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@ARTICLE{Stepien:157334,
      author       = {M. Stepien and P. Keski-Rahkonen and A. Kiss and N. Robinot
                      and T. Duarte-Salles and N. Murphy and G. Perlemuter and V.
                      Viallon and A. Tjønneland and A. L. Rostgaard-Hansen and C.
                      C. Dahm and K. Overvad and M.-C. Boutron-Ruault and F. R.
                      Mancini and Y. Mahamat-Saleh and K. Aleksandrova and R.
                      Kaaks$^*$ and T. Kühn$^*$ and A. Trichopoulou and A.
                      Karakatsani and S. Panico and R. Tumino and D. Palli and G.
                      Tagliabue and A. Naccarati and R. C. H. Vermeulen and H. B.
                      Bueno-de-Mesquita and E. Weiderpass and G. Skeie and J.
                      Ramón Quirós and E. Ardanaz and O. Mokoroa and N. Sala and
                      M.-J. Sánchez and J. M. Huerta and A. Winkvist and S.
                      Harlid and B. Ohlsson and K. Sjöberg and J. A. Schmidt and
                      N. Wareham and K.-T. Khaw and P. Ferrari and J. A. Rothwell
                      and M. Gunter and E. Riboli and A. Scalbert and M. Jenab},
      title        = {{M}etabolic perturbations prior to hepatocellular carcinoma
                      diagnosis - {F}indings from a prospective observational
                      cohort study.},
      journal      = {International journal of cancer},
      volume       = {148},
      number       = {3},
      issn         = {1097-0215},
      address      = {Bognor Regis},
      publisher    = {Wiley-Liss},
      reportid     = {DKFZ-2020-01563},
      pages        = {609-625},
      year         = {2020},
      note         = {2021 Feb 1;148(3):609-625},
      abstract     = {Hepatocellular carcinoma (HCC) development entails changes
                      in liver metabolism. Current knowledge on metabolic
                      perturbations in HCC is derived mostly from case-control
                      designs, with sparse information from prospective cohorts.
                      Our objective was to apply comprehensive metabolite
                      profiling to detect metabolites whose serum concentrations
                      are associated with HCC development, using biological
                      samples from within the prospective EPIC cohort (>520 000
                      participants,), where we identified 129 HCC cases matched
                      1:1 to controls. We conducted high resolution untargeted
                      liquid chromatography-mass spectrometry based metabolomics
                      on serum samples collected at recruitment prior to cancer
                      diagnosis. Multivariable conditional logistic regression was
                      applied controlling for dietary habits, alcohol consumption,
                      smoking, body size, hepatitis infection and liver
                      dysfunction. Corrections for multiple comparisons were
                      applied. Of 9206 molecular features detected, 220
                      discriminated HCC cases from controls. Detailed feature
                      annotation revealed 92 metabolites associated with HCC risk;
                      14 of which were unambiguously identified using pure
                      reference standards. Positive HCC risk associations were
                      observed for N1-acetylspermidine, isatin,
                      p-hydroxyphenyllactic acid, tyrosine, sphingosine,
                      L,L-cyclo(leucylprolyl), glycochenodeoxycholic acid,
                      glycocholic acid, and 7-methylguanine. Inverse risk
                      associations were observed for retinol,
                      dehydroepiandrosterone sulfate, glycerophosphocholine,
                      γ-carboxyethyl hydroxychroman, and creatine. Discernible
                      differences for these metabolites were observed between
                      cases and controls up to 10 years prior to diagnosis. Our
                      observations highlight the diversity of metabolic
                      perturbations involved in HCC development and replicate
                      previous observations (metabolism of bile acids, amino
                      acids, phospholipids) made in Asian and Scandinavian
                      populations. These findings emphasize the role of metabolic
                      pathways associated with steroid metabolism and immunity and
                      specific dietary and environmental exposures in HCC
                      development. This article is protected by copyright. All
                      rights reserved.},
      cin          = {C020},
      ddc          = {610},
      cid          = {I:(DE-He78)C020-20160331},
      pnm          = {313 - Cancer risk factors and prevention (POF3-313)},
      pid          = {G:(DE-HGF)POF3-313},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:32734650},
      doi          = {10.1002/ijc.33236},
      url          = {https://inrepo02.dkfz.de/record/157334},
}