.31, p = 0.077). The relationship between gallstones and CRC among men was inverse but not significant (HR = 0.81, 95%CI 0.63–1.04, p = 0.10). Additional adjustment for details of reproductive history or waist circumference yielded minimal changes to the observed associations. Further research is required to confirm the nature of the association between gallstones and CRC by sex.

  • 11. Ward, Heather A.
    et al.
    Whitman, Julia
    Muller, David C.
    Johansson, Mattias
    Jakszyn, Paula
    Weiderpass, Elisabete
    Palli, Domenico
    Fanidi, Anouar
    Vermeulen, Roel
    Tjonneland, Anne
    Hansen, Louise
    Dahm, Christina C.
    Overvad, Kim
    Severi, Gianluca
    Boutron-Ruault, Marie-Christine
    Affret, Aurelie
    Kaaks, Rudolf
    Fortner, Renee
    Boeing, Heiner
    Trichopoulou, Antonia
    La Vecchia, Carlo
    Kotanidou, Anastasia
    Berrino, Franco
    Krogh, Vittorio
    Tumino, Rosario
    Ricceri, Fulvio
    Panico, Salvatore
    Bueno-de-Mesquita, H. Bas
    Peeters, Petra H.
    Nost, Therese Haugdahl
    Sandanger, Torkjel M.
    Ramon Quiros, Jose
    Agudo, Antonio
    Rodriguez-Barranco, Miguel
    Larranaga, Nerea
    Maria Huerta, Jose
    Ardanaz, Eva
    Drake, Isabel
    Brunnstrom, Hans
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Travis, Ruth C.
    Freisling, Heinz
    Stepien, Magdalena
    Merritt, Melissa A.
    Riboli, Elio
    Cross, Amanda J.
    Haem iron intake and risk of lung cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort2019In: European Journal of Clinical Nutrition, ISSN 0954-3007, E-ISSN 1476-5640, Vol. 73, no 8, p. 1122-1132Article in journal (Refereed)
    Abstract [en]

    Background: Epidemiological studies suggest that haem iron, which is found predominantly in red meat and increases endogenous formation of carcinogenic N-nitroso compounds, may be positively associated with lung cancer. The objective was to examine the relationship between haem iron intake and lung cancer risk using detailed smoking history data and serum cotinine to control for potential confounding.  

    Methods: In the European Prospective Investigation into Cancer and Nutrition (EPIC), 416,746 individuals from 10 countries completed demographic and dietary questionnaires at recruitment. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident lung cancer (n = 3731) risk relative to haem iron, non-haem iron, and total dietary iron intake. A corresponding analysis was conducted among a nested subset of 800 lung cancer cases and 1489 matched controls for whom serum cotinine was available.

    Results: Haem iron was associated with lung cancer risk, including after adjustment for details of smoking history (time since quitting, number of cigarettes per day): as a continuous variable (HR per 0.3 mg/1000 kcal 1.03, 95% CI 1.00-1.07), and in the highest versus lowest quintile (HR 1.16, 95% CI 1.02-1.32; trend across quintiles: P = 0.035). In contrast, non-haem iron intake was related inversely with lung cancer risk; however, this association attenuated after adjustment for smoking history. Additional adjustment for serum cotinine did not considerably alter the associations detected in the nested case-control subset.

    Conclusions: Greater haem iron intake may be modestly associated with lung cancer risk.

  • 12. Zamora-Ros, Raul
    et al.
    Alghamdi, Muath A.
    Cayssials, Valerie
    Franceschi, Silvia
    Almquist, Martin
    Hennings, Joakim
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Sandström, Maria
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Tsilidis, Konstantinos K.
    Weiderpass, Elisabete
    Boutron-Ruault, Marie-Christine
    Hammer Bech, Bodil
    Overvad, Kim
    Tjonneland, Anne
    Petersen, Kristina E. N.
    Mancini, Francesca Romana
    Mahamat-Saleh, Yahya
    Bonnet, Fabrice
    Kuehn, Tilman
    Fortner, Renee T.
    Boeing, Heiner
    Trichopoulou, Antonia
    Bamia, Christina
    Martimianaki, Georgia
    Masala, Giovanna
    Grioni, Sara
    Panico, Salvatore
    Tumino, Rosario
    Fasanelli, Francesca
    Skeie, Guri
    Braaten, Tonje
    Lasheras, Cristina
    Salamanca-Fernandez, Elena
    Amiano, Pilar
    Chirlaque, Maria-Dolores
    Barricarte, Aurelio
    Manjer, Jonas
    Wallstrom, Peter
    Bueno-de-Mesquita, H. Bas
    Peeters, Petra H.
    Khaw, Kay-Thee
    Wareham, Nicholas J.
    Schmidt, Julie A.
    Aune, Dagfinn
    Byrnes, Graham
    Scalbert, Augustin
    Agudo, Antonio
    Rinaldi, Sabina
    Coffee and tea drinking in relation to the risk of differentiated thyroid carcinoma: results from the European Prospective Investigation into Cancer and Nutrition (EPIC) study2019In: European Journal of Nutrition, ISSN 1436-6207, E-ISSN 1436-6215, Vol. 58, no 8, p. 3303-3312Article in journal (Refereed)
    Abstract [en]

    Purpose: Coffee and tea constituents have shown several anti-carcinogenic activities in cellular and animal studies, including against thyroid cancer (TC). However, epidemiological evidence is still limited and inconsistent. Therefore, we aimed to investigate this association in a large prospective study.

    Methods: The study was conducted in the EPIC (European Prospective Investigation into Cancer and Nutrition) cohort, which included 476,108 adult men and women. Coffee and tea intakes were assessed through validated country-specific dietary questionnaires.

    Results: During a mean follow-up of 14 years, 748 first incident differentiated TC cases (including 601 papillary and 109 follicular TC) were identified. Coffee consumption (per 100 mL/day) was not associated either with total differentiated TC risk (HRcalibrated 1.00, 95% CI 0.97–1.04) or with the risk of TC subtypes. Tea consumption (per 100 mL/day) was not associated with the risk of total differentiated TC (HRcalibrated 0.98, 95% CI 0.95–1.02) and papillary tumor (HRcalibrated 0.99, 95% CI 0.95–1.03), whereas an inverse association was found with follicular tumor risk (HRcalibrated 0.90, 95% CI 0.81–0.99), but this association was based on a sub-analysis with a small number of cancer cases.

    Conclusions: In this large prospective study, coffee and tea consumptions were not associated with TC risk.

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