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  • 1. Assi, Nada
    et al.
    Fages, Anne
    Vineis, Paolo
    Chadeau-Hyam, Marc
    Stepien, Magdalena
    Duarte-Salles, Talita
    Byrnes, Graham
    Boumaza, Houda
    Knueppel, Sven
    Kuehn, Tilman
    Palli, Domenico
    Bamia, Christina
    Boshuizen, Hendriek
    Bonet, Catalina
    Overvad, Kim
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. International Agency for Research on Cancer (IARC-WHO), Lyon, France.
    Travis, Ruth
    Gunter, Marc J.
    Lund, Eiliv
    Dossus, Laure
    Elena-Herrmann, Benedicte
    Riboli, Elio
    Jenab, Mazda
    Viallon, Vivian
    Ferrari, Pietro
    A statistical framework to model the meeting-in-the-middle principle using metabolomic data: application to hepatocellular carcinoma in the EPIC study2015In: Mutagenesis, ISSN 0267-8357, E-ISSN 1464-3804, Vol. 30, no 6, p. 743-753Article in journal (Refereed)
    Abstract [en]

    Metabolomics is a potentially powerful tool for identification of biomarkers associated with lifestyle exposures and risk of various diseases. This is the rationale of the 'meeting-in-the-middle' concept, for which an analytical framework was developed in this study. In a nested case-control study on hepatocellular carcinoma (HCC) within the European Prospective Investigation into Cancer and nutrition (EPIC), serum H-1 nuclear magnetic resonance (NMR) spectra (800 MHz) were acquired for 114 cases and 222 matched controls. Through partial least square (PLS) analysis, 21 lifestyle variables (the 'predictors', including information on diet, anthropometry and clinical characteristics) were linked to a set of 285 metabolic variables (the 'responses'). The three resulting scores were related to HCC risk by means of conditional logistic regressions. The first PLS factor was not associated with HCC risk. The second PLS metabolomic factor was positively associated with tyrosine and glucose, and was related to a significantly increased HCC risk with OR = 1.11 (95% CI: 1.02, 1.22, P = 0.02) for a 1SD change in the responses score, and a similar association was found for the corresponding lifestyle component of the factor. The third PLS lifestyle factor was associated with lifetime alcohol consumption, hepatitis and smoking, and had negative loadings on vegetables intake. Its metabolomic counterpart displayed positive loadings on ethanol, glutamate and phenylalanine. These factors were positively and statistically significantly associated with HCC risk, with 1.37 (1.05, 1.79, P = 0.02) and 1.22 (1.04, 1.44, P = 0.01), respectively. Evidence of mediation was found in both the second and third PLS factors, where the metabolomic signals mediated the relation between the lifestyle component and HCC outcome. This study devised a way to bridge lifestyle variables to HCC risk through NMR metabolomics data. This implementation of the 'meeting-in-the-middle' approach finds natural applications in settings characterised by high-dimensional data, increasingly frequent in the omics generation.

  • 2. Baglietto, Laura
    et al.
    Ponzi, Erica
    Haycock, Philip
    Hodge, Allison
    Bianca Assumma, Manuela
    Jung, Chol-Hee
    Chung, Jessica
    Fasanelli, Francesca
    Guida, Florence
    Campanella, Gianluca
    Chadeau-Hyam, Marc
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Ala, Ugo
    Provero, Paolo
    Wong, Ee Ming
    Joo, Jihoon
    English, Dallas R
    Kazmi, Nabila
    Lund, Eiliv
    Faltus, Christian
    Kaaks, Rudolf
    Risch, Angela
    Barrdahl, Myrto
    Sandanger, Torkjel M
    Southey, Melissa C
    Giles, Graham G
    Johansson, Mattias
    International Agency for Research on Cancer, Lyon, France.
    Vineis, Paolo
    Polidoro, Silvia
    Relton, Caroline L
    Severi, Gianluca
    DNA methylation changes measured in pre-diagnostic peripheral blood samples are associated with smoking and lung cancer risk2017In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 140, no 1, p. 50-61Article in journal (Refereed)
    Abstract [en]

    DNA methylation changes are associated with cigarette smoking. We used the Illumina Infinium HumanMethylation450 array to determine whether methylation in DNA from pre-diagnostic, peripheral blood samples is associated with lung cancer risk. We used a case-control study nested within the EPIC-Italy cohort and a study within the MCCS cohort as discovery sets (a total of 552 case-control pairs). We validated the top signals in 429 case-control pairs from another 3 studies. We identified six CpGs for which hypomethylation was associated with lung cancer risk: cg05575921 in the AHRR gene (p-valuepooled  = 4 × 10(-17) ), cg03636183 in the F2RL3 gene (p-valuepooled  = 2 × 10 (- 13) ), cg21566642 and cg05951221 in 2q37.1 (p-valuepooled  = 7 × 10(-16) and 1 × 10(-11) respectively), cg06126421 in 6p21.33 (p-valuepooled  = 2 × 10(-15) ) and cg23387569 in 12q14.1 (p-valuepooled  = 5 × 10(-7) ). For cg05951221 and cg23387569 the strength of association was virtually identical in never and current smokers. For all these CpGs except for cg23387569, the methylation levels were different across smoking categories in controls (p-valuesheterogeneity  ≤ 1.8 x10 (- 7) ), were lowest for current smokers and increased with time since quitting for former smokers. We observed a gain in discrimination between cases and controls measured by the area under the ROC curve of at least 8% (p-values ≥ 0.003) in former smokers by adding methylation at the 6 CpGs into risk prediction models including smoking status and number of pack-years. Our findings provide convincing evidence that smoking and possibly other factors lead to DNA methylation changes measurable in peripheral blood that may improve prediction of lung cancer risk.

  • 3. Bakker, Marije F.
    et al.
    Peeters, Petra H. M.
    Klaasen, Veronique M.
    Bueno-de-Mesquita, H. Bas
    Jansen, Eugene H. J. M.
    Ros, Martine M.
    Travier, Noemie
    Olsen, Anja
    Tjønneland, Anne
    Overvad, Kim
    Rinaldi, Sabina
    Romieu, Isabelle
    Brennan, Paul
    Boutron-Ruault, Marie-Christine
    Perquier, Florence
    Cadeau, Claire
    Boeing, Heiner
    Aleksandrova, Krasimira
    Kaaks, Rudolf
    Kühn, Tilman
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Vineis, Paolo
    Krogh, Vittorio
    Panico, Salvatore
    Masala, Giovanna
    Tumino, Rosario
    Weiderpass, Elisabete
    Skeie, Guri
    Lund, Eiliv
    Ramon Quirós, J.
    Ardanaz, Eva
    Navarro, Carmen
    Amiano, Pilar
    Sánchez, María-José
    Buckland, Genevieve
    Ericson, Ulrika
    Sonestedt, Emily
    Johansson, Matthias
    Umeå University, Faculty of Medicine, Department of Biobank Research. International Agency for Research on Cancer, Lyon, France.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Travis, Ruth C.
    Key, Timothy J.
    Khaw, Kay-Tee
    Wareham, Nick
    Riboli, Elio
    van Gils, Carla H.
    Plasma carotenoids, vitamin C, tocopherols, and retinol and the risk of breast cancer in the European Prospective Investigation into Cancer and Nutrition cohort2016In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 103, no 2, p. 454-464Article in journal (Refereed)
    Abstract [en]

    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 alpha-carotene, beta-carotene, lycopene, lutein, zeaxanthin, beta-cryptoxanthin, retinol, alpha-tocopherol, gamma-tocopherol, and 454 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, alpha-carotene (OR: 0.61; 95% CI: 0.39, 0.98) and beta-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 beta-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 beta-carotene and alpha-carotene are associated with lower breast cancer risk of ER tumors.

  • 4. Baltar, Valéria Troncoso
    et al.
    Xun, Wei W
    Johansson, Mattias
    International Agency for Research on Cancer, Lyon, France.
    Ferrari, Pietro
    Chuang, Shu-Chun
    Relton, Caroline
    Ueland, Per Magne
    Midttun, Oivind
    Slimani, Nadia
    Jenab, Mazda
    Clavel-Chapelon, Françoise
    Boutron-Ruault, Marie-Christine
    Fagherazzi, Guy
    Kaaks, Rudolf
    Rohrmann, Sabine
    Boeing, Heiner
    Weikert, Cornelia
    Bueno-de-Mesquita, Bas
    Boshuizen, Hendriek
    van Gils, Carla H
    Onland-Moret, N Charlotte
    Agudo, Antonio
    Barricarte, Aurelio
    Navarro, Carmen
    Rodríguez, Laudina
    Castaño, José Maria Huerta
    Larrañaga, Nerea
    Khaw, Kay-Tee
    Wareham, Nick
    Allen, Naomi E
    Crowe, Francesca
    Gallo, Valentina
    Norat, Teresa
    Krogh, Vittorio
    Masala, Giovanna
    Panico, Salvatore
    Sacerdote, Carlotta
    Tumino, Rosario
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Rasmuson, Torgny
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Roswall, Nina
    Tjønneland, Anne
    Riboli, Elio
    Brennan, Paul
    Vineis, Paolo
    A structural equation modelling approach to explore the role of B vitamins and immune markers in lung cancer risk2013In: European Journal of Epidemiology, ISSN 0393-2990, E-ISSN 1573-7284, Vol. 28, no 8, p. 677-688Article in journal (Refereed)
    Abstract [en]

    The one-carbon metabolism (OCM) is considered key in maintaining DNA integrity and regulating gene expression, and may be involved in the process of carcinogenesis. Several B-vitamins and amino acids have been implicated in lung cancer risk, via the OCM directly as well as immune system activation. However it is unclear whether these factors act independently or through complex mechanisms. The current study applies structural equations modelling (SEM) to further disentangle the mechanisms involved in lung carcinogenesis. SEM allows simultaneous estimation of linear relations where a variable can be the outcome in one equation and the predictor in another, as well as allowing estimation using latent variables (factors estimated by correlation matrix). A large number of biomarkers have been analysed from 891 lung cancer cases and 1,747 controls nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Four putative mechanisms in the OCM and immunity were investigated in relation to lung cancer risk: methionine-homocysteine metabolism, folate cycle, transsulfuration, and mechanisms involved in inflammation and immune activation, all adjusted for tobacco exposure. The hypothesized SEM model confirmed a direct and protective effect for factors representing methionine-homocysteine metabolism (p = 0.020) and immune activation (p = 0.021), and an indirect protective effect of folate cycle (p = 0.019), after adjustment for tobacco smoking. In conclusion, our results show that in the investigation of the involvement of the OCM, the folate cycle and immune system in lung carcinogenesis, it is important to consider complex pathways (by applying SEM) rather than the effects of single vitamins or nutrients (e.g. using traditional multiple regression). In our study SEM were able to suggest a greater role of the methionine-homocysteine metabolism and immune activation over other potential mechanisms.

  • 5. Brenner, Darren R
    et al.
    Amos, Christopher I
    Brhane, Yonathan
    Timofeeva, Maria N
    Caporaso, Neil
    Wang, Yufei
    Christiani, David C
    Bickeböller, Heike
    Yang, Ping
    Albanes, Demetrius
    Stevens, Victoria L
    Gapstur, Susan
    McKay, James
    Boffetta, Paolo
    Zaridze, David
    Szeszenia-Dabrowska, Neonilia
    Lissowska, Jolanta
    Rudnai, Peter
    Fabianova, Eleonora
    Mates, Dana
    Bencko, Vladimir
    Foretova, Lenka
    Janout, Vladimir
    Krokan, Hans E
    Skorpen, Frank
    Gabrielsen, Maiken E
    Vatten, Lars
    Njølstad, Inger
    Chen, Chu
    Goodman, Gary
    Lathrop, Mark
    Vooder, Tõnu
    Välk, Kristjan
    Nelis, Mari
    Metspalu, Andres
    Broderick, Peter
    Eisen, Timothy
    Wu, Xifeng
    Zhang, Di
    Chen, Wei
    Spitz, Margaret R
    Wei, Yongyue
    Su, Li
    Xie, Dong
    She, Jun
    Matsuo, Keitaro
    Matsuda, Fumihiko
    Ito, Hidemi
    Risch, Angela
    Heinrich, Joachim
    Rosenberger, Albert
    Muley, Thomas
    Dienemann, Hendrik
    Field, John K
    Raji, Olaide
    Chen, Ying
    Gosney, John
    Liloglou, Triantafillos
    Davies, Michael P A
    Marcus, Michael
    McLaughlin, John
    Orlow, Irene
    Han, Younghun
    Li, Yafang
    Zong, Xuchen
    Johansson, Mattias
    Genetic Epidemiology Division, International Agency for Research on Cancer, Lyon, France.
    Liu, Geoffrey
    Tworoger, Shelley S
    Le Marchand, Loic
    Henderson, Brian E
    Wilkens, Lynne R
    Dai, Juncheng
    Shen, Hongbing
    Houlston, Richard S
    Landi, Maria T
    Brennan, Paul
    Hung, Rayjean J
    Identification of lung cancer histology-specific variants applying Bayesian framework variant prioritization approaches within the TRICL and ILCCO consortia2015In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 36, no 11, p. 1314-1326Article in journal (Refereed)
    Abstract [en]

    Large-scale genome-wide association studies (GWAS) have likely uncovered all common variants at the GWAS significance level. Additional variants within the suggestive range (0.0001> P > 5×10−8) are, however, still of interest for identifying causal associations. This analysis aimed to apply novel variant prioritization approaches to identify additional lung cancer variants that may not reach the GWAS level. Effects were combined across studies with a total of 33456 controls and 6756 adenocarcinoma (AC; 13 studies), 5061 squamous cell carcinoma (SCC; 12 studies) and 2216 small cell lung cancer cases (9 studies). Based on prior information such as variant physical properties and functional significance, we applied stratified false discovery rates, hierarchical modeling and Bayesian false discovery probabilities for variant prioritization. We conducted a fine mapping analysis as validation of our methods by examining top-ranking novel variants in six independent populations with a total of 3128 cases and 2966 controls. Three novel loci in the suggestive range were identified based on our Bayesian framework analyses: KCNIP4 at 4p15.2 (rs6448050, P = 4.6×10−7) and MTMR2 at 11q21 (rs10501831, P = 3.1×10−6) with SCC, as well as GAREM at 18q12.1 (rs11662168, P = 3.4×10−7) with AC. Use of our prioritization methods validated two of the top three loci associated with SCC (P = 1.05×10−4 for KCNIP4, represented by rs9799795) and AC (P = 2.16×10−4 for GAREM, represented by rs3786309) in the independent fine mapping populations. This study highlights the utility of using prior functional data for sequence variants in prioritization analyses to search for robust signals in the suggestive range.

  • 6. Brenner, Darren R
    et al.
    Yannitsos, Demetra H
    Farris, Megan S
    Johansson, Mattias
    Genetic Epidemiology Group, International Agency for Research on Cancer, Lyon, France.
    Friedenreich, Christine M
    Leisure-time physical activity and lung cancer risk: a systematic review and meta-analysis2016In: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 95, p. 17-27Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: We conducted a systematic review and meta-analysis of the association between recreational physical activity and lung cancer risk to update previous analyses and to examine population subgroups of interest defined by smoking status and histology.

    MATERIALS AND METHODS: We searched the PubMed database for studies up to May 2015. Individual study characteristics were abstracted including study design, number of cases, assessment of recreational physical activity and type and level of adjustment for confounding factors. Combined effect estimates were calculated for the overall associations and across subgroups of interest.

    RESULTS: We identified 28 studies that were eligible for inclusion in the meta-analysis. The overall analysis indicated an inverse association between recreational physical activity and lung cancer risk (Relative Risk (RR), 0.76; 95% Confidence Interval (CI), 0.69-0.85, p-value: <0.001). Similar inverse associations with risk were also noted for all evaluated histological subtypes, including adenocarcinoma (RR, 0.80; 95% CI, 0.72-0.88), squamous (RR, 0.80; 95% CI, 0.71-0.90) and small cell (RR, 0.79; 95% CI, 0.66-0.94). When we examined effects by smoking status, inverse associations between recreational physical activity and lung cancer risk were observed among former (RR, 0.77; 95% CI, 0.69-0.85) and current smokers (RR, 0.77; 95% CI, 0.72-0.83), but not among never smokers (RR, 0.96; 95% CI, 0.79-1.18).

    CONCLUSION: Results from this meta-analysis suggest that regular recreational physical activity may be associated with reduced risk of lung cancer. Only four studies examining never smokers were identified, suggesting the need for additional research in this population.

  • 7. Buckland, G.
    et al.
    Travier, N.
    Huerta, J. M.
    Bueno-de-Mesquita, H. B(As)
    Siersema, P. D.
    Skeie, G.
    Weiderpass, E.
    Engeset, D.
    Ericson, U.
    Ohlsson, B.
    Agudo, A.
    Romieu, I.
    Ferrari, P.
    Freisling, H.
    Colorado-Yohar, S.
    Li, K.
    Kaaks, R.
    Pala, V.
    Cross, A. J.
    Riboli, E.
    Trichopoulou, A.
    Lagiou, P.
    Bamia, C.
    Boutron-Ruault, M. C.
    Fagherazzi, G.
    Dartois, L.
    May, A. M.
    Peeters, P. H.
    Panico, S.
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. International Agency for Research on Cancer (IARC-WHO), France.
    Wallner, Bengt
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Palli, D.
    Key, T. J.
    Khaw, K. T.
    Ardanaz, E.
    Overvad, K.
    Tjonneland, A.
    Dorronsoro, M.
    Sanchez, M. J.
    Quiros, J. R.
    Naccarati, A.
    Tumino, R.
    Boeing, H.
    Gonzalez, C. A.
    Healthy lifestyle index and risk of gastric adenocarcinoma in the EPIC cohort study2015In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 137, no 3, p. 598-606Article in journal (Refereed)
    Abstract [en]

    Several modifiable lifestyle factors, including smoking, alcohol, certain dietary factors and weight are independently associated with gastric cancer (GC); however, their combined impact on GC risk is unknown. We constructed a healthy lifestyle index to investigate the joint influence of these behaviors on GC risk within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. The analysis included 461,550 participants (662 first incident GC cases) with a mean follow-up of 11.4 years. A healthy lifestyle index was constructed, assigning 1 point for each healthy behavior related to smoking status, alcohol consumption and diet quality (represented by the Mediterranean diet) for assessing overall GC and also body mass index for cardia GC and 0 points otherwise. Risk of GC was calculated using Cox proportional hazards regression models while adjusting for relevant confounders. The highest versus lowest score in the healthy lifestyle index was associated with a significant lower risk of GC, by 51% overall (HR 0.49 95% CI 0.35, 0.70), by 77% for cardia GC (HR 0.23 95% CI 0.08, 0.68) and by 47% for noncardia GC (HR 0.53 (95% CI 0.32, 0.87), p-trends<0.001. Population attributable risk calculations showed that 18.8% of all GC and 62.4% of cardia GC cases could have been prevented if participants in this population had followed the healthy lifestyle behaviors of this index. Adopting several healthy lifestyle behaviors including not smoking, limiting alcohol consumption, eating a healthy diet and maintaining a normal weight is associated with a large decreased risk of GC. What's new? Several modifiable lifestyle factors, including smoking status, alcohol consumption, diet quality and weight, have been independently associated with gastric cancer. Behavioral patterns often cluster, however, lifestyle scores can be used to analyse overlapping risk factors. In this study, the authors used a healthy-lifestyle index to evaluate the combined effects of all of the above factors on the risk of developing gastric cancer (GC). They found that following a healthy lifestyle dramatically decreases the burden of gastric cancer.

  • 8. Campa, Daniele
    et al.
    Hüsing, Anika
    Chang-Claude, Jenny
    Dostal, Lucie
    Boeing, Heiner
    Kröger, Janine
    Tjønneland, Anne
    Roswall, Nina
    Overvad, Kim
    Dahm, Christina C
    Rodríguez, Laudina
    Sala, Núria
    Pérez, Maria José Sánchez
    Larrañaga, Nerea
    Chirlaque, Maria-Dolores
    Ardanaz, Eva
    Khaw, Kay-Tee
    Wareham, Nick
    Allen, Naomi E
    Travis, Ruth C
    Trichopoulou, Antonia
    Naska, Androniki
    Bamia, Christina
    Palli, Domenico
    Sieri, Sabina
    Tumino, Rosario
    Sacerdote, Carlotta
    van Kranen, Henk J
    Bas Bueno-de-Mesquita, H
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. International Agency for Research on Cancer, Lyon, France.
    Chajes, Veronique
    Rinaldi, Sabina
    Romieu, Isabelle
    Siddiq, Afshan
    Norat, Teresa
    Riboli, Elio
    Kaaks, Rudolf
    Canzian, Federico
    Genetic variability of the fatty acid synthase pathway is not associated with prostate cancer risk in the European Prospective Investigation on Cancer (EPIC)2011In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 47, no 3, p. 420-427Article in journal (Refereed)
    Abstract [en]

    A western lifestyle, characterised by low rates of energy expenditure and a high-energy diet rich in animal protein, saturated fats and refined carbohydrates, is associated with high incidence of prostate cancer in men. A high-energy nutritional status results in insulin/IGF signalling in cells, which in turn stimulates synthesis of fatty acids. We investigated whether the genetic variability of the genes belonging to the fatty acid synthesis pathway is related to prostate cancer risk in 815 prostate cancer cases and 1266 controls from the European Prospective Investigation on Cancer (EPIC). Using a tagging approach and selecting 252 SNPs in 22 genes, we covered all the common genetic variation of this pathway. None of the SNPs reached statistical significance after adjusting for multiple comparisons. Common SNPs in the fatty acid synthase pathway are not major contributors to prostate cancer risk.

  • 9. Campa, Daniele
    et al.
    Kaaks, Rudolf
    Le Marchand, Loic
    Haiman, Christopher A.
    Travis, Ruth C.
    Berg, Christine D.
    Buring, Julie E.
    Chanock, Stephen J.
    Diver, W. Ryan
    Dostal, Lucie
    Fournier, Agnes
    Hankinson, Susan E.
    Henderson, Brian E.
    Hoover, Robert N.
    Isaacs, Claudine
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. International Agency for Research on Cancer (IARC), Lyon, France.
    Kolonel, Laurence N.
    Kraft, Peter
    Lee, I-Min
    McCarty, Catherine A.
    Overvad, Kim
    Panico, Salvatore
    Peeters, Petra H. M.
    Riboli, Elio
    Jose Sanchez, Maria
    Schumacher, Fredrick R.
    Skeie, Guri
    Stram, Daniel O.
    Thun, Michael J.
    Trichopoulos, Dimitrios
    Zhang, Shumin
    Ziegler, Regina G.
    Hunter, David J.
    Lindstroem, Sara
    Canzian, Federico
    Interactions Between Genetic Variants and Breast Cancer Risk Factors in the Breast and Prostate Cancer Cohort Consortium2011In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 103, no 16, p. 1252-1263Article in journal (Refereed)
    Abstract [en]

    Background Recently, several genome-wide association studies have identified various genetic susceptibility loci for breast cancer. Relatively little is known about the possible interactions between these loci and the established risk factors for breast cancer. Methods To assess interactions between single-nucleotide polymorphisms (SNPs) and established risk factors, we prospectively collected DNA samples and questionnaire data from 8576 breast cancer case subjects and 11 892 control subjects nested within the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3). We genotyped 17 germline SNPs (FGFR2-rs2981582, FGFR2-rs3750817, TNRC9-rs3803662, 2q35-rs13387042, MAP3K1-rs889312, 8q24-rs13281615, CASP8-rs1045485, LSP1-rs3817198, COL1A1-rs2075555, COX11-rs6504950, RNF146-rs2180341, 6q25-rs2046210, SLC4A7-rs4973768, NOTCH2-rs11249433, 5p12-rs4415084, 5p12-rs10941679, RAD51L1-rs999737), and odds ratios were estimated by logistic regression to confirm previously reported associations with breast cancer risk. We performed likelihood ratio test to assess interactions between 17 SNPs and nine established risk factors (age at menarche, parity, age at menopause, use of hormone replacement therapy, family history, height, body mass index, smoking status, and alcohol consumption), and a correction for multiple testing of 153 tests (adjusted P value threshold = .05/153 = 3 x 10(-4)) was done. Casecase comparisons were performed for possible differential associations of polymorphisms by subgroups of tumor stage, estrogen and progesterone receptor status, and age at diagnosis. All statistical tests were two-sided. Results We confirmed the association of 14 SNPs with breast cancer risk (P(trend) = 2.57 x 10(-3) -3.96 x 10(-19)). Three SNPs (LSP1-rs3817198, COL1A1-rs2075555, and RNF146-rs2180341) did not show association with breast cancer risk. After accounting for multiple testing, no statistically significant interactions were detected between the 17 SNPs and the nine risk factors. We also confirmed that SNPs in FGFR2 and TNRC9 were associated with greater risk of estrogen receptor-positive than estrogen receptor-negative breast cancer (P(heterogeneity) = .0016 for FGFR2-rs2981582 and P(heterogeneity) = .0053 for TNRC9-rs3803662). SNP 5p12-rs10941679 was statistically significantly associated with greater risk of progesterone receptor-positive than progesterone receptor-negative breast cancer (P(heterogeneity) = .0028). Conclusion This study does not support the hypothesis that known common breast cancer susceptibility loci strongly modify the associations between established risk factors and breast cancer.

  • 10. Cao, Yin
    et al.
    Lindström, Sara
    Schumacher, Fredrick
    Stevens, Victoria L.
    Albanes, Demetrius
    Berndt, Sonja I.
    Boeing, Heiner
    Bueno-de-Mesquita, H. Bas
    Canzian, Federico
    Chamosa, Saioa
    Chanock, Stephen J.
    Diver, W. Ryan
    Gapstur, Susan M.
    Gaziano, J. Michael
    Giovannucci, Edward L.
    Haiman, Christopher A.
    Henderson, Brian
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. International Agency for Research on Cancer, Lyon, France.
    Le Marchand, Loïc
    Palli, Domenico
    Rosner, Bernard
    Siddiq, Afshan
    Stampfer, Meir
    Stram, Daniel O.
    Tamimi, Rulla
    Travis, Ruth C.
    Trichopoulos, Dimitrios
    Willett, Walter C.
    Yeager, Meredith
    Kraft, Peter
    Hsing, Ann W.
    Pollak, Michael
    Lin, Xihong
    Ma, Jing
    Insulin-like growth factor pathway genetic polymorphisms, circulating IGF1 and IGFBP3, and prostate cancer survival2014In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 106, no 5, article id dju218Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The insulin-like growth factor (IGF) signaling pathway has been implicated in prostate cancer (PCa) initiation, but its role in progression remains unknown.

    METHODS: Among 5887 PCa patients (704 PCa deaths) of European ancestry from seven cohorts in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium, we conducted Cox kernel machine pathway analysis to evaluate whether 530 tagging single nucleotide polymorphisms (SNPs) in 26 IGF pathway-related genes were collectively associated with PCa mortality. We also conducted SNP-specific analysis using stratified Cox models adjusting for multiple testing. In 2424 patients (313 PCa deaths), we evaluated the association of prediagnostic circulating IGF1 and IGFBP3 levels and PCa mortality. All statistical tests were two-sided.

    RESULTS: The IGF signaling pathway was associated with PCa mortality (P = .03), and IGF2-AS and SSTR2 were the main contributors (both P = .04). In SNP-specific analysis, 36 SNPs were associated with PCa mortality with P-trend less than .05, but only three SNPs in the IGF2-AS remained statistically significant after gene-based corrections. Two were in linkage disequilibrium (r(2) = 1 for rs1004446 and rs3741211), whereas the third, rs4366464, was independent (r(2) = 0.03). The hazard ratios (HRs) per each additional risk allele were 1.19 (95% confidence interval [CI] = 1.06 to 1.34; P-trend = .003) for rs3741211 and 1.44 (95% CI = 1.20 to 1.73; P-trend < .001) for rs4366464. rs4366464 remained statistically significant after correction for all SNPs (P-trend.corr = .04). Prediagnostic IGF1 (HRhighest (vs lowest quartile) = 0.71; 95% CI = 0.48 to 1.04) and IGFBP3 (HR = 0.93; 95% Cl = 0.65 to 1.34) levels were not associated with PCa mortality.

    CONCLUSIONS: The IGF signaling pathway, primarily IGF2-AS and SSTR2 genes, may be important in PCa survival.

  • 11. Carreras-Torres, Robert
    et al.
    Haycock, Philip C
    Relton, Caroline L
    Martin, Richard M
    Smith, George Davey
    Kraft, Peter
    Gao, Chi
    Tworoger, Shelley
    Le Marchand, Loïc
    Wilkens, Lynne R
    Park, Sungshim L
    Haiman, Christopher
    Field, John K
    Davies, Michael
    Marcus, Michael
    Liu, Geoffrey
    Caporaso, Neil E
    Christiani, David C
    Wei, Yongyue
    Chen, Chu
    Doherty, Jennifer A
    Severi, Gianluca
    Goodman, Gary E
    Hung, Rayjean J
    Amos, Christopher I
    McKay, James
    Johansson, Mattias
    Section of Genetics, International Agency for Research on Cancer (IARC), Lyon, France.
    Brennan, Paul
    The causal relevance of body mass index in different histological types of lung cancer: a Mendelian randomization study2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 31121Article in journal (Refereed)
    Abstract [en]

    Body mass index (BMI) is inversely associated with lung cancer risk in observational studies, even though it increases the risk of several other cancers, which could indicate confounding by tobacco smoking or reverse causality. We used the two-sample Mendelian randomization (MR) approach to circumvent these limitations of observational epidemiology by constructing a genetic instrument for BMI, based on results from the GIANT consortium, which was evaluated in relation to lung cancer risk using GWAS results on 16,572 lung cancer cases and 21,480 controls. Results were stratified by histological subtype, smoking status and sex. An increase of one standard deviation (SD) in BMI (4.65 Kg/m(2)) raised the risk for lung cancer overall (OR = 1.13; P = 0.10). This was driven by associations with squamous cell (SQ) carcinoma (OR = 1.45; P = 1.2 × 10(-3)) and small cell (SC) carcinoma (OR = 1.81; P = 0.01). An inverse trend was seen for adenocarcinoma (AD) (OR = 0.82; P = 0.06). In stratified analyses, a 1 SD increase in BMI was inversely associated with overall lung cancer in never smokers (OR = 0.50; P = 0.02). These results indicate that higher BMI may increase the risk of certain types of lung cancer, in particular SQ and SC carcinoma.

  • 12. Companioni, Osmel
    et al.
    Bonet, Catalina
    Muñoz, Xavier
    Weiderpass, Elisabete
    Panico, Salvatore
    Tumino, Rosario
    Palli, Domenico
    Agnoli, Claudia
    Vineis, Paolo
    Boutron-Ruault, Marie-Christine
    Racine, Antoine
    Clavel-Chapelon, Françoise
    Travis, Ruth C
    Khaw, Kay-Tee
    Riboli, Elio
    Murphy, Neil
    Vergnaud, Anne-Claire
    Trichopoulou, Antonia
    Benetou, Vassiliki
    Trichopoulos, Dimitrios
    Lund, Eiliv
    Johansen, Dorthe
    Lindkvist, Björn
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. International Agency for Research on Cancer (IARC-WHO), Lyon, France.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Ardanaz, Eva
    Sánchez-Cantalejo, Emilio
    Huerta, Jose M
    Dorronsoro, Miren
    Quirós, José Ramón
    Tjonneland, Anne
    Mortensen, Lotte Maxild
    Overvad, Kim
    Chang-Claude, Jenny
    Rizzato, Cosmeri
    Boeing, Heiner
    de Mesquita, H Bas Bueno
    Siersema, Peter
    Peeters, Petra Hm
    Numans, Mattijs E
    Carneiro, Fatima
    Licaj, Idlir
    Freisling, Heinz
    Sala, Núria
    González, Carlos A
    Polymorphisms of H. pylori signaling pathway genes and gastric cancer risk in the European EPIC-eurgast cohort2014In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 134, no 1, p. 92-101Article in journal (Refereed)
    Abstract [en]

    Helicobacter pylori is a recognized causal factor of noncardia gastric cancer (GC). Lipopolysaccaride and peptidoglycan of this bacterium are recognized by CD14, TLR4 and NOD2 human proteins, while NFKB1 activates the transcription of pro-inflammatory cytokines to elicit an immune response. SNPs in these genes have been associated with GC in different populations. We genotyped 30 SNPs of these genes, in 365 gastric adenocarcinomas and 1284 matched controls from the EPIC cohort. The association with GC and its histological and anatomical subtypes was analyzed by logistic regression and corrected for multiple comparisons. Using a log-additive model we found a significant association between SNPs in CD14, NOD2 and TLR4 with GC risk. However, after applying the multiple comparisons tests only the NOD2 region remained significant (p=0.009). Analysis according to anatomical subtypes revealed NOD2 and NFKB1 SNPs associated with noncardia GC and CD14 SNPs associated with cardia GC, while analysis according to histological subtypes showed that CD14 was associated with intestinal but not diffuse GC. The multiple comparisons tests confirmed the association of NOD2 with noncardia GC (p=0.0003) and CD14 with cardia GC (p=0.01). Haplotype analysis was in agreement with single SNP results for NOD2 and CD14 genes. From these results we conclude that genetic variation in NOD2 associates with noncardia GC while variation in CD14 is associated with cardia GC.

  • 13. Dahm, Christina C.
    et al.
    Gorst-Rasmussen, Anders
    Crowe, Francesca L.
    Roswall, Nina
    Tjonneland, Anne
    Drogan, Dagmar
    Boeing, Heiner
    Teucher, Birgit
    Kaaks, Rudolf
    Adarakis, George
    Zylis, Dimosthenes
    Trichopoulou, Antonia
    Fedirko, Veronika
    Chajes, Veronique
    Jenab, Mazda
    Palli, Domenico
    Pala, Valeria
    Tumino, Rosario
    Ricceri, Fulvio
    van Kranen, Henk
    Bueno-de-Mesquita, H. Bas
    Quiros, Jose R.
    Sanchez, Maria-Jose
    Lujan-Barroso, Leila
    Larranaga, Nerea
    Chirlaque, Maria-Dolores
    Ardanaz, Eva
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. The Nutrition and Metabolism Section, International Agency for Research on Cancer, Lyon, France.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Khaw, Kay-Tee
    Wareham, Nick
    Wark, Petra A.
    Norat, Teresa
    Riboli, Elio
    Key, Tim J.
    Overvad, Kim
    Fatty acid patterns and risk of prostate cancer in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition2012In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 96, no 6, p. 1354-1361Article in journal (Refereed)
    Abstract [en]

    Background: Fatty acids in blood may be related to the risk of prostate cancer, but epidemiologic evidence is inconsistent. Blood fatty acids are correlated through shared food sources and common endogenous desaturation and elongation pathways. Studies of individual fatty acids cannot take this into account, but pattern analysis can. Treelet transform (TT) is a novel method that uses data correlation structures to derive sparse factors that explain variation. Objective: The objective was to gain further insight in the association between plasma fatty acids and risk of prostate cancer by applying TT to take data correlations into account. Design: We reanalyzed previously published data from a case-control study of prostate cancer nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. TT was used to derive factors explaining the variation in 26 plasma phospholipid fatty acids of 962 incident prostate cancer cases matched to 1061 controls. Multiple imputation was used to deal with missing data in covariates. ORs of prostate cancer according to factor scores were determined by using multivariable conditional logistic regression. Results: Four simple factors explained 38% of the variation in plasma fatty acids. A high score on a factor reflecting a long-chain n-3 PUFA pattern was associated with greater risk of prostate cancer (OR for highest compared with lowest quintile: 1.36; 95% CI: 0.99, 1.86; P-trend = 0.041). Conclusion: Pattern analyses using TT groupings of correlated fatty acids indicate that intake or metabolism of long-chain n-3 PUFAs may be relevant to prostate cancer etiology. Am J Clin Nutr 2012;96:1354-61.

  • 14. Delahaye-Sourdeix, Manon
    et al.
    Oliver, Javier
    Timofeeva, Maria N
    Gaborieau, Valérie
    Johansson, Mattias
    Genetic Epidemiology group (GEP), International Agency for Research on Cancer (IARC), Lyon, France .
    Chabrier, Amélie
    Wozniak, Magdalena B
    Brenner, Darren R
    Vallée, Maxime P
    Anantharaman, Devasena
    Lagiou, Pagona
    Holcátová, Ivana
    Richiardi, Lorenzo
    Kjaerheim, Kristina
    Agudo, Antonio
    Castellsagué, Xavier
    Macfarlane, Tatiana V
    Barzan, Luigi
    Canova, Cristina
    Thakker, Nalin S
    Conway, David I
    Znaor, Ariana
    Healy, Claire M
    Ahrens, Wolfgang
    Zaridze, David
    Szeszenia-Dabrowska, Neonilia
    Lissowska, Jolanta
    Fabianova, Eleonora
    Mates, Ioan Nicolae
    Bencko, Vladimir
    Foretova, Lenka
    Janout, Vladimir
    Curado, Maria Paula
    Koifman, Sergio
    Menezes, Ana
    Wünsch-Filho, Victor
    Eluf-Neto, José
    Boffetta, Paolo
    Garrote, Leticia Fernández
    Serraino, Diego
    Lener, Marcin
    Jaworowska, Ewa
    Lubiński, Jan
    Boccia, Stefania
    Rajkumar, Thangarajan
    Samant, Tanuja A
    Mahimkar, Manoj B
    Matsuo, Keitaro
    Franceschi, Silvia
    Byrnes, Graham
    Brennan, Paul
    McKay, James D
    The 12p13.33/RAD52 locus and genetic susceptibility to squamous cell cancers of upper aerodigestive tract2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 3, article id e0117639Article in journal (Refereed)
    Abstract [en]

    Genetic variants located within the 12p13.33/RAD52 locus have been associated with lung squamous cell carcinoma (LUSC). Here, within 5,947 UADT cancers and 7,789 controls from 9 different studies, we found rs10849605, a common intronic variant in RAD52, to be also associated with upper aerodigestive tract (UADT) squamous cell carcinoma cases (OR = 1.09, 95% CI: 1.04-1.15, p = 6x10(-4)). We additionally identified rs10849605 as a RAD52 cis-eQTL inUADT(p = 1x10(-3)) and LUSC (p = 9x10(-4)) tumours, with the UADT/LUSC risk allele correlated with increased RAD52 expression levels. The 12p13.33 locus, encompassing rs10849605/RAD52, was identified as a significant somatic focal copy number amplification in UADT(n = 374, q-value = 0.075) and LUSC (n = 464, q-value = 0.007) tumors and correlated with higher RAD52 tumor expression levels (p = 6x10(-48) and p = 3x10(-29) in UADT and LUSC, respectively). In combination, these results implicate increased RAD52 expression in both genetic susceptibility and tumorigenesis of UADT and LUSC tumors.

  • 15. Di Cesare, Mariachiara
    et al.
    Bentham, James
    Stevens, Gretchen A.
    Zhou, Bin
    Danaei, Goodarz
    Lu, Yuan
    Bixby, Honor
    Cowan, Melanie J.
    Riley, Leanne M.
    Hajifathalian, Kaveh
    Fortunato, Lea
    Taddei, Cristina
    Bennett, James E.
    Ikeda, Nayu
    Khang, Young-Ho
    Kyobutungi, Catherine
    Laxmaiah, Avula
    Li, Yanping
    Lin, Hsien-Ho
    Miranda, J. Jaime
    Mostafa, Aya
    Turley, Maria L.
    Paciorek, Christopher J.
    Gunter, Marc
    Ezzati, Majid
    Abdeen, Ziad A.
    Hamid, Zargar Abdul
    Abu-Rmeileh, Niveen M.
    Acosta-Cazares, Benjamin
    Adams, Robert
    Aekplakorn, Wichai
    Aguilar-Salinas, Carlos A.
    Ahmadvand, Alireza
    Ahrens, Wolfgang
    Ali, Mohamed M.
    Alkerwi, Ala'a
    Alvarez-Pedrerol, Mar
    Aly, Eman
    Amouyel, Philippe
    Amuzu, Antoinette
    Andersen, Lars Bo
    Anderssen, Sigmund A.
    Andrade, Dolores S.
    Anjana, Ranjit Mohan
    Aounallah-Skhiri, Hajer
    Ariansen, Inger
    Aris, Tahir
    Arlappa, Nimmathota
    Arveiler, Dominique
    Assah, Felix K.
    Avdicova, Maria
    Azizi, Fereidoun
    Babu, Bontha V.
    Balakrishna, Nagalla
    Bandosz, Piotr
    Banegas, Jose R.
    Barbagallo, Carlo M.
    Barcelo, Alberto
    Barkat, Amina
    Barros, Mauro V.
    Bata, Iqbal
    Batieha, Anwar M.
    Batista, Rosangela L.
    Baur, Louise A.
    Beaglehole, Robert
    Ben Romdhane, Habiba
    Benet, Mikhail
    Bernabe-Ortiz, Antonio
    Bernotiene, Gailute
    Bettiol, Heloisa
    Bhagyalaxmi, Aroor
    Bharadwaj, Sumit
    Bhargava, Santosh K.
    Bhatti, Zaid
    Bhutta, Zulfiqar A.
    Bi, HongSheng
    Bi, Yufang
    Bjerregaard, Peter
    Bjertness, Espen
    Bjertness, Marius B.
    Bjorkelund, Cecilia
    Blake, Margaret
    Blokstra, Anneke
    Bo, Simona
    Bobak, Martin
    Boddy, Lynne M.
    Boehm, Bernhard O.
    Boeing, Heiner
    Boissonnet, Carlos P.
    Bongard, Vanina
    Bovet, Pascal
    Braeckman, Lutgart
    Bragt, Marjolijn C. E.
    Brajkovich, Imperia
    Branca, Francesco
    Breckenkamp, Juergen
    Brenner, Hermann
    Brewster, Lizzy M.
    Brian, Garry R.
    Bruno, Graziella
    Bueno-de-Mesquita, H. B(as)
    Bugge, Anna
    Burns, Con
    Cabrera de Leon, Antonio
    Cacciottolo, Joseph
    Cama, Tilema
    Cameron, Christine
    Camolas, Jose
    Can, Gunay
    Candido, Ana Paula C.
    Capuano, Vincenzo
    Cardoso, Viviane C.
    Carvalho, Maria J.
    Casanueva, Felipe F.
    Casas, Juan-Pablo
    Caserta, Carmelo A.
    Castetbon, Katia
    Chamukuttan, Snehalatha
    Chan, Angelique W.
    Chan, Queenie
    Chaturvedi, Himanshu K.
    Chaturvedi, Nishi
    Chen, Chien-Jen
    Chen, Fangfang
    Chen, Huashuai
    Chen, Shuohua
    Chen, Zhengming
    Cheng, Ching-Yu
    Chetrit, Angela
    Chiolero, Arnaud
    Chiou, Shu-Ti
    Chirita-Emandi, Adela
    Cho, Yumi
    Christensen, Kaare
    Chudek, Jerzy
    Cifkova, Renata
    Claessens, Frank
    Clays, Els
    Concin, Hans
    Cooper, Cyrus
    Cooper, Rachel
    Coppinger, Tara C.
    Costanzo, Simona
    Cottel, Dominique
    Cowell, Chris
    Craig, Cora L.
    Crujeiras, Ana B.
    D'Arrigo, Graziella
    d'Orsi, Eleonora
    Dallongeville, Jean
    Damasceno, Albertino
    Damsgaard, Camilla T.
    Dankner, Rachel
    Dauchet, Luc
    De Backer, Guy
    De Bacquer, Dirk
    de Gaetano, Giovanni
    De Henauw, Stefaan
    De Smedt, Delphine
    Deepa, Mohan
    Deev, Alexander D.
    Dehghan, Abbas
    Delisle, Helene
    Delpeuch, Francis
    Dhana, Klodian
    Di Castelnuovo, Augusto F.
    Dias-da-Costa, Juvenal Soares
    Diaz, Alejandro
    Djalalinia, Shirin
    Do, Ha T. P.
    Dobson, Annette J.
    Donfrancesco, Chiara
    Doering, Angela
    Doua, Kouamelan
    Drygas, Wojciech
    Egbagbe, Eruke E.
    Eggertsen, Robert
    Ekelund, Ulf
    El Ati, Jalila
    Elliott, Paul
    Engle-Stone, Reina
    Erasmus, Rajiv T.
    Erem, Cihangir
    Eriksen, Louise
    Escobedo-de la Pena, Jorge
    Evans, Alun
    Faeh, David
    Fall, Caroline H.
    Farzadfar, Farshad
    Felix-Redondo, Francisco J.
    Ferguson, Trevor S.
    Fernandez-Berges, Daniel
    Ferrante, Daniel
    Ferrari, Marika
    Ferreccio, Catterina
    Ferrieres, Jean
    Finn, Joseph D.
    Fischer, Krista
    Monterubio Flores, Eric
    Foeger, Bernhard
    Foo, Leng Huat
    Forslund, Ann-Sofie
    Fortmann, Stephen P.
    Fouad, Heba M.
    Francis, Damian K.
    Franco, Maria do Carmo
    Franco, Oscar H.
    Frontera, Guillermo
    Fuchs, Flavio D.
    Fuchs, Sandra C.
    Fujita, Yuki
    Furusawa, Takuro
    Gaciong, Zbigniew
    Gafencu, Mihai
    Gareta, Dickman
    Garnett, Sarah P.
    Gaspoz, Jean-Michel
    Gasull, Magda
    Gates, Louise
    Geleijnse, Johanna M.
    Ghasemian, Anoosheh
    Giampaoli, Simona
    Gianfagna, Francesco
    Giovannelli, Jonathan
    Giwercman, Aleksander
    Goldsmith, Rebecca A.
    Gonzalez Gross, Marcela
    Gonzalez Rivas, Juan P.
    Bonet Gorbea, Mariano
    Gottrand, Frederic
    -Iversen, Sidsel Graff
    Grafnetter, Dusan
    Grajda, Aneta
    Grammatikopoulou, Maria G.
    Gregor, Ronald D.
    Grodzicki, Tomasz
    Grontved, Anders
    Gruden, Grabriella
    Grujic, Vera
    Gu, Dongfeng
    Guan, Ong Peng
    Gudnason, Vilmundur
    Guerrero, Ramiro
    Guessous, Idris
    Guimaraes, Andre L.
    Gulliford, Martin C.
    Gunnlaugsdottir, Johanna
    Guo, Xiu H.
    Guo, Yin
    Gupta, Prakash C.
    Gureje, Oye
    Gurzkowska, Beata
    Gutierrez, Laura
    Gutzwiller, Felix
    Halkjaer, Jytte
    Hardy, Rebecca
    Kumar, Rachakulla Hari
    Hayes, Alison J.
    He, Jiang
    Hendriks, Marleen Elisabeth
    Hernandez Cadena, Leticia
    Heshmat, Ramin
    Hihtaniemi, Ilpo Tapani
    Ho, Sai Yin
    Ho, Suzanne C.
    Hobbs, Michael
    Hofman, Albert
    Hormiga, Claudia M.
    Horta, Bernardo L.
    Houti, Leila
    Htay, Thein Thein
    Htet, Aung Soe
    Htike, Maung Maung Than
    Hu, Yonghua
    Hussieni, Abdullatif S.
    Huu, Chinh Nguyen
    Huybrechts, Inge
    Hwalla, Nahla
    Iacoviello, Licia
    Iannone, Anna G.
    Ibrahim, M. Mohsen
    Ikram, M. Arfan
    Irazola, Vilma E.
    Islam, Muhammad
    Iwasaki, Masanori
    Jackson, Rod T.
    Jacobs, Jeremy M.
    Jafar, Tazeen
    Jamil, Kazi M.
    Jamrozik, Konrad
    Jasienska, Grazyna
    Jiang, Chao Qiang
    Joffres, Michel
    Johansson, Mattias
    Jonas, Jost B.
    Jorgensen, Torben
    Joshi, Pradeep
    Juolevi, Anne
    Jurak, Gregor
    Juresa, Vesna
    Kaaks, Rudolf
    Kafatos, Anthony
    Kalter-Leibovici, Ofra
    Kapantais, Efthymios
    Kasaeian, Amir
    Katz, Joanne
    Kaur, Prabhdeep
    Kavousi, Maryam
    Keil, Ulrich
    Boker, Lital Keinan
    Kelishadi, Roya
    Kemper, Han H. C. G.
    Kengne, Andre P.
    Kersting, Mathilde
    Key, Timothy
    Khader, Yousef Saleh
    Khalili, Davood
    Khaw, Kay-Tee H.
    Khouw, Ilse M. S. L.
    Kiechl, Stefan
    Killewo, Japhet
    Kim, Jeongseon
    Kiyohara, Yutaka
    Klimont, Jeannette
    Kolle, Elin
    Kolsteren, Patrick
    Korrovits, Paul
    Koskinen, Seppo
    Kouda, Katsuyasu
    Koziel, Slawomir
    Kratzer, Wolfgang
    Krokstad, Steinar
    Kromhout, Daan
    Kruger, Herculina S.
    Kula, Krzysztof
    Kulaga, Zbigniew
    Kumar, R. Krishna
    Kusuma, Yadlapalli S.
    Kuulasmaa, Kari
    Laamiri, Fatima Zahra
    Laatikainen, Tiina
    Lachat, Carl
    Laid, Youcef
    Lam, Tai Hing
    Landrove, Orlando
    Lanska, Vera
    Lappas, Georg
    Laugsand, Lars E.
    Bao, Khanh Le Nguyen
    Le, Tuyen D.
    Leclercq, Catherine
    Lee, Jeannette
    Lee, Jeonghee
    Lehtimaki, Terho
    Lekhraj, Rampal
    Leon-Munoz, Luz M.
    Lim, Wei-Yen
    Fernanda Lima-Costa, M.
    Lin, Xu
    Linneberg, Allan
    Lissner, Lauren
    Litwin, Mieczyslaw
    Liu, Jing
    Lorbeer, Roberto
    Lotufo, Paulo A.
    Eugenio Lozano, Jose
    Luksiene, Dalia
    Lundqvist, Annamari
    Lunet, Nuno
    Lytsy, Per
    Ma, Guansheng
    Machi, Suka
    Maggi, Stefania
    Magliano, Dianna J.
    Makdisse, Marcia
    Malekzadeh, Reza
    Malhotra, Rahul
    Rao, Kodavanti Mallikharjuna
    Manios, Yannis
    Mann, Jim I.
    Manzato, Enzo
    Margozzini, Paula
    Markey, Oonagh
    Marques-Vidal, Pedro
    Marrugat, Jaume
    Martin-Prevel, Yves
    Martorell, Reynaldo
    Masoodi, Shariq R.
    Matsha, Tandi E.
    Mazur, Artur
    Mbanya, Jean Claude N.
    McFarlane, Shelly R.
    McGarvey, Stephen T.
    McKee, Martin
    McLachlan, Stela
    McLean, Rachael M.
    McNulty, Breige A.
    Yusof, Safiah Md
    Mediene-Benchekor, Sounnia
    Meirhaeghe, Aline
    Meisinger, Christa
    Mendes, Larissa L.
    Menezes, Ana Maria B.
    Mensink, Gert B. M.
    Meshram, Indrapal I.
    Metspalu, Andres
    Mi, Jie
    Michaelsen, Kim F.
    Mikkel, Kairit
    Miller, Jody C.
    Francisco Miquel, Juan
    Jaime Miranda, J.
    Misigoj-Durakovic, Marjeta
    Mohamed, Mostafa K.
    Mohammad, Kazem
    Mohammadifard, Noushin
    Mohan, Viswanathan
    Yusoff, Muhammad Fadhli Mohd
    Molbo, Drude
    Moller, Niels C.
    Molnar, Denes
    Mondo, Charles K.
    Monterrubio, Eric A.
    Monyeki, Kotsedi Daniel K.
    Moreira, Leila B.
    Morejon, Alain
    Moreno, Luis A.
    Morgan, Karen
    Mortensen, Erik Lykke
    Moschonis, George
    Mossakowska, Malgorzata
    Mota, Jorge
    Motlagh, Mohammad Esmaeel
    Motta, Jorge
    Mu, Thet Thet
    Muiesan, Maria Lorenza
    Mueller-Nurasyid, Martina
    Murphy, Neil
    Mursu, Jaakko
    Murtagh, Elaine M.
    Musa, Kamarul Imran
    Musil, Vera
    Nagel, Gabriele
    Nakamura, Harunobu
    Namesna, Jana
    Nang, Ei Ei K.
    Nangia, Vinay B.
    Nankap, Martin
    Narake, Sameer
    Maria Navarrete-Munoz, Eva
    Nenko, Ilona
    Neovius, Martin
    Nervi, Flavio
    Neuhauser, Hannelore K.
    Nguyen, Nguyen D.
    Nguyen, Quang Ngoc
    Nieto-Martinez, Ramfis E.
    Ning, Guang
    Ninomiya, Toshiharu
    Nishtar, Sania
    Noale, Marianna
    Norat, Teresa
    Noto, Davide
    Al Nsour, Mohannad
    O'Reilly, Dermot
    Ochoa-Aviles, Angelica M.
    Oh, Kyungwon
    Olayan, Iman H.
    Anselmo Olinto, Maria Teresa
    Oltarzewski, Maciej
    Omar, Mohd A.
    Ordunez, Pedro
    Ortiz, Ana P.
    Osler, Merete
    Osmond, Clive
    Ostojic, Sergej M.
    Otero, Johanna A.
    Overvad, Kim
    Paccaud, Fred Michel
    Padez, Cristina
    Pajak, Andrzej
    Palli, Domenico
    Palloni, Alberto
    Palmieri, Luigi
    Panda-Jonas, Songhomitra
    Panza, Francesco
    Parnell, Winsome R.
    Parsaeian, Mahboubeh
    Pednekar, Mangesh S.
    Peeters, Petra H.
    Peixoto, Sergio Viana
    Pereira, Alexandre C.
    Perez, Cynthia M.
    Peters, Annette
    Peykari, Niloofar
    Pham, Son Thai
    Pigeot, Iris
    Pikhart, Hynek
    Pilav, Aida
    Pilotto, Lorenza
    Pistelli, Francesco
    Pitakaka, Freda
    Piwonska, Aleksandra
    Piwonski, Jerzy
    Plans-Rubio, Pedro
    Poh, Bee Koon
    Porta, Miquel
    Portegies, Marileen L. P.
    Poulimeneas, Dimitrios
    Pradeepa, Rajendra
    Prashant, Mathur
    Price, Jacqueline F.
    Puiu, Maria
    Punab, Margus
    Qasrawi, Radwan F.
    Qorbani, Mostafa
    Bao, Tran Quoc
    Radic, Ivana
    Radisauskas, Ricardas
    Rahman, Mahmudur
    Raitakari, Olli
    Raj, Manu
    Rao, Sudha Ramachandra
    Ramachandran, Ambady
    Ramke, Jacqueline
    Ramos, Rafel
    Rampal, Sanjay
    Rasmussen, Finn
    Redon, Josep
    Reganit, Paul Ferdinand M.
    Ribeiro, Robespierre
    Riboli, Elio
    Rigo, Fernando
    de Wit, Tobias Floris Rinke
    Ritti-Dias, Raphael M.
    Rivera, Juan A.
    Robinson, Sian M.
    Robitaille, Cynthia
    Rodriguez-Artalejo, Fernando
    del Cristo Rodriguez-Perez, Maria
    Rodriguez-Villamizar, Laura A.
    Rojas-Martinez, Rosalba
    Rojroongwasinkul, Nipa
    Romaguera, Dora
    Ronkainen, Kimmo
    Rosengren, Annika
    Rouse, Ian
    Rubinstein, Adolfo
    Ruehli, Frank J.
    Rui, Ornelas
    Sandra Ruiz-Betancourt, Blanca
    Russo Horimoto, Andrea R. V.
    Rutkowski, Marcin
    Sabanayagam, Charumathi
    Sachdev, Harshpal S.
    Saidi, Olfa
    Salanave, Benoit
    Salazar Martinez, Eduardo
    Salomaa, Veikko
    Salonen, Jukka T.
    Salvetti, Massimo
    Sanchez-Abanto, Jose
    Sandjaja,
    Sans, Susana
    Santos, Diana A.
    Santos, Osvaldo
    dos Santos, Renata Nunes
    Santos, Rute
    Sardinha, Luis B.
    Sarrafzadegan, Nizal
    Saum, Kai-Uwe
    Savva, Savvas C.
    Scazufca, Marcia
    Rosario, Angelika Schaffrath
    Schargrodsky, Herman
    Schienkiewitz, Anja
    Schmidt, Ida Maria
    Schneider, Ione J.
    Schultsz, Constance
    Schutte, Aletta E.
    Sein, Aye Aye
    Senbanjo, Idowu O.
    Sepanlou, Sadaf G.
    Shalnova, Svetlana A.
    Shaw, Jonathan E.
    Shibuya, Kenji
    Shin, Youchan
    Shiri, Rahman
    Siantar, Rosalynn
    Sibai, Abla M.
    Silva, Antonio M.
    Santos Silva, Diego Augusto
    Simon, Mary
    Simons, Judith
    Simons, Leon A.
    Sjostrom, Michael
    Slowikowska-Hilczer, Jolanta
    Slusarczyk, Przemyslaw
    Smeeth, Liam
    Smith, Margaret C.
    Snijder, Marieke B.
    So, Hung-Kwan
    Sobngwi, Eugene
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Soekatri, Moesijanti Y. E.
    Solfrizzi, Vincenzo
    Sonestedt, Emily
    Sorensen, Thorkild I. A.
    Soric, Maroje
    Jerome, Charles Sossa
    Soumare, Aicha
    Staessen, Jan A.
    Starc, Gregor
    Stathopoulou, Maria G.
    Staub, Kaspar
    Stavreski, Bill
    Steene-Johannessen, Jostein
    Stehle, Peter
    Stein, Aryeh D.
    Stergiou, George S.
    Stessman, Jochanan
    Stieber, Jutta
    Stoeckl, Doris
    Stocks, Tanja
    Stokwiszewski, Jakub
    Stratton, Gareth
    Strufaldi, Maria Wany
    Sun, Chien-An
    Sundstrom, Johan
    Sung, Yn-Tz
    Sunyer, Jordi
    Suriyawongpaisal, Paibul
    Swinburn, Boyd A.
    Sy, Rody G.
    Szponar, Lucjan
    Tai, E. Shyong
    Tammesoo, Mari-Liis
    Tamosiunas, Abdonas
    Tang, Line
    Tang, Xun
    Tanser, Frank
    Tao, Yong
    Tarp, Jakob
    Tarqui-Mamani, Carolina B.
    Taylor, Anne
    Tchibindat, Felicite
    Thijs, Lutgarde
    Thuesen, Betina H.
    Tjonneland, Anne
    Tolonen, Hanna K.
    Tolstrup, Janne S.
    Topbas, Murat
    Topor-Madry, Roman
    Torrent, Maties
    Traissac, Pierre
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Trinh, Oanh T. H.
    Trivedi, Atul
    Tshepo, Lechaba
    Tulloch-Reid, Marshall K.
    Tuomainen, Tomi-Pekka
    Tuomilehto, Jaakko
    Tynelius, Per
    Tzotzas, Themistoklis
    Tzourio, Christophe
    Ueda, Peter
    Ukoli, Flora A. M.
    Ulmer, Hanno
    Unal, Belgin
    Valdivia, Gonzalo
    Vale, Susana
    Valvi, Damaskini
    van der Schouw, Yvonne T.
    Van Herck, Koen
    Minh, Hoang Van
    van Valkengoed, Irene G. M.
    Vanderschueren, Dirk
    Vanuzzo, Diego
    Vatten, Lars
    Vega, Tomas
    Velasquez-Melendez, Gustavo
    Veronesi, Giovanni
    Verschuren, W. M. Monique
    Viegi, Giovanni
    Viet, Lucie
    Viikari-Juntura, Eira
    Vineis, Paolo
    Vioque, Jesus
    Virtanen, Jyrki K.
    Visvikis-Siest, Sophie
    Viswanathan, Bharathi
    Vollenweider, Peter
    Voutilainen, Sari
    Vrijheid, Martine
    Wade, Alisha N.
    Wagner, Aline
    Walton, Janette
    Mohamud, Wan Nazaimoon Wan
    Wang, Ming-Dong
    Wang, Qian
    Wang, Ya Xing
    Wannamethee, S. Goya
    Wareham, Nicholas
    Weerasekera, Deepa
    Whincup, Peter H.
    Widhalm, Kurt
    Widyahening, Indah S.
    Wiecek, Andrzej
    Wilks, Rainford J.
    Willeit, Johann
    Wojtyniak, Bogdan
    Wong, Jyh Eiin
    Wong, Tien Yin
    Woo, Jean
    Woodward, Mark
    Wu, Frederick C.
    Wu, JianFeng
    Wu, Shou Ling
    Xu, Haiquan
    Xu, Liang
    Yamborisut, Uruwan
    Yan, Weili
    Yang, Xiaoguang
    Yardim, Nazan
    Ye, Xingwang
    Yiallouros, Panayiotis K.
    Yoshihara, Akihiro
    You, Qi Sheng
    Younger-Coleman, Novie O.
    Yusoff, Ahmad F.
    Zainuddin, Ahmad A.
    Zambon, Sabina
    Zdrojewski, Tomasz
    Zeng, Yi
    Zhao, Dong
    Zhao, Wenhua
    Zheng, Yingfeng
    Zhou, Maigeng
    Zhu, Dan
    Zimmermann, Esther
    Zuniga Cisneros, Julio
    Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19.2 million participants2016In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 387, no 10026, p. 1377-1396Article in journal (Refereed)
    Abstract [en]

    Background Underweight and severe and morbid obesity are associated with highly elevated risks of adverse health outcomes. We estimated trends in mean body-mass index (BMI), which characterises its population distribution, and in the prevalences of a complete set of BMI categories for adults in all countries.

    Methods We analysed, with use of a consistent protocol, population-based studies that had measured height and weight in adults aged 18 years and older. We applied a Bayesian hierarchical model to these data to estimate trends from 1975 to 2014 in mean BMI and in the prevalences of BMI categories (<18.5 kg/m(2) [underweight], 18.5 kg/m(2) to <20 kg/m(2), 20 kg/m(2) to <25 kg/m(2), 25 kg/m(2) to <30 kg/m(2), 30 kg/m(2) to <35 kg/m(2), 35 kg/m(2) to <40 kg/m(2), = 40 kg/m(2) [morbid obesity]), by sex in 200 countries and territories, organised in 21 regions. We calculated the posterior probability of meeting the target of halting by 2025 the rise in obesity at its 2010 levels, if post-2000 trends continue.

    Findings We used 1698 population-based data sources, with more than 19.2 million adult participants (9.9 million men and 9.3 million women) in 186 of 200 countries for which estimates were made. Global age-standardised mean BMI increased from 21.7 kg/m(2) (95% credible interval 21.3-22.1) in 1975 to 24.2 kg/m(2) (24.0-24.4) in 2014 in men, and from 22.1 kg/m(2) (21.7-22.5) in 1975 to 24.4 kg/m(2) (24.2-24.6) in 2014 in women. Regional mean BMIs in 2014 for men ranged from 21.4 kg/m(2) in central Africa and south Asia to 29.2 kg/m(2) (28.6-29.8) in Polynesia and Micronesia; for women the range was from 21.8 kg/m(2) (21.4-22.3) in south Asia to 32.2 kg/m(2) (31.5-32.8) in Polynesia and Micronesia. Over these four decades, age-standardised global prevalence of underweight decreased from 13.8% (10.5-17.4) to 8.8% (7.4-10.3) in men and from 14.6% (11.6-17.9) to 9.7% (8.3-11.1) in women. South Asia had the highest prevalence of underweight in 2014, 23.4% (17.8-29.2) in men and 24.0% (18.9-29.3) in women. Age-standardised prevalence of obesity increased from 3.2% (2.4-4.1) in 1975 to 10.8% (9.7-12.0) in 2014 in men, and from 6.4% (5.1-7.8) to 14.9% (13.6-16.1) in women. 2.3% (2.0-2.7) of the world's men and 5.0% (4.4-5.6) of women were severely obese (ie, have BMI = 35 kg/m(2)). Globally, prevalence of morbid obesity was 0.64% (0.46-0.86) in men and 1.6% (1.3-1.9) in women.

    Interpretation If post-2000 trends continue, the probability of meeting the global obesity target is virtually zero. Rather, if these trends continue, by 2025, global obesity prevalence will reach 18% in men and surpass 21% in women; severe obesity will surpass 6% in men and 9% in women. Nonetheless, underweight remains prevalent in the world's poorest regions, especially in south Asia. 

  • 16. Duell, Eric J
    et al.
    Lujan-Barroso, Leila
    Llivina, Claudia
    Muñoz, Xavier
    Jenab, Mazda
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Françoise
    Racine, Antoine
    Boeing, Heiner
    Buijsse, Brian
    Canzian, Federico
    Johnson, Theron
    Dalgård, Christine
    Overvad, Kim
    Tjønneland, Anne
    Olsen, Anja
    Sánchez, Soledad C
    Sánchez-Cantalejo, Emilio
    Huerta, José-María
    Ardanaz, Eva
    Dorronsoro, Miren
    Khaw, Kay-Tee
    Travis, Ruth C
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Rafnsson, Snorri
    Palli, Domenico
    Sacerdote, Carlotta
    Tumino, Rosario
    Panico, Salvatore
    Grioni, Sara
    Bueno-de-Mesquita, H Bas
    Ros, Martine M
    Numans, Mattijs E
    Peeters, Petra H
    Johansen, Dorthe
    Lindkvist, Björn
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. Genetic Epidemiology Group, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Skeie, Guri
    Weiderpass, Elisabete
    Duarte-Salles, Talita
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Riboli, Elio
    Sala, Núria
    González, Carlos A
    Vitamin C transporter gene (SLC23A1 and SLC23A2) polymorphisms, plasma vitamin C levels, and gastric cancer risk in the EPIC cohort2013In: Genes & Nutrition, ISSN 1555-8932, E-ISSN 1865-3499, Vol. 8, no 6, p. 549-560Article in journal (Refereed)
    Abstract [en]

    Vitamin C is known to protect mucosal tissues from oxidative stress and inhibit nitrosamine formation in the stomach. High consumption of fruits, particularly citrus, and higher circulating vitamin C concentrations may be inversely associated with gastric cancer (GC) risk. We investigated 20 polymorphisms in vitamin C transporter genes SCL23A1 and SCL23A2 and GC risk in 365 cases and 1,284 controls nested within the European Prospective Investigation into Cancer and Nutrition cohort. We also evaluated the association between these polymorphisms and baseline plasma vitamin C levels in a subset of participants. Four SNPs were predictors of plasma vitamin C levels (SLC23A1 rs11950646 and rs33972313; SLC23A2 rs6053005 and rs6133175) in multivariable linear regression models. One SNP (SLC23A2 rs6116569) was associated with GC risk, in particular non-cardia GC (OR = 1.63, 95 % CI = 1.11-2.39, based on 178 non-cardia cases), but this association was attenuated when plasma vitamin C was included in the logistic regression model. Haplotype analysis of SLC23A1 yielded no associations with GC. In SLC23A2, one haplotype was associated with both overall and non-cardia GC, another haplotype was associated with GC overall, and a third was associated with intestinal-type GC. Common variants in SLC23A1 and SLC23A2 may influence plasma vitamin C concentration independent of dietary intake, and variation in SLC23A2 may influence GC risk. Additional prospective studies in large populations and consortia are recommended. Investigation of variation in vitamin C transporter genes may shed light on the preventative properties of vitamin C in gastric carcinogenesis.

  • 17. Ekelund, Ulf
    et al.
    Ward, Heather A.
    Norat, Teresa
    Luan, Jian'an
    May, Anne M.
    Weiderpass, Elisabete
    Sharp, Stephen J.
    Overvad, Kim
    Ostergaard, Jane Nautrup
    TjOnneland, Anne
    Johnsen, Nina Fons
    Mesrine, Sylvie
    Foamier, Agnes
    Fagherazzi, Guy
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Li, Kuanrong
    Kaaks, Rudolf
    Ferrari, Pietro
    Licaj, Idlir
    Jenab, Mazda
    Bergmann, Manuela
    Boeing, Heiner
    Palli, Domenico
    Sieri, Sabina
    Panico, Salvatore
    Tumino, Rosario
    Vineis, Paolo
    Peeters, Petra H.
    Monnikhof, Evelyn
    Bueno-de-Mesquita, H. Bas
    Ramon Quiros, J.
    Agudo, Antonio
    Sanchez, Maria-Jose
    Maria Huerta, Jose
    Ardanaz, Eva
    Arriola, Larraitz
    Hedblad, Bo
    Wirfalt, Elisabet
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. International Agency for Research on Cancer (IARC), Lyon, France.
    Key, Timothy J.
    Travis, Ruth C.
    Khaw, Kay-Tee
    Brage, Soren
    Wareham, Nicholas J.
    Riboli, Elio
    Physical activity and all-cause mortality across levels of overall and abdominal adiposity in European men and women: the European Prospective Investigation into Cancer and Nutrition Study (EPIC)2015In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 101, no 3, p. 613-621Article in journal (Refereed)
    Abstract [en]

    Background: The higher risk of death resulting from excess adiposity may be attenuated by physical activity (PA). However, the theoretical number of deaths reduced by eliminating physical inactivity compared with overall and abdominal obesity remains unclear.

    Objective: We examined whether overall and abdominal adiposity modified the association between PA and all-cause mortality and estimated the population attributable fraction (PAF) and the years of life gained for these exposures.

    Design: This was a cohort study in 334,161 European men and women. The mean follow-up time was 12.4 y, corresponding to 4,154,915 person-years. Height, weight, and waist circumference (WC) were measured in the clinic. PA was assessed with a validated self-report instrument. The combined associations between PA, BMI, and WC with mortality were examined with Cox proportional hazards models, stratified by center and age group, and adjusted for sex, education, smoking, and alcohol intake. Center-specific PAF associated with inactivity, body mass index (BMI; in kg/m(2)) (>30), and WC (>= 102 cm for men, >= 88 cm for women) were calculated and combined in random-effects meta-analysis. Life-tables analyses were used to estimate gains in life expectancy for the exposures.

    Results: Significant interactions (PA x BMI and PA x WC) were observed, so HRs were estimated within BMI and WC strata. The hazards of all-cause mortality were reduced by 16-30% in moderately inactive individuals compared with those categorized as inactive in different strata of BMI and WC. Avoiding all inactivity would theoretically reduce all-cause mortality by 7.35% (95% CI: 5.88%, 8.83%). Corresponding estimates for avoiding obesity (BMI >30) were 3.66% (95% CI: 2.30%, 5.01%). The estimates for avoiding high WC were similar to those for physical inactivity.

    Conclusion: The greatest reductions in mortality risk were observed between the 2 lowest activity groups across levels of general and abdominal adiposity, which suggests that efforts to encourage even small increases in activity in inactive individuals may be beneficial to public health.

  • 18. Fanidi, Anouar
    et al.
    Relton, Caroline
    Ueland, Per Magne
    Midttun, Øivind
    Vollset, Stein Emil
    Travis, Ruth C.
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Bueno-de-Mesquita, H. B(as)
    Ros, Martine
    Boeing, Heiner
    Tumino, Rosario
    Panico, Salvatore
    Palli, Domenico
    Sieri, Sabina
    Vineis, Paolo
    Sánchez, María-José
    Huerta, José María
    Barricarte Gurrea, Aurelio
    Luján-Barroso, Leila
    Quirós, J. Ramón
    Tjønneland, Anne
    Halkjær, Jytte
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Françoise
    Cadeau, Claire
    Weiderpass, Elisabete
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Riboli, Elio
    Brennan, Paul
    Johansson, Mattias
    International Agency for Research on Cancer, Lyon, France.
    A prospective study of one-carbon metabolism biomarkers and cancer of the head and neck and esophagus2015In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 136, no 4, p. 915-927Article in journal (Refereed)
    Abstract [en]

    Experimental and epidemiological data suggest that factors of one-carbon metabolism are important in the pathogenesis of several cancers, but prospective data on head and neck cancer (HNC) and esophagus cancer are limited. The European Prospective Investigation into Cancer and Nutrition (EPIC) study recruited 385,747 participants from 10 countries who donated a blood sample. The current study included 516 cancer cases of the head and neck and esophagus and 516 individually matched controls. Plasma levels of vitamins B2, B6, B9 (folate), B12, and methionine and homocysteine were measured in pre-diagnostic plasma samples and analyzed in relation to HNC and esophagus cancer risk, as well as post-diagnosis all-cause mortality. After controlling for risk factors, study participants with higher levels of homocysteine had elevated risk of HNC, the odds ratio (OR) in conditional analysis when comparing the top and bottom quartiles of homocysteine [ORQ4vs. Q1] being 2.13 (95% confidence interval [95% CI] 1.13-4.00, p for trend 0.009). A slight decrease in HNC risk was also seen among subjects with higher levels of folate (ORQ4vs. Q1 0.63, 95% CI 0.35-1.16, p for trend 0.02). Subgroup analyses by anatomical sub-site indicated particularly strong associations with circulating homocysteine for oral cavity and gum cancer (p for trend 8 x 10(-4)), as well as for oropharynx cancer (p for trend 0.008). Plasma concentrations of the other investigated biomarkers did not display any clear association with risk or survival. In conclusion, study participants with elevated circulating levels of homocysteine had increased risk of developing squamous cell carcinoma of the head and neck. What's new? One-carbon metabolism (OCM) involves the transfer of a carbon unit from methyl donor nutrients to molecules involved in the synthesis and methylation of DNA. As a result, dietary imbalances or deficiencies in nutrients crucial for OCM may affect DNA replication, repair, and regulation, potentially facilitating cancer development. This analysis of circulating levels of OCM nutrients in head and neck cancer and esophageal cancer patients and matched controls reveals an association between elevated levels of the amino acid homocysteine and increased risk of squamous cell carcinoma of the head and neck. Risk was decreased slightly by elevated folate levels.

  • 19. Fasanelli, Francesca
    et al.
    Baglietto, Laura
    Ponzi, Erica
    Guida, Florence
    Campanella, Gianluca
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. Genetic Epidemiology Division, International Agency for Research on Cancer, Lyon, France.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Assumma, Manuela Bianca
    Naccarati, Alessio
    Chadeau-Hyam, Marc
    Ala, Ugo
    Faltus, Christian
    Kaaks, Rudolf
    Risch, Angela
    De Stavola, Bianca
    Hodge, Allison
    Giles, Graham G
    Southey, Melissa C
    Relton, Caroline L
    Haycock, Philip C
    Lund, Eiliv
    Polidoro, Silvia
    Sandanger, Torkjel M
    Severi, Gianluca
    Vineis, Paolo
    Hypomethylation of smoking-related genes is associated with future lung cancer in four prospective cohorts2015In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, article id 10192Article in journal (Refereed)
    Abstract [en]

    DNA hypomethylation in certain genes is associated with tobacco exposure but it is unknown whether these methylation changes translate into increased lung cancer risk. In an epigenome-wide study of DNA from pre-diagnostic blood samples from 132 case–control pairs in the NOWAC cohort, we observe that the most significant associations with lung cancer risk are for cg05575921 in AHRR (OR for 1 s.d.=0.37, 95% CI: 0.31–0.54, P-value=3.3 × 10−11) and cg03636183 in F2RL3 (OR for 1 s.d.=0.40, 95% CI: 0.31–0.56, P-value=3.9 × 10−10), previously shown to be strongly hypomethylated in smokers. These associations remain significant after adjustment for smoking and are confirmed in additional 664 case–control pairs tightly matched for smoking from the MCCS, NSHDS and EPIC HD cohorts. The replication and mediation analyses suggest that residual confounding is unlikely to explain the observed associations and that hypomethylation of these CpG sites may mediate the effect of tobacco on lung cancer risk.

  • 20. Fehringer, Gordon
    et al.
    Kraft, Peter
    Pharoah, Paul D P
    Eeles, Rosalind A
    Chatterjee, Nilanjan
    Schumacher, Fredrick R
    Schildkraut, Joellen M
    Lindstrom, Sara
    Brennan, Paul
    Bickeböller, Heike
    Houlston, Richard S
    Landi, Maria Teresa
    Caporaso, Neil E
    Risch, Angela
    Amin Al Olama, Ali
    Berndt, Sonja I
    Giovannucci, Edward
    Gronberg, Henrik
    Kote-Jarai, Zsofia
    Ma, Jing
    Muir, Kenneth
    Stampfer, Meir J
    Stevens, Victoria L
    Wiklund, Fredrik
    Willett, Walter C
    Goode, Ellen L
    Permuth, Jennifer B
    Risch, Harvey A
    Reid, Brett M
    Bezieau, Stéphane
    Brenner, Hermann
    Chan, Andrew T
    Chang-Claude, Jenny
    Hudson, Thomas J
    Kocarnik, Jonathan
    Newcomb, Polly A
    Schoen, Robert E
    Slattery, Martha L
    White, Emily
    Adank, Muriel A
    Ahsan, Habibul
    Aittomaki, Kristiina
    Baglietto, Laura
    Blomquist, Carl
    Canzian, Federico
    Czene, Kamila
    Dos Santos Silva, Isabel
    Eliassen, A Heather
    Figueroa, Jonine D
    Flesch-Janys, Dieter
    Fletcher, Olivia
    Garcia-Closas, Montserrat
    Gaudet, Mia M
    Johnson, Nichola
    Hall, Per
    Hazra, Aditi
    Hein, Rebecca
    Hofman, Albert
    Hopper, John L
    Irwanto, Astrid
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. International Agency for Research on Cancer, Lyon, France.
    Kaaks, Rudolf
    Kibriya, Muhammad G
    Lichtner, Peter
    Liu, Jian-Jun
    Lund, Eiliv
    Makalic, Enes
    Meindl, Alfons
    Müller-Myhsok, Bertram
    Muranen, Taru A
    Nevanlinna, Heli
    Peeters, Petra H
    Peto, Julian
    Prentice, Ross L
    Rahman, Nazneen
    Sanchez, Maria-Jose
    Schmidt, Daniel F
    Schmutzler, Rita K
    Southey, Melissa C
    Tamimi, Rulla M
    Travis, Ruth C
    Turnbull, Clare
    Uitterlinden, Andre G
    Wang, Zhaoming
    Whittemore, Alice S
    Yang, Xiaohong R
    Zheng, Wei
    Rafnar, Thorunn
    Gudmundsson, Julius
    Stacey, Simon N
    Stefansson, Kari
    Sulem, Patrick
    Chen, Y Ann
    Tyrer, Jonathan P
    Christiani, David C
    Wei, Yongyue
    Shen, Hongbing
    Hu, Zhibin
    Shu, Xiao-Ou
    Shiraishi, Kouya
    Takahashi, Atsushi
    Bossé, Yohan
    Obeidat, Ma'en
    Nickle, David
    Timens, Wim
    Freedman, Matthew L
    Li, Qiyuan
    Seminara, Daniela
    Chanock, Stephen J
    Gong, Jian
    Peters, Ulrike
    Gruber, Stephen B
    Amos, Christopher I
    Sellers, Thomas A
    Easton, Douglas F
    Hunter, David J
    Haiman, Christopher A
    Henderson, Brian E
    Hung, Rayjean J
    Cross-cancer genome-wide analysis of lung, ovary, breast, prostate and colorectal cancer reveals novel pleiotropic associations2016In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 76, no 17, p. 5103-5114Article in journal (Refereed)
    Abstract [en]

    Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-staged approach to conduct genome-wide association studies for lung, ovary, breast, prostate and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression.

  • 21. Freisling, Heinz
    et al.
    Pisa, Pedro T
    Ferrari, Pietro
    Byrnes, Graham
    Moskal, Aurelie
    Dahm, Christina C
    Vergnaud, Anne-Claire
    Boutron-Ruault, Marie-Christine
    Fagherazzi, Guy
    Cadeau, Claire
    Kühn, Tilman
    Neamat-Allah, Jasmine
    Buijsse, Brian
    Boeing, Heiner
    Halkjær, Jytte
    Tjonneland, Anne
    Hansen, Camilla P
    Quirós, J Ramón
    Travier, Noémie
    Molina-Montes, Esther
    Amiano, Pilar
    Huerta, José M
    Barricarte, Aurelio
    Khaw, Kay-Tee
    Wareham, Nicholas
    Key, Tim J
    Romaguera, Dora
    Lu, Yunxia
    Lassale, Camille M
    Naska, Androniki
    Orfanos, Philippos
    Trichopoulou, Antonia
    Masala, Giovanna
    Pala, Valeria
    Berrino, Franco
    Tumino, Rosario
    Ricceri, Fulvio
    de Magistris, Maria Santucci
    Bueno-de-Mesquita, H Bas
    Ocké, Marga C
    Sonestedt, Emily
    Ericson, Ulrika
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. International Agency for Research on Cancer (IARC-WHO), Lyon, France.
    Skeie, Guri
    Weiderpass, Elisabete
    Braaten, Tonje
    Peeters, Petra H M
    Slimani, Nadia
    Main nutrient patterns are associated with prospective weight change in adults from 10 European countries2016In: European Journal of Nutrition, ISSN 1436-6207, E-ISSN 1436-6215, Vol. 55, no 6, p. 2093-2104Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Various food patterns have been associated with weight change in adults, but it is unknown which combinations of nutrients may account for such observations. We investigated associations between main nutrient patterns and prospective weight change in adults.

    METHODS: This study includes 235,880 participants, 25-70 years old, recruited between 1992 and 2000 in 10 European countries. Intakes of 23 nutrients were estimated from country-specific validated dietary questionnaires using the harmonized EPIC Nutrient DataBase. Four nutrient patterns, explaining 67 % of the total variance of nutrient intakes, were previously identified from principal component analysis. Body weight was measured at recruitment and self-reported 5 years later. The relationship between nutrient patterns and annual weight change was examined separately for men and women using linear mixed models with random effect according to center controlling for confounders.

    RESULTS: Mean weight gain was 460 g/year (SD 950) and 420 g/year (SD 940) for men and women, respectively. The annual differences in weight gain per one SD increase in the pattern scores were as follows: principal component (PC) 1, characterized by nutrients from plant food sources, was inversely associated with weight gain in men (-22 g/year; 95 % CI -33 to -10) and women (-18 g/year; 95 % CI -26 to -11). In contrast, PC4, characterized by protein, vitamin B2, phosphorus, and calcium, was associated with a weight gain of +41 g/year (95 % CI +2 to +80) and +88 g/year (95 % CI +36 to +140) in men and women, respectively. Associations with PC2, a pattern driven by many micro-nutrients, and with PC3, a pattern driven by vitamin D, were less consistent and/or non-significant.

    CONCLUSIONS: We identified two main nutrient patterns that are associated with moderate but significant long-term differences in weight gain in adults.

  • 22. Gu, Fangyi
    et al.
    Schumacher, Fredrick R
    Canzian, Federico
    Allen, Naomi E
    Albanes, Demetrius
    Berg, Christine D
    Berndt, Sonja I
    Boeing, Heiner
    Bueno-de-Mesquita, H Bas
    Buring, Julie E
    Chabbert-Buffet, Nathalie
    Chanock, Stephen J
    Clavel-Chapelon, Françoise
    Dumeaux, Vanessa
    Gaziano, J Michael
    Giovannucci, Edward L
    Haiman, Christopher A
    Hankinson, Susan E
    Hayes, Richard B
    Henderson, Brian E
    Hunter, David J
    Hoover, Robert N
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. International Agency for Research on Cancer (IARC), Lyon, France.
    Key, Timothy J
    Khaw, Kay-Tee
    Kolonel, Laurence N
    Lagiou, Pagona
    Lee, I-Min
    LeMarchand, Loic
    Lund, Eiliv
    Ma, Jing
    Onland-Moret, N Charlotte
    Overvad, Kim
    Rodriguez, Laudina
    Sacerdote, Carlotta
    Sánchez, Maria-José
    Stampfer, Meir J
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Stram, Daniel O
    Thomas, Gilles
    Thun, Michael J
    Tjønneland, Anne
    Trichopoulos, Dimitrios
    Tumino, Rosario
    Virtamo, Jarmo
    Weinstein, Stephanie J
    Willett, Walter C
    Yeager, Meredith
    Zhang, Shumin M
    Kaaks, Rudolf
    Riboli, Elio
    Ziegler, Regina G
    Kraft, Peter
    Eighteen insulin-like growth factor pathway genes, circulating levels of IGF-I and its binding protein, and risk of prostate and breast cancer2010In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 19, no 11, p. 2877-2887Article in journal (Refereed)
    Abstract [en]

    Background: Circulating levels of insulin-like growth factor I (IGF-I) and its main binding protein, IGF binding protein 3 (IGFBP-3), have been associated with risk of several types of cancer. Heritable factors explain up to 60% of the variation in IGF-I and IGFBP-3 in studies of adult twins.

    Methods: We systematically examined common genetic variation in 18 genes in the IGF signaling pathway for associations with circulating levels of IGF-I and IGFBP-3. A total of 302 single nucleotide polymorphisms (SNP) were genotyped in >5,500 Caucasian men and 5,500 Caucasian women from the Breast and Prostate Cancer Cohort Consortium.

    Results: After adjusting for multiple testing, SNPs in the IGF1 and SSTR5 genes were significantly associated with circulating IGF-I (P < 2.1 × 10−4); SNPs in the IGFBP3 and IGFALS genes were significantly associated with circulating IGFBP-3. Multi-SNP models explained R2 = 0.62% of the variation in circulating IGF-I and 3.9% of the variation in circulating IGFBP-3. We saw no significant association between these multi-SNP predictors of circulating IGF-I or IGFBP-3 and risk of prostate or breast cancers.

    Conclusion: Common genetic variation in the IGF1 and SSTR5 genes seems to influence circulating IGF-I levels, and variation in IGFBP3 and IGFALS seems to influence circulating IGFBP-3. However, these variants explain only a small percentage of the variation in circulating IGF-I and IGFBP-3 in Caucasian men and women.

    Impact: Further studies are needed to explore contributions from other genetic factors such as rare variants in these genes and variation outside of these genes.

  • 23. Gusev, Alexander
    et al.
    Shi, Huwenbo
    Kichaev, Gleb
    Pomerantz, Mark
    Li, Fugen
    Long, Henry W
    Ingles, Sue A
    Kittles, Rick A
    Strom, Sara S
    Rybicki, Benjamin A
    Nemesure, Barbara
    Isaacs, William B
    Zheng, Wei
    Pettaway, Curtis A
    Yeboah, Edward D
    Tettey, Yao
    Biritwum, Richard B
    Adjei, Andrew A
    Tay, Evelyn
    Truelove, Ann
    Niwa, Shelley
    Chokkalingam, Anand P
    John, Esther M
    Murphy, Adam B
    Signorello, Lisa B
    Carpten, John
    Leske, M Cristina
    Wu, Suh-Yuh
    Hennis, Anslem J M
    Neslund-Dudas, Christine
    Hsing, Ann W
    Chu, Lisa
    Goodman, Phyllis J
    Klein, Eric A
    Witte, John S
    Casey, Graham
    Kaggwa, Sam
    Cook, Michael B
    Stram, Daniel O
    Blot, William J
    Eeles, Rosalind A
    Easton, Douglas
    Kote-Jarai, ZSofia
    Al Olama, Ali Amin
    Benlloch, Sara
    Muir, Kenneth
    Giles, Graham G
    Southey, Melissa C
    Fitzgerald, Liesel M
    Gronberg, Henrik
    Wiklund, Fredrik
    Aly, Markus
    Henderson, Brian E
    Schleutker, Johanna
    Wahlfors, Tiina
    Tammela, Teuvo L J
    Nordestgaard, Børge G
    Key, Tim J
    Travis, Ruth C
    Neal, David E
    Donovan, Jenny L
    Hamdy, Freddie C
    Pharoah, Paul
    Pashayan, Nora
    Khaw, Kay-Tee
    Stanford, Janet L
    Thibodeau, Stephen N
    McDonnell, Shannon K
    Schaid, Daniel J
    Maier, Christiane
    Vogel, Walther
    Luedeke, Manuel
    Herkommer, Kathleen
    Kibel, Adam S
    Cybulski, Cezary
    Wokolorczyk, Dominika
    Kluzniak, Wojciech
    Cannon-Albright, Lisa
    Teerlink, Craig
    Brenner, Hermann
    Dieffenbach, Aida K
    Arndt, Volker
    Park, Jong Y
    Sellers, Thomas A
    Lin, Hui-Yi
    Slavov, Chavdar
    Kaneva, Radka
    Mitev, Vanio
    Batra, Jyotsna
    Spurdle, Amanda
    Clements, Judith A
    Teixeira, Manuel R
    Pandha, Hardev
    Michael, Agnieszka
    Paulo, Paula
    Maia, Sofia
    Kierzek, Andrzej
    Conti, David V
    Albanes, Demetrius
    Berg, Christine
    Berndt, Sonja I
    Campa, Daniele
    Crawford, E David
    Diver, W Ryan
    Gapstur, Susan M
    Gaziano, J Michael
    Giovannucci, Edward
    Hoover, Robert
    Hunter, David J
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Kraft, Peter
    Le Marchand, Loic
    Lindström, Sara
    Navarro, Carmen
    Overvad, Kim
    Riboli, Elio
    Siddiq, Afshan
    Stevens, Victoria L
    Trichopoulos, Dimitrios
    Vineis, Paolo
    Yeager, Meredith
    Trynka, Gosia
    Raychaudhuri, Soumya
    Schumacher, Frederick R
    Price, Alkes L
    Freedman, Matthew L
    Haiman, Christopher A
    Pasaniuc, Bogdan
    Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation.2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 10979Article in journal (Refereed)
    Abstract [en]

    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.

  • 24. Henrion, Marc Y R
    et al.
    Purdue, Mark P
    Scelo, Ghislaine
    Broderick, Peter
    Frampton, Matthew
    Ritchie, Alastair
    Meade, Angela
    Li, Peng
    McKay, James
    Johansson, Mattias
    International Agency for Research on Cancer, Lyon, France .
    Lathrop, Mark
    Larkin, James
    Rothman, Nathaniel
    Wang, Zhaoming
    Chow, Wong-Ho
    Stevens, Victoria L
    Diver, W Ryan
    Albanes, Demetrius
    Virtamo, Jarmo
    Brennan, Paul
    Eisen, Timothy
    Chanock, Stephen
    Houlston, Richard S
    Common variation at 1q24.1 (ALDH9A1) is a potential risk factor for renal cancer2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 3, article id e0122589Article in journal (Refereed)
    Abstract [en]

    So far six susceptibility loci for renal cell carcinoma (RCC) have been discovered by genome-wide association studies (GWAS). To identify additional RCC common risk loci, we performed a meta-analysis of published GWAS (totalling 2,215 cases and 8,566 controls of Western-European background) with imputation using 1000 Genomes Project and UK10K Project data as reference panels and followed up the most significant association signals [22 single nucleotide polymorphisms (SNPs) and 3 indels in eight genomic regions] in 383 cases and 2,189 controls from The Cancer Genome Atlas (TCGA). A combined analysis identified a promising susceptibility locus mapping to 1q24.1 marked by the imputed SNP rs3845536 (Pcombined =2.30x10-8). Specifically, the signal maps to intron 4 of the ALDH9A1 gene (aldehyde dehydrogenase 9 family, member A1). We further evaluated this potential signal in 2,461 cases and 5,081 controls from the International Agency for Research on Cancer (IARC) GWAS of RCC cases and controls from multiple European regions. In contrast to earlier findings no association was shown in the IARC series (P=0.94; Pcombined =2.73x10-5). While variation at 1q24.1 represents a potential risk locus for RCC, future replication analyses are required to substantiate our observation.

  • 25.
    Holmström, Benny
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. International Agency for Research on Cancer (IARC), Lyon, France.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stenman, Ulf-Håkan
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Prostate specific antigen for early detection of prostate cancer: longitudinal study2009In: BMJ (Clinical research ed.), ISSN 1468-5833, Vol. 339, p. b3537-Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To evaluate if prostate specific antigen test attains validity standards required for screening in view of recent prostate cancer screening trial results.

    DESIGN: Case-control study nested in longitudinal cohort.

    SETTING: Västerbotten Intervention Project cohort, Umeå, Sweden.

    PARTICIPANTS: 540 cases and 1034 controls matched for age and date of blood draw.

    MAIN OUTCOME MEASURE: Validity of prostate specific antigen for prediction of subsequent prostate cancer diagnosis by record linkage to cancer registry.

    RESULTS: Blood samples were drawn on average 7.1 (SD 3.7) years before diagnosis. The area under the curve for prostate specific antigen was 0.84 (95% confidence interval 0.82 to 0.86). At prostate specific antigen cut-off values of 3, 4, and 5 ng/ml, sensitivity estimates were 59%, 44%, and 33%, and specificity estimates were 87%, 92%, and 95%. The positive likelihood ratio commonly considered to "rule in disease" is 10; in this study the positive likelihood ratios were 4.5, 5.5, and 6.4 for prostate specific antigen cut-off values of 3, 4, and 5 ng/ml. The negative likelihood ratio commonly considered to "rule out disease" is 0.1; in this study the negative likelihood ratios were 0.47, 0.61, and 0.70 for prostate specific antigen cut-off values of 3, 4, and 5 ng/ml. For a cut-off of 1.0 ng/ml, the negative likelihood ratio was 0.08.

    CONCLUSIONS: No single cut-off value for prostate specific antigen concentration attained likelihood ratios formally required for a screening test. Prostate specific antigen concentrations below 1.0 ng/ml virtually ruled out a prostate cancer diagnosis during the follow-up. Additional biomarkers for early detection of prostate cancer are needed before population based screening for prostate cancer should be introduced.

  • 26.
    Holmström, Benny
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Johansson, Mattias
    International Agency for Research on Cancer (IARC), Lyon, France.
    Bratt, Ola
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    PSA-testet håller inte för screening: bra – men inte tillräckligt bra2009In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 107, no 7, p. 436, 438-439Article in journal (Refereed)
    Abstract [sv]

    Prostatacancer är den vanligaste cancersjukdomen och den vanligaste cancerrelaterade dödsorsaken bland män i Sverige. Screening för prostataspecifikt antigen (PSA) minskade dödligheten i prostatacancer med 20 procent i en stor randomiserad studie. En utvärdering av PSA-test med sannolikhetskvot (likelihood ratio) visade att det inte uppfyller kriterierna för ett screeningtest. Män ska ha information om PSA-testets för- och nackdelar innan testet utförs. En broschyr med sådan information finns tillgänglig på <http://www.socialstyrelsen.se/publikationer2007/2007-114-90>.

  • 27. Jakszyn, Paula G
    et al.
    Allen, Naomi E
    Lujan-Barroso, Leila
    Gonzalez, Carlos A
    Key, Timothy J
    Fonseca-Nunes, Ana
    Tjønneland, Anne
    Føns-Johnsen, Nina
    Overvad, Kim
    Teucher, Birgit
    Li, Kuanrong
    Boeing, Heiner
    Trichopoulou, Antonia
    Oikonomou, Eleni
    Sarantopoulou, Maria
    Saieva, Calogero
    Krogh, Vittorio
    Tumino, Rosario
    Ricceri, Fulvio
    Bueno-de-Mesquita, H Bas
    Huerta, José M
    Ardanaz, Eva
    Arguelles, Marcial V
    Molina-Montes, Esther
    Larrañaga, Nerea
    Wirfält, Elisabet
    Wallström, Peter
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Surgery, Urology Service, Memorial Sloan-Kettering Cancer Center, New York.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Surgery, Urology Service, Memorial Sloan-Kettering Cancer Center, New York.
    Khaw, Kay-Tee
    Jenab, Mazda
    Fedirko, Veronika
    Riboli, Elio
    Nitrosamines and Heme Iron and Risk of Prostate Cancer in the European Prospective Investigation into Cancer and Nutrition.2012In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 21, no 3, p. 547-551Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The evidence about nitrosamines and heme iron intake and cancer risk is limited, despite the biologic plausibility of the hypothesis that these factors might increase cancer risk. We investigated the association between dietary nitrosamines and heme iron and the risk of prostate cancer among participants of European Prospective Investigation into Cancer and Nutrition (EPIC).METHODS: Data on food consumption and complete follow-up for cancer occurrence was available for 139,005 men, recruited in 8 European countries. Estimates of HRs were obtained by proportional hazard models, stratified by age at recruitment, and study center, and adjusted for total energy intake, smoking status, marital status, dairy products, educational level, and body mass index.RESULTS: After a mean follow-up of 10 years, 4,606 participants were diagnosed with first incident prostate cancer. There was no overall association between prostate cancer risk and nitrosamines exposure (preformed and endogenous) or heme iron intake (HR for a doubling of intake: 1.00; 95% CI: 0.98-1.03 for N-Nitrosodimethlyamine, 0.95; 95% CI: 0.88-1.03 for endogenous Nitrosocompounds, and 1.00; 95 CI: 0.97-1.03 for heme iron).Conclusions and Impact: Our findings do not support an effect of nitrosamines (endogenous and exogenous) and heme iron intake on prostate cancer risk.

  • 28. Jakszyn, Paula
    et al.
    Lujan-Barroso, Leila
    Agudo, Antonio
    Bueno-de-Mesquita, H Bas
    Molina, Esther
    Sanchez, Ma Jose
    Fonseca-Nunes, Ana
    Siersema, Peter D
    Matiello, Amalia
    Tumino, Rosario
    Saieva, Calogero
    Pala, Valeria
    Vineis, Paolo
    Boutron-Ruault, Marie-Christine
    Racine, Antoine
    Bastide, Nadie
    Travis, Ruth C
    Khaw, Kay-Tee
    Riboli, Elio
    Murphy, Neil
    Vergnaud, Anne-Claire
    Trichopoulou, Antonia
    Valanou, Elissavet
    Oikonomidou, EDespina
    Weiderpass, Elisabete
    Skeie, Guri
    Johansen, Dorthe
    Lindkvist, Bjorn
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. International Agency for Research on Cancer (IARC/WHO), Lyon, France.
    Duarte-Salles, Talita
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Freisling, Heinz
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Barricarte, Aurelio
    Huerta, Jose Ma
    Amiano, Pilar
    Tjonneland, Anne
    Overvad, Kim
    Kuehn, Tilman
    Grote, Verena
    Boeing, Heiner
    Peeters, Petra HM
    Gonzalez, Carlos A
    Meat and heme iron intake and esophageal adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition study2013In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 133, no 11, p. 2744-2750Article in journal (Refereed)
    Abstract [en]

    Although recent studies suggest that high intakes of meat and heme iron are risk factors for several types of cancer, studies in relation to esophageal adenocarcinoma (EAC) are scarce. Previous results in the European Prospective Investigation into Cancer and Nutrition (EPIC) based on a relatively small number of cases suggested a positive association between processed meat and EAC. In this study, we investigate the association between intake of different types of meats and heme iron intake and EAC risk in a larger number of cases from EPIC. The study included 481,419 individuals and 137 incident cases of EAC that occurred during an average of 11 years of follow-up. Dietary intake of meat (unprocessed/processed red and white meat) was assessed by validated center-specific questionnaires. Heme iron was calculated as a type-specific percentage of the total iron content in meat. After adjusting for relevant confounders, we observed a statistically significant positive association of EAC risk with heme iron and processed meat intake, with HR: 1.67, 95% CI: 1.05-2.68 and HR: 2.27, 95% CI:1.33-3.89, respectively, for comparison of the highest vs. lowest tertile of intake. Our results suggest a potential association between higher intakes of processed meat and heme iron and risk of EAC.

  • 29.
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Prostate cancer aetiology: epidemiological studies of the IGF- and one-carbon metabolism pathways2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The aim of this thesis was to investigate the involvement of the insulin-like growth factor- and the one-carbon metabolism pathways in prostate cancer aetiology, studying both circulating biomarkers and genetic variation. Papers included in the thesis were conducted within the case-control study CAncer Prostate in Sweden (CAPS), and the two prospective studies European Prospective Investigation into nutrition and Cancer (EPIC), and Northern Sweden Health and Disease Cohort (NSHDC).

    In paper I, we investigated the relation between genetic variants of the IGF1 gene and prostate cancer risk within the CAPS study. We found that a common haplotype within the 3’ region of the IGF1 gene is associated with increased prostate cancer risk.

    In paper II, we investigated if the variants of the IGF1 gene that were associated with prostate cancer risk in paper I, are also associated with circulating levels of IGF1. Circulating levels of IGF1 were analysed in controls from the CAPS study and three haplotype tagging SNPs (htSNPs) were genotyped in subjects from the NSHDC study in which circulating IGF1 had previously been analysed. The genetic variants previously associated with increased prostate cancer risk were now also found to be associated with elevated levels of circulating IGF1. We concluded that variation in the 3’ region of the IGF1 gene affects prostate cancer risk by influencing circulating levels of IGF1.

    In paper III, we investigated if variants of the IGFBP1, IGFBP3 and IGFALS genes are associated with i) prostate cancer risk, ii) circulating concentrations of total and intact IGFBP3, and iii) prostate cancer-specific survival probability. In addition, we investigated if circulating concentrations of total and intact IGFBP3 are associated with prostate cancer-specific survival probability. No association between genetic variation and overall prostate cancer risk or survival was observed, but we found a strong association between elevated levels of intact IGFBP3 and increased risk of prostate cancer-specific death. We could, however, not exclude that this association was confounded by treatment or by the tumour.

    In paper IV, we investigated if circulating levels of folate and vitamin B12 are associated with prostate cancer risk within the EPIC study. We observed no associations between levels of folate, vitamin B12 and overall prostate cancer risk, but elevated levels of vitamin B12 were associated with increased risk of advanced stage disease.

    In paper V, we investigated if circulating levels of ten B-vitamins and related metabolites within the one-carbon metabolism pathway are associated with prostate cancer risk within the NSHDC study. Overall positive associations with prostate cancer risk were observed for levels of choline, vitamin B2 and vitamin B12, and inverse associations were observed for levels of homocysteine and MMA. We also observed a biologically plausible risk modification by smoking status on the association between vitamin B12 and risk; in non-smokers vitamin B12 was positively associated with risk, whereas the association between vitamin B12 and risk was inverse or null in ever/current-smokers.

    In summary, our results suggest that genetic variation of the IGF1 gene affects prostate cancer risk by affecting circulating levels of IGF1. The association between circulating concentrations of intact IGFBP3 and prostate cancer-specific survival is intriguing, but further studies are needed to conclude if this association is caused by confounding. We also observed associations between several factors of one-carbon metabolism and risk, but these associations were statistically week and require confirmation in other prospective studies.

  • 30.
    Johansson, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Appleby, Paul N
    Allen, Naomi E
    Travis, Ruth C
    Roddam, Andrew W
    Egevad, Lars
    Jenab, Mazda
    Rinaldi, Sabina
    Kiemeney, Lambertus A
    Bueno-de-Mesquita, H Bas
    Vollset, Stein Emil
    Ueland, Per M
    Sánchez, Maria-José
    Quirós, J Ramón
    González, Carlos A
    Larrañaga, Nerea
    Chirlaque, María Dolores
    Ardanaz, Eva
    Sieri, Sabina
    Palli, Domenico
    Vineis, Paolo
    Tumino, Rosario
    Linseisen, Jakob
    Kaaks, Rudolf
    Boeing, Heiner
    Pischon, Tobias
    Psaltopoulou, Theodora
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Khaw, Kay-Tee
    Bingham, Sheila
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Riboli, Elio
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Urologi och andrologi.
    Key, Timothy J
    Circulating concentrations of folate and vitamin B12 in relation to prostate cancer risk: results from the European prospective investigation into cancer and nutrition study2008In: Cancer Epidemiol Biomarkers Prev, ISSN 1055-9965, Vol. 17, no 2, p. 279-285Article in journal (Refereed)
    Abstract [en]

    Background: Determinants of one-carbon metabolism, such as folate and vitamin B12, have been implicated in cancer development. Previous studies have not provided conclusive evidence for the importance of circulating concentrations of folate and vitamin B12 in prostate cancer etiology. The aim of the present study was to investigate the relationship between prostate cancer risk and circulating concentrations of folate and vitamin B12 in a large prospective cohort. Methods: We analyzed circulating concentrations of folate and vitamin B12 in 869 cases and 1,174 controls, individually matched on center, age, and date of recruitment, nested within the European Prospective Investigation into Cancer and Nutrition cohort. Relative risks (RR) for prostate cancer were estimated using conditional logistic regression models. Results: Overall, no significant associations were observed for circulating concentrations of folate (Ptrend = 0.62) or vitamin B12 (Ptrend = 0.21) with prostate cancer risk. RRs for a doubling in folate and vitamin B12 concentrations were 1.03 [95% confidence interval (95% CI), 0.92-1.16] and 1.12 (95% CI, 0.94-1.35), respectively. In the subgroup of cases diagnosed with advanced stage prostate cancer, elevated concentrations of vitamin B12 were associated with increased risk (RR for a doubling in concentration, 1.69; 95% CI, 1.05-2.72, Ptrend = 0.03). No other subgroup analyses resulted in a statistically significant association. Conclusion: This study does not provide strong support for an association between prostate cancer risk and circulating concentrations of folate or vitamin B12. Elevated concentrations of vitamin B12 may be associated with an increased risk for advanced stage prostate cancer, but this association requires examination in other large prospective studies. (Cancer Epidemiol Biomarkers Prev 2007;17(2):279–85)

  • 31.
    Johansson, Mattias
    et al.
    International Agency for Research on Cancer, Lyon, France.
    Fanidi, Anouar
    Muller, David C.
    Bassett, Julie K.
    Midttun, Oivind
    Vollset, Stein Emil
    Travis, Ruth C.
    Palli, Domenico
    Mattiello, Amalia
    Sieri, Sabina
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Weiderpass, Elisabete
    Skeie, Guri
    Gonzalez, Carlos A.
    Dorronsoro, Miren
    Peeters, Petra H.
    Bueno-de-Mesquita, H. B(as).
    Ros, Martine M.
    Ruault, Marie-Christine Boutron
    Fagherazzi, Guy
    Clavel, Francoise
    Sanchez, Maria-Jose
    Barricarte Gurrea, Aurelio
    Navarro, Carmen
    Ramon Quiros, J.
    Overvad, Kim
    Tjonneland, Anne
    Aleksandrova, Krassimira
    Vineis, Paolo
    Gunter, Marc J.
    Kaaks, Rudolf
    Giles, Graham
    Relton, Caroline
    Riboli, Elio
    Boeing, Heiner
    Ueland, Per Magne
    Severi, Gianluca
    Brennan, Paul
    Circulating Biomarkers of One-Carbon Metabolism in Relation to Renal Cell Carcinoma Incidence and Survival2014In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 106, no 12, article id dju327Article in journal (Refereed)
    Abstract [en]

    Background: The etiology of renal cell carcinoma (RCC) is only partially understood, but a metabolic component appears likely. We investigated biomarkers of one-carbon metabolism and RCC onset and survival. Methods: The European Prospective Investigation into Cancer and Nutrition (EPIC) recruited 385 747 participants with blood samples between 1992 and 2000, and this analysis included 556 RCC case-control pairs. A subsequent replication study included 144 case-control pairs nested within the Melbourne Collaborative Cohort Study (MCCS). Plasma concentrations of vitamin B2, vitamin B6, folate, vitamin B12, methionine and homocysteine were measured in prediagnostic samples and evaluated with respect to RCC risk using conditional and unconditional logistic regression models, and to all-cause mortality in RCC cases using Cox regression models. All statistical tests were two-sided. Results: EPIC participants with higher plasma concentrations of vitamin B6 had lower risk of RCC, the odds ratio comparing the 4th and 1st quartiles (OR4vs1) being 0.40 95% confidence interval [CI] = 0.28 to 0.57, P-trend < .001. We found similar results after adjusting for potential confounders (adjusted P-trend < .001). In survival analysis, the hazard ratio for all-cause mortality in RCC cases when comparing the 4th and 1st quartiles (HR4vs1) of vitamin B6 was 0.57 (95% CI = 0.37 to 0.87, P-trend < .001). Subsequent replication of these associations within the MCCS yielded very similar results for both RCC risk (OR4vs1 = 0.47, 95% CI = 0.23 to 0.99, P-trend = .07) and all-cause mortality (HR4vs1 = 0.56, 95% CI = 0.27 to 1.17, P-trend = .02). No association was evident for the other measured biomarkers. Conclusion: Study participants with higher circulating concentrations of vitamin B6 had lower risk of RCC and improved survival following diagnosis in two independent cohorts.

  • 32.
    Johansson, Mattias
    et al.
    International Agency for Research on Cancer (IARC-WHO), Lyon, France.
    Holmström, Benny
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Hinchliffe, Sally R
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stenman, Ulf-Håkan
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Wiklund, Fredrik
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Combining 33 genetic variants with prostate-specific antigen for prediction of prostate cancer: longitudinal study2012In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 130, no 1, p. 129-137Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate if a genetic risk score including 33 common genetic variants improves prediction of prostate cancer when added to measures of prostate-specific antigen (PSA). We conducted a case-control study nested within the Northern Sweden Health and Disease Cohort (NSHDC), a prospective cohort in northern Sweden. A total of 520 cases and 988 controls matched for age, and date of blood draw were identified by linkage between the regional cancer register and the NSHDC. Receiver operating characteristic curves with area under curve (AUC) estimates were used as measures of prostate cancer prediction. The AUC for the genetic risk score was 64.3% [95% confidence interval (CI) = 61.4-67.2], and the AUC for total PSA and the ratio of free to total PSA was 86.2% (95% CI = 84.4-88.1). A model including the genetic risk score, total PSA and the ratio of free to total PSA increased the AUC to 87.2% (95% CI = 85.4-89.0, p difference = 0.002). The addition of a genetic risk score to PSA resulted in a marginal improvement in prostate cancer prediction that would not seem useful for clinical risk assessment.

  • 33.
    Johansson, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    McKay, James D.
    Rinaldi, Sabina
    Wiklund, Fredrik
    Adami, Hans-Olov
    Grönberg, Henrik
    Kaaks, Rudolf
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Genetic and plasma variation of insuline-like growth factor binding proteins in relation to prostate cancer incidence and survivalManuscript (Other (popular science, discussion, etc.))
  • 34.
    Johansson, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. International Agency for Research against Cancer, Lyon, France.
    McKay, James D
    Rinaldi, Sabina
    Wiklund, Fredrik
    Adami, Hans-Olov
    Grönberg, Henrik
    Kaaks, Rudolf
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Genetic and plasma variation of insulin-like growth factor binding proteins in relation to prostate cancer incidence and survival2009In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 69, no 12, p. 1281-1291Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Binding proteins regulate bioavailability of insulin-like growth factor-I (IGF-I) in the circulation and affect apoptosis of tumor cells in the prostate. We analyzed genetic variation within genes coding for IGF binding proteins in relation to prostate cancer incidence and survival. We also investigated if circulating IGFBP3 affects prostate cancer-specific survival. MATERIALS AND METHODS: Eleven haplotype tagging SNPs and two single SNPs in the IGFBP1, IGFBP3, and IGFALS genes were genotyped within the CAncer Prostate in Sweden (CAPS) study including 2,774 cases and 1,736 controls. Plasma samples for analyses of total- and intact IGFBP3 levels were available for 1,521 cases and 909 controls. Complete follow-up of vital status was achieved by linkage to the Swedish Cause of Death Register. RESULTS: We found no clear association between the genetic variants and prostate cancer incidence or survival. The rare allele of the IGFBP3 SNP rs2854744 was associated with elevated plasma levels of total IGFBP3 (P(trend) = 9 x 10(-8)), but not intact IGFBP3 (P(trend) = 0.16). Elevated levels of total- (P(trend) = 0.03) and intact IGFBP3 (P(trend) = 6 x 10(-14)) were associated with increased risk of prostate cancer specific death. Treatment and tumor characteristics accounted for the association with total IGFBP3, whereas the association with intact IGFBP3 was attenuated, but still statistically significant in adjusted analysis (P(trend-adjusted) = 0.0004). Elevated intact IGFBP3 was also significantly associated with increased risk of prostate cancer-specific death among patients who were chemically or surgically castrated (P(trend-adjusted) = 0.0003), and among patients who had not been treated (P(trend-adjusted) = 0.02). CONCLUSIONS: Circulating levels of intact IGFBP3 measured after diagnosis is associated with increased risk of prostate cancer-specific death.

  • 35.
    Johansson, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    McKay, James D
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Canzian, Federico
    Boillot, Catherine
    Wiklund, Fredrik
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Adami, Hans-Olov
    Bälter, Katarina
    Grönberg, Henrik
    Kaaks, Rudolf
    Comprehensive evaluation of genetic variation in the IGF1 gene and risk of prostate cancer2007In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 120, no 3, p. 539-542Article in journal (Refereed)
    Abstract [en]

    Insulin-like growth factor-I (IGF1) stimulates cell proliferation, decreases apoptosis, and has been implicated in cancer development. Epidemiological studies have shown elevated levels of circulating IGF1 to be associated with increased risk of prostate cancer. To what extent genetic variation in the IGF1 gene is related to prostate cancer risk is largely unknown. We performed a comprehensive haplotype tagging (HT) assessment of single nucleotide polymorphisms (SNPs) representing the common haplotype variation in the IGF1 gene. We genotyped 10 SNPs (9 haplotype tagging SNPs (htSNPs)) within Cancer Prostate in Sweden (CAPS), a case–control study of 2,863 cases and 1,737 controls, in order to investigate if genetic variation in the IGF1 gene is associated with prostate cancer risk. Three haplotype blocks were identified across the IGF1 gene and 9 SNPs were selected as haplotype tagging SNPs. Common haplotypes in the block covering the 3′ region of the IGF1 gene showed significant global association with prostate cancer risk (p = 0.004), with one particular haplotype giving an odds ratio of 1.46 (95% CI = 1.15–1.84, p = 0.002). This haplotype had a prevalence of 5% in the study population. Our results indicate that common variation in the IGF1 gene, particularly in the 3′ region, may affect prostate cancer risk. Further studies on genetic variations in the IGF1 gene in relation to prostate cancer risk as well as to circulating levels of IGF1 are needed to confirm this novel finding.

  • 36.
    Johansson, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. International Agency for Research on Cancer (IARC), Lyon, France.
    McKay, James D
    Wiklund, Fredrik
    Rinaldi, Sabina
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Bälter, Katarina
    Adami, Hans-Olov
    Grönberg, Henrik
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Kaaks, Rudolf
    Genetic variation in the SST gene and its receptors in relation to circulating levels of insulin-like growth factor-I, IGFBP3, and prostate cancer risk2009In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 18, no 5, p. 1644-1650Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Somatostatin (SST) and its receptors (SSTR1-5) may have a role in prostate cancer by influencing the IGFI hormone axis or through direct effects on prostate epithelia. We have investigated if genetic variation in the SST and SSTR1-5 genes influences prostate cancer risk and/or circulating IGFI and IGFBP3 hormone levels. MATERIALS AND METHODS: We analyzed 28 haplotype tagging single nucleotide polymorphisms in the SST and SSTR1-5 genes in a case-control/genetic association study to investigate the association between genetic variation and prostate cancer risk. The study included 2863 cases and 1737 controls from the Cancer Prostate in Sweden (CAPS) study. To investigate the genetic influence on circulating hormone levels, plasma concentrations of IGFI and IGFBP3 were analyzed in 874 controls of the CAPS study and 550 male subjects from the Northern Sweden Health and Disease Cohort (NSHDC). RESULTS: No clear association between prostate cancer risk and genetic variation of the SST and SSTR1-5 genes was identified. The SSTR5 missense single nucleotide polymorphism rs4988483 was associated with circulating IGFI (P = 0.002) and IGFBP3 (P = 0.0003) hormone levels in CAPS controls, with a per allele decrease of approximately 11%. This decrease was replicated in NSHDC for circulating IGFBP3 (P = 0.01) but not for IGFI (P = 0.09). Combining CAPS and NSHDC subjects indicated evidence of association between rs4988483 and both IGFBP3 (P = 2 x 10(-5)) and IGFI (P = 0.0004) hormone levels. CONCLUSIONS: Our results suggest that genetic variation in the SSTR5 gene and, particularly, the rs4988483 single nucleotide polymorphism influence circulating IGFI and IGFBP3 hormone levels with no measurable effect on prostate cancer risk. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1644-50).

  • 37.
    Johansson, Mattias
    et al.
    International Agency for Research on Cancer, Lyon, France.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Surgery, Urology Service, Memorial Sloan-Kettering Cancer Center, New York.
    Guidelines are too important to be left to clinical experts2012In: CMJA. Canadian Medical Association Journal. Onlineutg. Med tittel: ECMAJ. ISSN 1488-2329, ISSN 0820-3946, E-ISSN 1488-2329, Vol. 184, no 2, p. 159-160Article in journal (Refereed)
  • 38.
    Johansson, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Wiklund, Fredrik
    Adami, Hans-Olov
    Bälter, Katarina
    Grönberg, Henrik
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    The MTHFR 677C --> T polymorphism and risk of prostate cancer: results from the CAPS study2007In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 18, no 10, p. 1169-1174Article in journal (Refereed)
    Abstract [en]

    The methylenetetrahydrafolate reductase (MTHFR) enzyme may influence cancer development by affecting DNA methylation, synthesis and repair. The MTHFR 677C→T single nucleotide polymorphism (SNP) has been associated with decreased enzyme activity and has therefore been implicated in cancer development. We analyzed the MTHFR 677C→T SNP in 2,777 incident prostate cancer cases and 1,639 population controls from the CAncer Prostate in Sweden study (CAPS). No significant association was found overall between prostate cancer risk and the 677C→T SNP (p = 0.27) with heterozygote (CT) and homozygote (TT) allele carriers showing ORs of 1.12 (95% CI: 0.98–1.27) and 1.02 (95% CI: 0.80–1.30), respectively. In the subgroup of low risk prostate cancer, heterozygote—but not homozygote—allele carriers displayed a slight over-risk with an OR of 1.21 (95% CI: 1.03–1.41). Among men under 65 years of age, the 677C→T SNP was associated with prostate cancer risk (p = 0.007), with odds ratios of 1.33 (95% CI: 1.09–1.63) for heterozygote allele carriers and 0.86 (95% CI: 0.6–1.24) for homozygote allele carriers. However, this association was attributed to a shift in the genotype distribution in the young controls. In conclusion, our results do not provide strong support for the hypothesis that the MTHFR 677C→T polymorphism is related to prostate cancer risk.

  • 39.
    Johansson, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Vollset, Stein Emil
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Key, Tim
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Ueland, Per M
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Prospective investigation of one-carbon metabolism in relation to prostate cancer risk: results from the NSHDC studyManuscript (Other academic)
  • 40.
    Johansson, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. International Agency for Research on Cancer (IARC-WHO), Lyon, France.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Vollset, Stein Emil
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Key, Tim
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Midttun, Øivind
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Ueland, Per M
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    One-carbon metabolism and prostate cancer risk: prospective investigation of seven circulating B vitamins and metabolites2009In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 18, no 5, p. 1538-1543Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Components of one-carbon metabolism are believed to influence cancer development with suggested mechanisms, including DNA methylation and DNA repair mechanisms. However, few prospective studies have investigated one-carbon metabolism in relation to prostate cancer risk, and the results have been conflicting. The aim of this study was to do a comprehensive investigation of the components of one-carbon metabolism in relation to prostate cancer risk. A panel of seven circulating B vitamins and related metabolites was selected, most of which have not been studied before. MATERIALS AND METHODS: We analyzed plasma concentrations of betaine, choline, cysteine, methionine, methylmalonic acid (MMA), vitamin B2, and vitamin B6 in 561 cases and 1,034 controls matched for age and recruitment date, nested within the population-based Northern Sweden Health and Disease Cohort. Relative risks of prostate cancer were estimated by conditional logistic regression. RESULTS: Positive associations with prostate cancer risk were observed for choline and vitamin B2, and an inverse association was observed for MMA. The relative risks for a doubling in concentrations were 1.46 [95% confidence interval (95% CI), 1.04-2.05; P(trend) = 0.03] for choline, 1.11 (95% CI, 1.00-1.23; P(trend) = 0.04) for vitamin B2, and 0.78 (95% CI, 0.63-0.97; P(trend) = 0.03) for MMA. Concentrations of betaine, cysteine, methionine, and vitamin B6 were not associated with prostate cancer risk. CONCLUSION: The results of this large prospective study suggest that elevated plasma concentrations of choline and vitamin B2 may be associated with an increased risk of prostate cancer. These novel findings support a role of one-carbon metabolism in prostate cancer etiology and warrant further investigation. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1538-43).

  • 41. Kachuri, Linda
    et al.
    Amos, Christopher I.
    Mckay, James D.
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Vineis, Paolo
    Bueno-de-Mesquita, H. Bas
    Boutron-Ruault, Marie-Christine
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Quiros, J. Ramon
    Sieri, Sabina
    Travis, Ruth C.
    Weiderpass, Elisabete
    Le Marchand, Loic
    Henderson, Brian E.
    Wilkens, Lynne
    Goodman, Gary E.
    Chen, Chu
    Doherty, Jennifer A.
    Christiani, David C.
    Wei, Yongyue
    Su, Li
    Tworoger, Shelley
    Zhang, Xuehong
    Kraft, Peter
    Zaridze, David
    Field, John K.
    Marcus, Michael W.
    Davies, Michael P. A.
    Hyde, Russell
    Caporaso, Neil E.
    Landi, Maria Teresa
    Severi, Gianluca
    Giles, Graham G.
    Liu, Geoffrey
    McLaughlin, John R.
    Li, Yafang
    Xiao, Xiangjun
    Fehringer, Gord
    Zong, Xuchen
    Denroche, Robert E.
    Zuzarte, Philip C.
    McPherson, John D.
    Brennan, Paul
    Hung, Rayjean J.
    Fine mapping of chromosome 5p15.33 based on a targeted deep sequencing and high density genotyping identifies novel lung cancer susceptibility loci2016In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 37, no 1, p. 96-105Article in journal (Refereed)
    Abstract [en]

    Chromosome 5p15.33 has been identified as a lung cancer susceptibility locus, however the underlying causal mechanisms were not fully elucidated. Previous fine-mapping studies of this locus have relied on imputation or investigated a small number of known, common variants. This study represents a significant advance over previous research by investigating a large number of novel, rare variants, as well as their underlying mechanisms through telomere length. Variants for this fine-mapping study were identified through a targeted deep sequencing (average depth of coverage greater than 4000x) of 576 individuals. Subsequently, 4652 SNPs, including 1108 novel SNPs, were genotyped in 5164 cases and 5716 controls of European ancestry. After adjusting for known risk loci, rs2736100 and rs401681, we identified a new, independent lung cancer susceptibility variant in LPCAT1: rs139852726 (OR = 0.46, P = 4.73x10(-9)), and three new adenocarcinoma risk variants in TERT: rs61748181 (OR = 0.53, P = 2.64x10(-6)), rs112290073 (OR = 1.85, P = 1.27x10(-5)), rs138895564 (OR = 2.16, P = 2.06x10(-5); among young cases, OR = 3.77, P = 8.41x10(-4)). In addition, we found that rs139852726 (P = 1.44x10(-3)) was associated with telomere length in a sample of 922 healthy individuals. The gene-based SKAT-O analysis implicated TERT as the most relevant gene in the 5p15.33 region for adenocarcinoma (P = 7.84x10(-7)) and lung cancer (P = 2.37x10(-5)) risk. In this largest fine-mapping study to investigate a large number of rare and novel variants within 5p15.33, we identified novel lung and adenocarcinoma susceptibility loci with large effects and provided support for the role of telomere length as the potential underlying mechanism.

  • 42. Key, Timothy J.
    et al.
    Appleby, Paul N.
    Travis, Ruth C.
    Albanes, Demetrius
    Alberg, Anthony J.
    Barricarte, Aurelio
    Black, Amanda
    Boeing, Heiner
    Bueno-de-Mesquita, H. Bas
    Chan, June M.
    Chen, Chu
    Cook, Michael B.
    Donovan, Jenny L.
    Galan, Pilar
    Gilbert, Rebecca
    Giles, Graham G.
    Giovannucci, Edward
    Goodman, Gary E.
    Goodman, Phyllis J.
    Gunter, Marc J.
    Hamdy, Freddie C.
    Heliovaara, Markku
    Helzlsouer, Kathy J.
    Henderson, Brian E.
    Hercberg, Serge
    Hoffman-Bolton, Judy
    Hoover, Robert N.
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. International Agency for Research on Cancer, Lyon, France.
    Khaw, Kay-Tee
    King, Irena B.
    Knekt, Paul
    Kolonel, Laurence N.
    Le Marchand, Loic
    Mannisto, Satu
    Martin, Richard M.
    Meyer, Haakon E.
    Mondul, Alison M.
    Moy, Kristin A.
    Neal, David E.
    Neuhouser, Marian L.
    Palli, Domenico
    Platz, Elizabeth A.
    Pouchieu, Camille
    Rissanen, Harri
    Schenk, Jeannette M.
    Severi, Gianluca
    Stampfer, Meir J.
    Tjonneland, Anne
    Touvier, Mathilde
    Trichopoulou, Antonia
    Weinstein, Stephanie J.
    Ziegler, Regina G.
    Zhou, Cindy Ke
    Allen, Naomi E.
    Carotenoids, retinol, tocopherols, and prostate cancer risk: pooled analysis of 15 studies2015In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 102, no 5, p. 1142-1157Article in journal (Refereed)
    Abstract [en]

    Background: Individual studies have suggested that circulating carotenoids, retinol, or tocopherols may be associated with prostate cancer risk, but the studies have not been large enough to provide precise estimates of associations, particularly by stage and grade of disease. Objective: The objective of this study was to conduct a pooled analysis of the associations of the concentrations of 7 carotenoids, retinol, alpha-tocopherol, and gamma-tocopherol with risk of prostate cancer and to describe whether any associations differ by stage or grade of the disease or other factors. Design: Principal investigators of prospective studies provided individual participant data for prostate cancer cases and controls. Risk by study-specific fifths of each biomarker was estimated by using multivariable-adjusted conditional logistic regression in matched case-control sets. Results: Data were available for up to 11,239 cases (including 1654 advanced stage and 1741 aggressive) and 18,541 controls from 15 studies. Lycopene was not associated with overall risk of prostate cancer, but there was statistically significant heterogeneity by stage of disease, and the OR for aggressive disease for the highest compared with the lowest fifth of lycopene was 0.65 (95% CI: 0.46, 0.91; P-trend = 0.032). No other carotenoid was significantly associated with overall risk of prostate cancer or with risk of advanced-stage or aggressive disease. For retinol, the OR for the highest compared with the lowest fifth was 1.13 (95% CI: 1.04, 1.22; P-trend = 0.015). For alpha-tocopherol, the OR for the highest compared with the lowest fifth was 0.86 (95% CI: 0.78, 0.94; P-trend < 0.001), with significant heterogeneity by stage of disease; the OR for aggressive prostate cancer was 0.74 (95% CI: 0.59, 0.92; P-trend = 0.001). gamma-Tocopherol was not associated with risk. Conclusions: Overall prostate cancer risk was positively associated with retinol and inversely associated with alpha-tocopherol, and risk of aggressive prostate cancer was inversely associated with lycopene and alpha-tocopherol. Whether these associations reflect causal relations is unclear.

  • 43. Kreimer, Aimee R.
    et al.
    Brennan, Paul
    Kuhs, Krystle A. Lang
    Waterboer, Tim
    Clifford, Gary
    Franceschi, Silvia
    Michel, Angelika
    Willhauck-Fleckenstein, Martina
    Riboli, Elio
    Castellsague, Xavier
    Hildesheim, Allan
    Fortner, Renee Turzanski
    Kaaks, Rudolf
    Palli, Domenico
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Panico, Salvatore
    Clavel-Chapelon, Francoise
    Boutron-Ruault, Marie-Christine
    Mesrine, Sylvie
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Peeters, Petra H.
    Cross, Amanda J.
    Bueno-de-Mesquita, H. Bas
    Vineis, Paolo
    Larranaga, Nerea
    Pala, Valeria
    Sanchez, Maria-Jose
    Navarro, Carmen
    Barricarte, Aurelio
    Tumino, Rosario
    Khaw, Kay-Tee
    Wareham, Nicholas
    Boeing, Heiner
    Steffen, Annika
    Travis, Ruth C.
    Ramon Quiros, J.
    Weiderpass, Elisabete
    Pawlita, Michael
    Johansson, Mattias
    International Agency for Research on Cancer, Lyon, France.
    Human Papillomavirus Antibodies and Future Risk of Anogenital Cancer: A Nested Case-Control Study in the European Prospective Investigation Into Cancer and Nutrition Study2015In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 33, no 8, p. 877-884Article in journal (Refereed)
    Abstract [en]

    Purpose Human papillomavirus (HPV) type 16 (HPV16) causes cancer at several anatomic sites. In the European Prospective Investigation Into Cancer and Nutrition study, HPV16 E6 seropositivity was present more than 10 years before oropharyngeal cancer diagnosis and was nearly absent in controls. The current study sought to evaluate the extent to which HPV16 E6 antibodies are present before diagnosis of anogenital cancers within the same cohort. Methods Four hundred incident anogenital cancers (273 cervical, 24 anal, 67 vulvar, 12 vaginal, and 24 penile cancers) with prediagnostic blood samples (collected on average 3 and 8 years before diagnosis for cervix and noncervix cancers, respectively) and 718 matched controls were included. Plasma was analyzed for antibodies against HPV16 E6 and multiple other HPV proteins and genotypes and evaluated in relation to risk using unconditional logistic regression. Results HPV16 E6 seropositivity was present in 29.2% of individuals (seven of 24 individuals) who later developed anal cancer compared with 0.6% of controls (four of 718 controls) who remained cancer free (odds ratio [OR], 75.9; 95% CI, 17.9 to 321). HPV16 E6 seropositivity was less common for cancers of the cervix (3.3%), vagina (8.3%), vulva (1.5%), and penis (8.3%). No associations were seen for non-type 16 HPV E6 antibodies, apart from anti-HPV58 E6 and anal cancer (OR, 6.8; 95% CI, 1.4 to 33.1). HPV16 E6 seropositivity tended to increase in blood samples drawn closer in time to cancer diagnosis. Conclusion HPV16 E6 seropositivity is relatively common before diagnosis of anal cancer but rare for other HPV-related anogenital cancers.

  • 44. Kreimer, Aimée R
    et al.
    Johansson, Mattias
    International Agency for Research on Cancer, Lyon, France.
    Waterboer, Tim
    Kaaks, Rudolf
    Chang-Claude, Jenny
    Drogen, Dagmar
    Tjønneland, Anne
    Overvad, Kim
    Quirós, J Ramón
    González, Carlos A
    Sánchez, Maria José
    Larrañaga, Nerea
    Navarro, Carmen
    Barricarte, Aurelio
    Travis, Ruth C
    Khaw, Kay-Tee
    Wareham, Nick
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Peeters, Petra H M
    Panico, Salvatore
    Masala, Giovanna
    Grioni, Sara
    Tumino, Rosario
    Vineis, Paolo
    Bueno-de-Mesquita, H Bas
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Manjer, Jonas
    Ekström, Johanna
    Skeie, Guri
    Lund, Eiliv
    Weiderpass, Elisabete
    Ferrari, Pietro
    Byrnes, Graham
    Romieu, Isabelle
    Riboli, Elio
    Hildesheim, Allan
    Boeing, Heiner
    Pawlita, Michael
    Brennan, Paul
    Evaluation of human papillomavirus antibodies and risk of subsequent head and neck cancer2013In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 31, no 21, p. 2708-2715Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Human papillomavirus type 16 (HPV16) infection is causing an increasing number of oropharyngeal cancers in the United States and Europe. The aim of our study was to investigate whether HPV antibodies are associated with head and neck cancer risk when measured in prediagnostic sera.

    METHODS: We identified 638 participants with incident head and neck cancers (patients; 180 oral cancers, 135 oropharynx cancers, and 247 hypopharynx/larynx cancers) and 300 patients with esophageal cancers as well as 1,599 comparable controls from within the European Prospective Investigation Into Cancer and Nutrition cohort. Prediagnostic plasma samples from patients (collected, on average, 6 years before diagnosis) and control participants were analyzed for antibodies against multiple proteins of HPV16 as well as HPV6, HPV11, HPV18, HPV31, HPV33, HPV45, and HPV52. Odds ratios (ORs) of cancer and 95% CIs were calculated, adjusting for potential confounders. All-cause mortality was evaluated among patients using Cox proportional hazards regression.

    RESULTS: HPV16 E6 seropositivity was present in prediagnostic samples for 34.8% of patients with oropharyngeal cancer and 0.6% of controls (OR, 274; 95% CI, 110 to 681) but was not associated with other cancer sites. The increased risk of oropharyngeal cancer among HPV16 E6 seropositive participants was independent of time between blood collection and diagnosis and was observed more than 10 years before diagnosis. The all-cause mortality ratio among patients with oropharyngeal cancer was 0.30 (95% CI, 0.13 to 0.67), for patients who were HPV16 E6 seropositive compared with seronegative.

    CONCLUSION: HPV16 E6 seropositivity was present more than 10 years before diagnosis of oropharyngeal cancers.

  • 45. Lang Kuhs, Krystle A
    et al.
    Anantharaman, Devasena
    Waterboer, Tim
    Johansson, Mattias
    International Agency for Research on Cancer (IARC), Lyon, France.
    Brennan, Paul
    Michel, Angelika
    Willhauck-Fleckenstein, Martina
    Purdue, Mark P
    Holcátová, Ivana
    Ahrens, Wolfgang
    Lagiou, Pagona
    Polesel, Jerry
    Simonato, Lorenzo
    Merletti, Franco
    Healy, Claire M
    Kjaerheim, Kristina
    Conway, David I
    Macfarlane, Tatiana V
    Thomson, Peter
    Castellsagué, Xavier
    Znaor, Ariana
    Black, Amanda
    Huang, Wen-Yi
    Krogh, Vittorio
    Trichopoulou, Antonia
    Bueno-de-Mesquita, H B As
    Clavel-Chapelon, Françoise
    Weiderpass, Elisabete
    Ekström, Johanna
    Riboli, Elio
    Tjønneland, Anne
    Sánchez, María-José
    Travis, Ruth C
    Hildesheim, Allan
    Pawlita, Michael
    Kreimer, Aimée R
    Human Papillomavirus 16 E6 Antibodies in Individuals without Diagnosed Cancer: A Pooled Analysis2015In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 24, no 4, p. 683-689Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The increasing incidence of oropharyngeal cancer in many developed countries has been attributed to human papillomavirus type 16 (HPV16) infections. Recently, HPV16 E6 serology has been identified as a promising early marker for oropharyngeal cancer. Therefore, characterization of HPV16 E6 seropositivity among individuals without cancer is warranted.

    METHODS: A total of 4,666 controls were pooled from several studies of cancer and HPV seropositivity, all tested within the same laboratory. HPV16 E6 seropositive controls were classified as having (i) moderate [mean fluorescent intensity (MFI) ≥ 484 and <1,000] or (ii) high seroreactivity (MFI ≥ 1,000). Associations of moderate and high HPV16 E6 seroreactivity with (i) demographic risk factors; and seropositivity for (ii) other HPV16 proteins (E1, E2, E4, E7, and L1), and (iii) E6 proteins from non-HPV16 types (HPV6, 11, 18, 31, 33, 45, and 52) were evaluated.

    RESULTS: Thirty-two (0.7%) HPV16 E6 seropositive controls were identified; 17 (0.4%) with moderate and 15 (0.3%) with high seroreactivity. High HPV16 E6 seroreactivity was associated with former smoking [odds ratio (OR), 5.5; 95% confidence interval (CI), 1.2-51.8], and seropositivity against HPV16 L1 (OR, 4.8; 95% CI, 1.3-15.4); E2 (OR, 7.7; 95% CI, 1.4-29.1); multiple HPV16 proteins (OR, 25.3; 95% CI, 2.6-119.6 for three HPV16 proteins beside E6) and HPV33 E6 (OR, 17.7; 95% CI, 1.9-81.8). No associations were observed with moderate HPV16 E6 seroreactivity.

    CONCLUSIONS: High HPV16 E6 seroreactivity is rare among individuals without diagnosed cancer and was not explained by demographic factors.

    IMPACT: Some HPV16 E6 seropositive individuals without diagnosed HPV-driven cancer, especially those with seropositivity against other HPV16 proteins, may harbor a biologically relevant HPV16 infection.

  • 46. Lesseur, Corina
    et al.
    Diergaarde, Brenda
    Olshan, Andrew F
    Wünsch-Filho, Victor
    Ness, Andrew R
    Liu, Geoffrey
    Lacko, Martin
    Eluf-Neto, José
    Franceschi, Silvia
    Lagiou, Pagona
    Macfarlane, Gary J
    Richiardi, Lorenzo
    Boccia, Stefania
    Polesel, Jerry
    Kjaerheim, Kristina
    Zaridze, David
    Johansson, Mattias
    Menezes, Ana M
    Curado, Maria Paula
    Robinson, Max
    Ahrens, Wolfgang
    Canova, Cristina
    Znaor, Ariana
    Castellsagué, Xavier
    Conway, David I
    Holcátová, Ivana
    Mates, Dana
    Vilensky, Marta
    Healy, Claire M
    Szeszenia-Dąbrowska, Neonila
    Fabiánová, Eleonóra
    Lissowska, Jolanta
    Grandis, Jennifer R
    Weissler, Mark C
    Tajara, Eloiza H
    Nunes, Fabio D
    de Carvalho, Marcos B
    Thomas, Steve
    Hung, Rayjean J
    Peters, Wilbert H M
    Herrero, Rolando
    Cadoni, Gabriella
    Bueno-de-Mesquita, H Bas
    Steffen, Annika
    Agudo, Antonio
    Shangina, Oxana
    Xiao, Xiangjun
    Gaborieau, Valérie
    Chabrier, Amélie
    Anantharaman, Devasena
    Boffetta, Paolo
    Amos, Christopher I
    McKay, James D
    Brennan, Paul
    Genome-wide association analyses identify new susceptibility loci for oral cavity and pharyngeal cancer2016In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 48, no 12, p. 1544-1550Article in journal (Refereed)
    Abstract [en]

    We conducted a genome-wide association study of oral cavity and pharyngeal cancer in 6,034 cases and 6,585 controls from Europe, North America and South America. We detected eight significantly associated loci (P < 5 × 10(-8)), seven of which are new for these cancer sites. Oral and pharyngeal cancers combined were associated with loci at 6p21.32 (rs3828805, HLA-DQB1), 10q26.13 (rs201982221, LHPP) and 11p15.4 (rs1453414, OR52N2-TRIM5). Oral cancer was associated with two new regions, 2p23.3 (rs6547741, GPN1) and 9q34.12 (rs928674, LAMC3), and with known cancer-related loci-9p21.3 (rs8181047, CDKN2B-AS1) and 5p15.33 (rs10462706, CLPTM1L). Oropharyngeal cancer associations were limited to the human leukocyte antigen (HLA) region, and classical HLA allele imputation showed a protective association with the class II haplotype HLA-DRB1*1301-HLA-DQA1*0103-HLA-DQB1*0603 (odds ratio (OR) = 0.59, P = 2.7 × 10(-9)). Stratified analyses on a subgroup of oropharyngeal cases with information available on human papillomavirus (HPV) status indicated that this association was considerably stronger in HPV-positive (OR = 0.23, P = 1.6 × 10(-6)) than in HPV-negative (OR = 0.75, P = 0.16) cancers.

  • 47. Lindstroem, Sara
    et al.
    Schumacher, Fredrick R
    Cox, David
    Travis, Ruth C
    Albanes, Demetrius
    Allen, Naomi E.
    Andriole, Gerald
    Berndt, Sonja I
    Boeing, Heiner
    Bueno-de-Mesquita, H Bas
    Crawford, E David
    Diver, W Ryan
    Gaziano, J Michael
    Giles, Graham G
    Giovannucci, Edward
    Gonzalez, Carlos A
    Henderson, Brian
    Hunter, David J
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. International Agency for Research on Cancer, Lyon, France.
    Kolonel, Laurence N
    Ma, Jing
    Le Marchand, Loic
    Pala, Valeria
    Stampfer, Meir
    Stram, Daniel O
    Thun, Michael J
    Tjonneland, Anne
    Trichopoulos, Dimitrios
    Virtamo, Jarmo
    Weinstein, Stephanie J
    Willett, Walter C
    Yeager, Meredith
    Hayes, Richard B
    Severi, Gianluca
    Haiman, Christopher A
    Chanock, Stephen J
    Kraft, Peter
    Common genetic variants in prostate cancer risk prediction-results from the NCI breast and prostate cancer cohort consortium (BPC3)2012In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 21, no 3, p. 437-444Article in journal (Refereed)
    Abstract [en]

    Background: One of the goals of personalized medicine is to generate individual risk profiles that could identify individuals in the population that exhibit high risk. The discovery of more than two-dozen independent single-nucleotide polymorphism markers in prostate cancer has raised the possibility for such risk stratification. In this study, we evaluated the discriminative and predictive ability for prostate cancer risk models incorporating 25 common prostate cancer genetic markers, family history of prostate cancer, and age.

    Methods: We fit a series of risk models and estimated their performance in 7,509 prostate cancer cases and 7,652 controls within the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3). We also calculated absolute risks based on SEER incidence data.

    Results: The best risk model (C-statistic = 0.642) included individual genetic markers and family history of prostate cancer. We observed a decreasing trend in discriminative ability with advancing age (P = 0.009), with highest accuracy in men younger than 60 years (C-statistic = 0.679). The absolute ten-year risk for 50-year-old men with a family history ranged from 1.6% (10th percentile of genetic risk) to 6.7% (90th percentile of genetic risk). For men without family history, the risk ranged from 0.8% (10th percentile) to 3.4% (90th percentile).

    Conclusions: Our results indicate that incorporating genetic information and family history in prostate cancer risk models can be particularly useful for identifying younger men that might benefit from prostate-specific antigen screening.

    Impact: Although adding genetic risk markers improves model performance, the clinical utility of these genetic risk models is limited.

  • 48. Lindstrom, Sara
    et al.
    Schumacher, Fredrick
    Siddiq, Afshan
    Travis, Ruth C.
    Campa, Daniele
    Berndt, Sonja I.
    Diver, W. Ryan
    Severi, Gianluca
    Allen, Naomi
    Andriole, Gerald
    Bueno-de-Mesquita, Bas
    Chanock, Stephen J.
    Crawford, David
    Gaziano, J. Michael
    Giles, Graham G.
    Giovannucci, Edward
    Guo, Carolyn
    Haiman, Christopher A.
    Hayes, Richard B.
    Halkjaer, Jytte
    Hunter, David J.
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. International Agency for Research on Cancer, Lyon, France .
    Kaaks, Rudolf
    Kolonel, Laurence N.
    Navarro, Carmen
    Riboli, Elio
    Sacerdote, Carlotta
    Stampfer, Meir
    Stram, Daniel O.
    Thun, Michael J.
    Trichopoulos, Dimitrios
    Virtamo, Jarmo
    Weinstein, Stephanie J.
    Yeager, Meredith
    Henderson, Brian
    Ma, Jing
    Le Marchand, Loic
    Albanes, Demetrius
    Kraft, Peter
    Characterizing Associations and SNP-Environment Interactions for GWAS-Identified Prostate Cancer Risk Markers-Results from BPC32011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 2, article id e17142Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) have identified multiple single nucleotide polymorphisms (SNPs) associated with prostate cancer risk. However, whether these associations can be consistently replicated, vary with disease aggressiveness (tumor stage and grade) and/or interact with non-genetic potential risk factors or other SNPs is unknown. We therefore genotyped 39 SNPs from regions identified by several prostate cancer GWAS in 10,501 prostate cancer cases and 10,831 controls from the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). We replicated 36 out of 39 SNPs (P-values ranging from 0.01 to 10(-28)). Two SNPs located near KLK3 associated with PSA levels showed differential association with Gleason grade (rs2735839, P = 0.0001 and rs266849, P = 0.0004; case-only test), where the alleles associated with decreasing PSA levels were inversely associated with low-grade (as defined by Gleason grade,8) tumors but positively associated with high-grade tumors. No other SNP showed differential associations according to disease stage or grade. We observed no effect modification by SNP for association with age at diagnosis, family history of prostate cancer, diabetes, BMI, height, smoking or alcohol intake. Moreover, we found no evidence of pair-wise SNP-SNP interactions. While these SNPs represent new independent risk factors for prostate cancer, we saw little evidence for effect modification by other SNPs or by the environmental factors examined.

  • 49. McKay, James D
    et al.
    Kaaks, Rudolf
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Biessy, Carine
    Wiklund, Fredik
    Bälter, Katarina
    Adami, Hans-Olov
    Boillot, Catherine
    Gioia-Patricola, Lydie
    Canzian, Federico
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Grönberg, Henrik
    Haplotype-based analysis of common variation in the growth hormone receptor gene and prostate cancer risk2007In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 16, no 1, p. 169-173Article in journal (Refereed)
    Abstract [en]

    The growth hormone receptor (GHR) is potentially involved in prostate cancer through its role in stimulating insulin-like growth factor I production and its cellular effects on prostate epithelium. We have used a haplotype-based tagging approach within CAncer Prostate Sweden, a large retrospective case-control study of 2,863 cases and 1,737 controls to investigate if genetic variation in the GHR gene influences prostate cancer risk. One haplotype in the 3' region of the GHR gene was found associated with prostate cancer risk in elderly men (>65 years old at the time of diagnosis), with heterozygote haplotype carriers having an odds ratio of 1.65 (95% confidence interval, 1.21-2.16; P = 0.0009, Pcorrected = 0.03). GHR function has been implicated in the determination of body mass index. Interestingly, the same haplotype associated with risk in the 3' end of the GHR gene was also associated with a decrease in body mass index in controls (P = 0.003, Pcorrected = 0.05), possibly indicating some functionality with this haplotype. These results suggest that whereas genetic variation in the GHR gene does not seem to play a major role in prostate cancer etiology, one haplotype in the 3' region may be potentially relevant to cases with later onset of prostate cancer.

  • 50. Muller, David C.
    et al.
    Fanidi, Anouar
    Midttun, Oivind
    Steffen, Annika
    Dossus, Laure
    Boutron-Ruault, Marie-Christine
    Severi, Gianluca
    Kuehn, Tilman
    Katzke, Verena
    Alonso de la Torreon, Ramon
    Gonzalez, Carlos A.
    Sanchez, Maria-Jose
    Dorronsoro, Miren
    Santiuste, Carmen
    Barricarte, Aurelio
    Khaw, Kay-Tee
    Wareham, Nick
    Travis, Ruth C.
    Trichopoulou, Antonia
    Giotaki, Maria
    Trichopoulos, Dimitrios
    Palli, Domenico
    Krogh, Vittorio
    Tumino, Rosario
    Vineis, Paolo
    Panico, Salvatore
    Tjonneland, Anne
    Olsen, Anja
    Bueno-de-Mesquita, H. Bas
    Peeters, Petra H.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Wennberg, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Weiderpass, Elisabete
    Murphy, Neil
    Riboli, Elio
    Ueland, Per Magne
    Boeing, Heiner
    Brennan, Paul
    Johansson, Mattias
    International Agency for Research on Cancer (IARC-WHO), Lyon, France.
    Circulating 25-Hydroxyvitamin D-3 in Relation to Renal Cell Carcinoma Incidence and Survival in the EPIC Cohort2014In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 180, no 8, p. 810-820Article in journal (Refereed)
    Abstract [en]

    Normal renal function is essential for vitamin D metabolism, but it is unclear whether circulating vitamin D is associated with risk of renal cell carcinoma (RCC). We assessed whether 25-hydroxyvitamin D-3 (25(OH)D-3) was associated with risk of RCC and death after RCC diagnosis in the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC recruited 385,747 participants with blood samples between 1992 and 2000. The current study included 560 RCC cases, 557 individually matched controls, and 553 additional controls. Circulating 25(OH)D-3 was assessed by mass spectrometry. Conditional and unconditional logistic regression models were used to calculate odds ratios and 95% confidence intervals. Death after RCC diagnosis was assessed using Cox proportional hazards models and flexible parametric survival models. A doubling of 25(OH)D-3 was associated with 28% lower odds of RCC after adjustment for season of and age at blood collection, sex, and country of recruitment (odds ratio = 0.72, 95% confidence interval: 0.60, 0.86; P = 0.0004). This estimatewas attenuated somewhat after additional adjustment for smoking status at baseline, circulating cotinine, body mass index (weight (kg)/height (m)(2)), and alcohol intake (odds ratio = 0.82, 95% confidence interval: 0.68, 0.99; P = 0.038). There was also some indication that both low and high 25(OH)D-3 levels were associated with higher risk of death from any cause among RCC cases.

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