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Metabolic perturbations prior to hepatocellular carcinoma diagnosis : Findings from a prospective observational cohort study

Stepien, Magdalena ; Keski-Rahkonen, Pekka ; Kiss, Agneta ; Robinot, Nivonirina ; Duarte-Salles, Talita ; Murphy, Neil ; Perlemuter, Gabriel ; Viallon, Vivian ; Tjønneland, Anne and Rostgaard-Hansen, Agnetha Linn , et al. (2020) In International Journal of Cancer
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 European Prospective Investigation into Cancer and Nutrition (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... (More)

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 European Prospective Investigation into Cancer and Nutrition (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, of which 14 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 and 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.

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organization
publishing date
type
Contribution to journal
publication status
in press
subject
keywords
hepatocellular carcinoma, prospective observational cohort, untargeted metabolomics
in
International Journal of Cancer
publisher
John Wiley and Sons Inc.
external identifiers
  • pmid:32734650
  • scopus:85089996286
ISSN
0020-7136
DOI
10.1002/ijc.33236
language
English
LU publication?
yes
id
09c34782-6bfd-446b-b2b5-8bde853b96df
date added to LUP
2020-09-15 13:34:46
date last changed
2020-09-16 04:49:41
@article{09c34782-6bfd-446b-b2b5-8bde853b96df,
  abstract     = {<p>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 European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (&gt;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, of which 14 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 and 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.</p>},
  author       = {Stepien, Magdalena and Keski-Rahkonen, Pekka and Kiss, Agneta and Robinot, Nivonirina and Duarte-Salles, Talita and Murphy, Neil and Perlemuter, Gabriel and Viallon, Vivian and Tjønneland, Anne and Rostgaard-Hansen, Agnetha Linn and Dahm, Christina C. and Overvad, Kim and Boutron-Ruault, Marie Christine and Mancini, Francesca Romana and Mahamat-Saleh, Yahya and Aleksandrova, Krasimira and Kaaks, Rudolf and Kühn, Tilman and Trichopoulou, Antonia and Karakatsani, Anna and Panico, Salvatore and Tumino, Rosario and Palli, Domenico and Tagliabue, Giovanna and Naccarati, Alessio and Vermeulen, Roel C.H. and Bueno-de-Mesquita, Hendrik Bastiaan and Weiderpass, Elisabete and Skeie, Guri and Ramón Quirós, Jose and Ardanaz, Eva and Mokoroa, Olatz and Sala, Núria and Sánchez, Maria Jose and Huerta, José María and Winkvist, Anna and Harlid, Sophia and Ohlsson, Bodil and Sjöberg, Klas and Schmidt, Julie A. and Wareham, Nick and Khaw, Kay Tee and Ferrari, Pietro and Rothwell, Joseph A. and Gunter, Marc and Riboli, Elio and Scalbert, Augustin and Jenab, Mazda},
  issn         = {0020-7136},
  language     = {eng},
  month        = {01},
  publisher    = {John Wiley and Sons Inc.},
  series       = {International Journal of Cancer},
  title        = {Metabolic perturbations prior to hepatocellular carcinoma diagnosis : Findings from a prospective observational cohort study},
  url          = {http://dx.doi.org/10.1002/ijc.33236},
  doi          = {10.1002/ijc.33236},
  year         = {2020},
}