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ResearchIn-Press PreviewMetabolismOncology Open Access | 10.1172/jci.insight.171225

Altered plasma metabolite levels can be detected years before a glioma diagnosis

Sebastian Löding,1 Ulrika Andersson,2 Rudolf Kaaks,3 Matthias B. Schulze,4 Valeria Pala,5 Ilona Urbarova,6 Pilar Amiano,7 Sandra M. Colorado-Yohar,8 Marcela Guevara,9 Alicia K. Heath,10 Anastasia Chrysovalantou Chatziioannou,11 Mattias Johansson,12 Lars Nyberg,13 Henrik Antti,1 Benny Björkblom,1 and Beatrice Melin14

1Department of Chemistry, Umeå University, Umeå, Sweden

2Biobank Research Unit, Umeå University, Umeå, Sweden

3Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

4Department of Molecular Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany

5Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

6Department of Community Medicine, University of Tromso, Tromsø, Norway

7Epidemiology of Chronic and Comunnicable Diseases Area, Biodonostia Health Research Institute, San Sebastian, Spain

8Department of Epidemiology, Murcia Regional Health Council, IMIB, Murcia, Spain

9Navarra Institute for Health Research, Instituto de Salud Pública y Laboral de Navarra, Pamplona, Spain

10Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom

11Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France

12Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France

13Department of Radiation Sciences, Diagnostic Radiology, Umeå University, Umeå, Sweden

14Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden

Find articles by Löding, S. in: JCI | PubMed | Google Scholar |

1Department of Chemistry, Umeå University, Umeå, Sweden

2Biobank Research Unit, Umeå University, Umeå, Sweden

3Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

4Department of Molecular Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany

5Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

6Department of Community Medicine, University of Tromso, Tromsø, Norway

7Epidemiology of Chronic and Comunnicable Diseases Area, Biodonostia Health Research Institute, San Sebastian, Spain

8Department of Epidemiology, Murcia Regional Health Council, IMIB, Murcia, Spain

9Navarra Institute for Health Research, Instituto de Salud Pública y Laboral de Navarra, Pamplona, Spain

10Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom

11Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France

12Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France

13Department of Radiation Sciences, Diagnostic Radiology, Umeå University, Umeå, Sweden

14Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden

Find articles by Andersson, U. in: JCI | PubMed | Google Scholar

1Department of Chemistry, Umeå University, Umeå, Sweden

2Biobank Research Unit, Umeå University, Umeå, Sweden

3Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

4Department of Molecular Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany

5Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

6Department of Community Medicine, University of Tromso, Tromsø, Norway

7Epidemiology of Chronic and Comunnicable Diseases Area, Biodonostia Health Research Institute, San Sebastian, Spain

8Department of Epidemiology, Murcia Regional Health Council, IMIB, Murcia, Spain

9Navarra Institute for Health Research, Instituto de Salud Pública y Laboral de Navarra, Pamplona, Spain

10Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom

11Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France

12Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France

13Department of Radiation Sciences, Diagnostic Radiology, Umeå University, Umeå, Sweden

14Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden

Find articles by Kaaks, R. in: JCI | PubMed | Google Scholar |

1Department of Chemistry, Umeå University, Umeå, Sweden

2Biobank Research Unit, Umeå University, Umeå, Sweden

3Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

4Department of Molecular Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany

5Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

6Department of Community Medicine, University of Tromso, Tromsø, Norway

7Epidemiology of Chronic and Comunnicable Diseases Area, Biodonostia Health Research Institute, San Sebastian, Spain

8Department of Epidemiology, Murcia Regional Health Council, IMIB, Murcia, Spain

9Navarra Institute for Health Research, Instituto de Salud Pública y Laboral de Navarra, Pamplona, Spain

10Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom

11Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France

12Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France

13Department of Radiation Sciences, Diagnostic Radiology, Umeå University, Umeå, Sweden

14Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden

Find articles by Schulze, M. in: JCI | PubMed | Google Scholar

1Department of Chemistry, Umeå University, Umeå, Sweden

2Biobank Research Unit, Umeå University, Umeå, Sweden

3Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

4Department of Molecular Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany

5Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

6Department of Community Medicine, University of Tromso, Tromsø, Norway

7Epidemiology of Chronic and Comunnicable Diseases Area, Biodonostia Health Research Institute, San Sebastian, Spain

8Department of Epidemiology, Murcia Regional Health Council, IMIB, Murcia, Spain

9Navarra Institute for Health Research, Instituto de Salud Pública y Laboral de Navarra, Pamplona, Spain

10Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom

11Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France

12Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France

13Department of Radiation Sciences, Diagnostic Radiology, Umeå University, Umeå, Sweden

14Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden

Find articles by Pala, V. in: JCI | PubMed | Google Scholar |

1Department of Chemistry, Umeå University, Umeå, Sweden

2Biobank Research Unit, Umeå University, Umeå, Sweden

3Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

4Department of Molecular Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany

5Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

6Department of Community Medicine, University of Tromso, Tromsø, Norway

7Epidemiology of Chronic and Comunnicable Diseases Area, Biodonostia Health Research Institute, San Sebastian, Spain

8Department of Epidemiology, Murcia Regional Health Council, IMIB, Murcia, Spain

9Navarra Institute for Health Research, Instituto de Salud Pública y Laboral de Navarra, Pamplona, Spain

10Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom

11Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France

12Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France

13Department of Radiation Sciences, Diagnostic Radiology, Umeå University, Umeå, Sweden

14Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden

Find articles by Urbarova, I. in: JCI | PubMed | Google Scholar |

1Department of Chemistry, Umeå University, Umeå, Sweden

2Biobank Research Unit, Umeå University, Umeå, Sweden

3Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

4Department of Molecular Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany

5Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

6Department of Community Medicine, University of Tromso, Tromsø, Norway

7Epidemiology of Chronic and Comunnicable Diseases Area, Biodonostia Health Research Institute, San Sebastian, Spain

8Department of Epidemiology, Murcia Regional Health Council, IMIB, Murcia, Spain

9Navarra Institute for Health Research, Instituto de Salud Pública y Laboral de Navarra, Pamplona, Spain

10Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom

11Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France

12Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France

13Department of Radiation Sciences, Diagnostic Radiology, Umeå University, Umeå, Sweden

14Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden

Find articles by Amiano, P. in: JCI | PubMed | Google Scholar |

1Department of Chemistry, Umeå University, Umeå, Sweden

2Biobank Research Unit, Umeå University, Umeå, Sweden

3Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

4Department of Molecular Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany

5Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

6Department of Community Medicine, University of Tromso, Tromsø, Norway

7Epidemiology of Chronic and Comunnicable Diseases Area, Biodonostia Health Research Institute, San Sebastian, Spain

8Department of Epidemiology, Murcia Regional Health Council, IMIB, Murcia, Spain

9Navarra Institute for Health Research, Instituto de Salud Pública y Laboral de Navarra, Pamplona, Spain

10Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom

11Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France

12Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France

13Department of Radiation Sciences, Diagnostic Radiology, Umeå University, Umeå, Sweden

14Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden

Find articles by Colorado-Yohar, S. in: JCI | PubMed | Google Scholar |

1Department of Chemistry, Umeå University, Umeå, Sweden

2Biobank Research Unit, Umeå University, Umeå, Sweden

3Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

4Department of Molecular Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany

5Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

6Department of Community Medicine, University of Tromso, Tromsø, Norway

7Epidemiology of Chronic and Comunnicable Diseases Area, Biodonostia Health Research Institute, San Sebastian, Spain

8Department of Epidemiology, Murcia Regional Health Council, IMIB, Murcia, Spain

9Navarra Institute for Health Research, Instituto de Salud Pública y Laboral de Navarra, Pamplona, Spain

10Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom

11Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France

12Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France

13Department of Radiation Sciences, Diagnostic Radiology, Umeå University, Umeå, Sweden

14Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden

Find articles by Guevara, M. in: JCI | PubMed | Google Scholar |

1Department of Chemistry, Umeå University, Umeå, Sweden

2Biobank Research Unit, Umeå University, Umeå, Sweden

3Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

4Department of Molecular Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany

5Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

6Department of Community Medicine, University of Tromso, Tromsø, Norway

7Epidemiology of Chronic and Comunnicable Diseases Area, Biodonostia Health Research Institute, San Sebastian, Spain

8Department of Epidemiology, Murcia Regional Health Council, IMIB, Murcia, Spain

9Navarra Institute for Health Research, Instituto de Salud Pública y Laboral de Navarra, Pamplona, Spain

10Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom

11Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France

12Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France

13Department of Radiation Sciences, Diagnostic Radiology, Umeå University, Umeå, Sweden

14Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden

Find articles by Heath, A. in: JCI | PubMed | Google Scholar |

1Department of Chemistry, Umeå University, Umeå, Sweden

2Biobank Research Unit, Umeå University, Umeå, Sweden

3Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

4Department of Molecular Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany

5Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

6Department of Community Medicine, University of Tromso, Tromsø, Norway

7Epidemiology of Chronic and Comunnicable Diseases Area, Biodonostia Health Research Institute, San Sebastian, Spain

8Department of Epidemiology, Murcia Regional Health Council, IMIB, Murcia, Spain

9Navarra Institute for Health Research, Instituto de Salud Pública y Laboral de Navarra, Pamplona, Spain

10Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom

11Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France

12Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France

13Department of Radiation Sciences, Diagnostic Radiology, Umeå University, Umeå, Sweden

14Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden

Find articles by Chatziioannou, A. in: JCI | PubMed | Google Scholar |

1Department of Chemistry, Umeå University, Umeå, Sweden

2Biobank Research Unit, Umeå University, Umeå, Sweden

3Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

4Department of Molecular Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany

5Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

6Department of Community Medicine, University of Tromso, Tromsø, Norway

7Epidemiology of Chronic and Comunnicable Diseases Area, Biodonostia Health Research Institute, San Sebastian, Spain

8Department of Epidemiology, Murcia Regional Health Council, IMIB, Murcia, Spain

9Navarra Institute for Health Research, Instituto de Salud Pública y Laboral de Navarra, Pamplona, Spain

10Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom

11Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France

12Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France

13Department of Radiation Sciences, Diagnostic Radiology, Umeå University, Umeå, Sweden

14Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden

Find articles by Johansson, M. in: JCI | PubMed | Google Scholar |

1Department of Chemistry, Umeå University, Umeå, Sweden

2Biobank Research Unit, Umeå University, Umeå, Sweden

3Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

4Department of Molecular Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany

5Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

6Department of Community Medicine, University of Tromso, Tromsø, Norway

7Epidemiology of Chronic and Comunnicable Diseases Area, Biodonostia Health Research Institute, San Sebastian, Spain

8Department of Epidemiology, Murcia Regional Health Council, IMIB, Murcia, Spain

9Navarra Institute for Health Research, Instituto de Salud Pública y Laboral de Navarra, Pamplona, Spain

10Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom

11Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France

12Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France

13Department of Radiation Sciences, Diagnostic Radiology, Umeå University, Umeå, Sweden

14Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden

Find articles by Nyberg, L. in: JCI | PubMed | Google Scholar |

1Department of Chemistry, Umeå University, Umeå, Sweden

2Biobank Research Unit, Umeå University, Umeå, Sweden

3Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

4Department of Molecular Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany

5Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

6Department of Community Medicine, University of Tromso, Tromsø, Norway

7Epidemiology of Chronic and Comunnicable Diseases Area, Biodonostia Health Research Institute, San Sebastian, Spain

8Department of Epidemiology, Murcia Regional Health Council, IMIB, Murcia, Spain

9Navarra Institute for Health Research, Instituto de Salud Pública y Laboral de Navarra, Pamplona, Spain

10Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom

11Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France

12Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France

13Department of Radiation Sciences, Diagnostic Radiology, Umeå University, Umeå, Sweden

14Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden

Find articles by Antti, H. in: JCI | PubMed | Google Scholar

1Department of Chemistry, Umeå University, Umeå, Sweden

2Biobank Research Unit, Umeå University, Umeå, Sweden

3Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

4Department of Molecular Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany

5Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

6Department of Community Medicine, University of Tromso, Tromsø, Norway

7Epidemiology of Chronic and Comunnicable Diseases Area, Biodonostia Health Research Institute, San Sebastian, Spain

8Department of Epidemiology, Murcia Regional Health Council, IMIB, Murcia, Spain

9Navarra Institute for Health Research, Instituto de Salud Pública y Laboral de Navarra, Pamplona, Spain

10Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom

11Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France

12Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France

13Department of Radiation Sciences, Diagnostic Radiology, Umeå University, Umeå, Sweden

14Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden

Find articles by Björkblom, B. in: JCI | PubMed | Google Scholar |

1Department of Chemistry, Umeå University, Umeå, Sweden

2Biobank Research Unit, Umeå University, Umeå, Sweden

3Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

4Department of Molecular Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany

5Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

6Department of Community Medicine, University of Tromso, Tromsø, Norway

7Epidemiology of Chronic and Comunnicable Diseases Area, Biodonostia Health Research Institute, San Sebastian, Spain

8Department of Epidemiology, Murcia Regional Health Council, IMIB, Murcia, Spain

9Navarra Institute for Health Research, Instituto de Salud Pública y Laboral de Navarra, Pamplona, Spain

10Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom

11Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France

12Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France

13Department of Radiation Sciences, Diagnostic Radiology, Umeå University, Umeå, Sweden

14Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden

Find articles by Melin, B. in: JCI | PubMed | Google Scholar

Published August 31, 2023 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.171225.
Copyright © 2023, Löding et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published August 31, 2023 - Version history
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Abstract

Genetic and metabolic changes in tissue and blood are reported to occur several years before glioma diagnosis. As gliomas are currently detected late, a liquid biopsy for early detection could impact the quality of life and prognosis of patients. Here, we present a nested case-control study of 550 pre-diagnostic glioma cases and 550 healthy controls, from the Northern Sweden Health and Disease study (NSHDS) and the European Prospective Investigation into Cancer and Nutrition (EPIC) study. We identified 93 significantly altered metabolites related to glioma development up to eight years before diagnosis. Out of these metabolites, a panel of 20 selected metabolites showed strong disease correlation and consistent progression pattern towards diagnosis in both the NSHDS and EPIC cohorts, and separated favorably future cases from controls independently of biological sex. The blood metabolite panel also successfully separated both lower grade glioma and glioblastoma cases from controls, up to eight years before diagnosis in NSHDS (glioma AUC=0.85, P=3.1e-12; glioblastoma AUC=0.85, P=6.3e-8), and up to two years before diagnosis in EPIC (glioma AUC=0.81, P=0.005; glioblastoma AUC=0.89, P=0.04). Pathway enrichment analysis detected metabolites related to the TCA-cycle, Warburg effect, gluconeogenesis, cysteine-, pyruvate- and tyrosine metabolism as the most affected.

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