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

N1 - (Ekstern)

PY - 2021

Y1 - 2021

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 - Journal article

C2 - 32734650

AN - SCOPUS:85089996286

VL - 148

SP - 609

EP - 625

JO - Acta - Unio Internationalis Contra Cancrum

JF - Acta - Unio Internationalis Contra Cancrum

SN - 0898-6924

IS - 3

ER -