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000136013 0247_ $$2doi$$a10.1158/1055-9965.EPI-17-0649
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000136013 0247_ $$2ISSN$$a1538-7755
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000136013 041__ $$aeng
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000136013 1001_ $$aAssi, Nada$$b0
000136013 245__ $$aAre Metabolic Signatures Mediating the Relationship between Lifestyle Factors and Hepatocellular Carcinoma Risk? Results from a Nested Case-Control Study in EPIC.
000136013 260__ $$aPhiladelphia, Pa.$$bAACR$$c2018
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000136013 520__ $$aBackground: The 'meeting-in-the-middle' (MITM) is a principle to identify exposure biomarkers that are also predictors of disease. The MITM statistical framework was applied in a nested case-control study of hepatocellular carcinoma (HCC) within European Prospective Investigation into Cancer and Nutrition (EPIC), where healthy lifestyle index (HLI) variables were related to targeted serum metabolites.Methods: Lifestyle and targeted metabolomic data were available from 147 incident HCC cases and 147 matched controls. Partial least squares analysis related 7 lifestyle variables from a modified HLI to a set of 132 serum-measured metabolites and a liver function score. Mediation analysis evaluated whether metabolic profiles mediated the relationship between each lifestyle exposure and HCC risk.Results: Exposure-related metabolic signatures were identified. Particularly, the body mass index (BMI)-associated metabolic component was positively related to glutamic acid, tyrosine, PC aaC38:3, and liver function score and negatively to lysoPC aC17:0 and aC18:2. The lifetime alcohol-specific signature had negative loadings on sphingomyelins (SM C16:1, C18:1, SM(OH) C14:1, C16:1 and C22:2). Both exposures were associated with increased HCC with total effects (TE) = 1.23 (95% confidence interval = 0.93-1.62) and 1.40 (1.14-1.72), respectively, for BMI and alcohol consumption. Both metabolic signatures mediated the association between BMI and lifetime alcohol consumption and HCC with natural indirect effects, respectively, equal to 1.56 (1.24-1.96) and 1.09 (1.03-1.15), accounting for a proportion mediated of 100% and 24%.Conclusions: In a refined MITM framework, relevant metabolic signatures were identified as mediators in the relationship between lifestyle exposures and HCC risk.Impact: The understanding of the biological basis for the relationship between modifiable exposures and cancer would pave avenues for clinical and public health interventions on metabolic mediators. Cancer Epidemiol Biomarkers Prev; 27(5); 531-40. ©2018 AACR.
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000136013 7001_ $$aThomas, Duncan C$$b1
000136013 7001_ $$aLeitzmann, Michael$$b2
000136013 7001_ $$aStepien, Magdalena$$b3
000136013 7001_ $$aChajès, Véronique$$b4
000136013 7001_ $$aPhilip, Thierry$$b5
000136013 7001_ $$aVineis, Paolo$$b6
000136013 7001_ $$aBamia, Christina$$b7
000136013 7001_ $$aBoutron-Ruault, Marie-Christine$$b8
000136013 7001_ $$aSandanger, Torkjel M$$b9
000136013 7001_ $$aMolinuevo, Amaia$$b10
000136013 7001_ $$aBoshuizen, Hendriek C$$b11
000136013 7001_ $$aSundkvist, Anneli$$b12
000136013 7001_ $$0P:(DE-He78)0907a10ba1dc8f53f04907f54f6fdcfe$$aKühn, Tilman$$b13$$udkfz
000136013 7001_ $$aTravis, Ruth C$$b14
000136013 7001_ $$aOvervad, Kim$$b15
000136013 7001_ $$aRiboli, Elio$$b16
000136013 7001_ $$aGunter, Marc J$$b17
000136013 7001_ $$aScalbert, Augustin$$b18
000136013 7001_ $$aJenab, Mazda$$b19
000136013 7001_ $$aFerrari, Pietro$$b20
000136013 7001_ $$aViallon, Vivian$$b21
000136013 773__ $$0PERI:(DE-600)2036781-8$$a10.1158/1055-9965.EPI-17-0649$$gVol. 27, no. 5, p. 531 - 540$$n5$$p531 - 540$$tCancer epidemiology, biomarkers & prevention$$v27$$x1538-7755$$y2018
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