期刊
INTERNATIONAL JOURNAL OF CANCER
卷 148, 期 3, 页码 609-625出版社
WILEY
DOI: 10.1002/ijc.33236
关键词
hepatocellular carcinoma; prospective observational cohort; untargeted metabolomics
类别
资金
- French National Cancer Institute (L'Institut National du Cancer
- INCA) [2014-1-RT-02-CIRC-1]
- European Commission (DG-SANCO)
- International Agency for Research on Cancer
- Danish Cancer Society (Denmark)
- Ligue Contre le Cancer
- Institut Gustave Roussy
- Mutuelle Generale de l'Education Nationale
- Institut National de la Sante et de la Recherche Medicale (INSERM) (France)
- Deutsches Krebsforschungszentrum (DKFZ)
- Federal Ministry of Education and Research (Germany)
- Hellenic Health Foundation (Greece)
- Italian Association for Research on Cancer (AIRC)
- National Research Council
- AIRE-ONLUS Ragusa
- Dutch Ministry of Public Health, Welfare and Sports (VWS)
- Netherlands Cancer Registry (NKR)
- LK Research Funds
- Dutch Prevention Funds
- Dutch ZON (Zorg Onderzoek Nederland)
- World Cancer Research Fund (WCRF)
- Statistics Netherlands (the Netherlands)
- Nordic Center of Excellence Programme on Food, Nutrition and Health (Norway)
- Health Research Fund (FIS)
- Regional Government of Andalucia
- Regional Government of Asturias
- Regional Government of Basque Country
- Regional Government of Murcia [6236]
- Regional Government of Navarra
- ISCIII RETIC [RD06/0020]
- Catalan Institute of Oncology (Spain)
- Swedish Cancer Society
- Swedish Scientific Council
- Regional Government of Skane (Sweden)
- Regional Government of Vasterbotten (Sweden)
- Cancer Research UK [14136, C570/A16491]
- Medical Research Council [1000143, MR/M012190/1]
- Deutsche Krebshilfe
- AVIS Ragusa
- Sicilian Government (Italy)
- MRC [MC_UU_12015/1, MR/N003284/1, MC_UU_00006/1, G0500300] Funding Source: UKRI
This study utilized metabolite profiling to identify 92 metabolites associated with HCC development, including both positive and inverse risk associations. The findings underscore the importance of metabolic pathways linked to steroid metabolism, immunity, and specific dietary and environmental exposures in HCC development. These observations replicate previous findings in Asian and Scandinavian populations, highlighting the diversity of metabolic perturbations involved in HCC development.
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 forN1-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, gamma-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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