TY - JOUR
T1 - Metabolic perturbations prior to hepatocellular carcinoma diagnosis
T2 - Findings from a prospective observational cohort study
AU - Stepien, Magdalena
AU - Keski-Rahkonen, Pekka
AU - Kiss, Agneta
AU - Robinot, Nivonirina
AU - Duarte-Salles, Talita
AU - Murphy, Neil
AU - Perlemuter, Gabriel
AU - Viallon, Vivian
AU - Tjønneland, Anne
AU - Rostgaard-Hansen, Agnetha Linn
AU - Dahm, Christina C.
AU - Overvad, Kim
AU - Boutron-Ruault, Marie Christine
AU - Mancini, Francesca Romana
AU - Mahamat-Saleh, Yahya
AU - Aleksandrova, Krasimira
AU - Kaaks, Rudolf
AU - Kühn, Tilman
AU - Trichopoulou, Antonia
AU - Karakatsani, Anna
AU - Panico, Salvatore
AU - Tumino, Rosario
AU - Palli, Domenico
AU - Tagliabue, Giovanna
AU - Naccarati, Alessio
AU - Vermeulen, Roel C.H.
AU - Bueno-de-Mesquita, Hendrik Bastiaan
AU - Weiderpass, Elisabete
AU - Skeie, Guri
AU - Ramón Quirós, Jose
AU - Ardanaz, Eva
AU - Mokoroa, Olatz
AU - Sala, Núria
AU - Sánchez, Maria Jose
AU - Huerta, José María
AU - Winkvist, Anna
AU - Harlid, Sophia
AU - Ohlsson, Bodil
AU - Sjöberg, Klas
AU - Schmidt, Julie A.
AU - Wareham, Nick
AU - Khaw, Kay Tee
AU - Ferrari, Pietro
AU - Rothwell, Joseph A.
AU - Gunter, Marc
AU - Riboli, Elio
AU - Scalbert, Augustin
AU - Jenab, Mazda
PY - 2021/2/1
Y1 - 2021/2/1
N2 - 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.
AB - 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.
KW - hepatocellular carcinoma
KW - prospective observational cohort
KW - untargeted metabolomics
UR - http://www.scopus.com/inward/record.url?scp=85089996286&partnerID=8YFLogxK
U2 - 10.1002/ijc.33236
DO - 10.1002/ijc.33236
M3 - Article
C2 - 32734650
AN - SCOPUS:85089996286
SN - 0020-7136
VL - 148
SP - 609
EP - 625
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 3
ER -
