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Metabolic signatures in blood for early detection of glioma
Umeå University, Faculty of Science and Technology, Department of Chemistry.ORCID iD: 0000-0001-9228-0625
2024 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Metaboliska signaturer i blod för tidig upptäckt av gliom (Swedish)
Abstract [en]

Glioma is the most common malignant primary brain tumor among adults and is often detected at a late stage of the disease. Treatment often include surgical resection of the tumor followed by combined radiochemotherapy. Yet, the prognosis given to glioma patients is often poor, with the median survival for the most common and aggressive glioma subtype glioblastoma being only 15 months. Due to limited treatment options and poor prognosis, an earlier detection of gliomas could potentially improve the outcome and quality of life for patients. Intriguingly, previous studies have shown that the glioma development may actually start several years before clinical diagnosis is given. In this thesis, a search for altered metabolite levels in blood related to glioma development was conducted, to find biomarkers that show potential to be targets in an early detection tool of glioma and to improve the understanding of the mechanism of the disease.

In Paper I, pre-diagnostic metabolite levels in blood were analyzed from glioma cases that had been collected several years before they were diagnosed together with matched controls. A panel of 20 metabolites were discovered that could predict glioma development up to 8 years before diagnosis in the discovery cohort and up to 2 years before diagnosis in the validation cohort. The altered metabolites showed indication of an altered energy metabolism and imbalanced redox homeostasis.

In Paper II, the altered metabolite levels within 8 years to glioma diagnosis related to an altered energy metabolism was replicated. Longitudinal blood metabolite analysis from years before diagnosis to the time of surgery revealed an altered amino acid metabolism. A set of metabolites with diagnostic potential at surgery and years before diagnosis was presented.

In Paper III, a discovery analysis was conducted on altered metabolite levels at the time of glioma surgery compared to years before diagnosis. A large set of metabolites was significantly altered at surgery, with several metabolic pathways altered including the amino acid metabolism. The pre-diagnostic 20-metabolite panel discovered in Paper I was revisited and their levels were analyzed at surgery, where 8 metabolites showed further significantly elevated levels at surgery as compared to years before, indicating early detection and diagnostic potential for those metabolites.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2024. , p. 67
Keywords [en]
Glioma, glioblastoma, liquid biopsy, blood, metabolites, early detection, surgery, N-lactoyl-amino-acids, N-lactoyl-phenylalanine
National Category
Cancer and Oncology Analytical Chemistry Bioinformatics (Computational Biology)
Identifiers
URN: urn:nbn:se:umu:diva-230465ISBN: 9789180705011 (print)ISBN: 9789180705028 (electronic)OAI: oai:DiVA.org:umu-230465DiVA, id: diva2:1902615
Public defence
2024-11-08, Stora hörsalen (KBE303), KBC-huset, Linnaeus väg 6, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2024-10-11 Created: 2024-10-01 Last updated: 2024-10-02Bibliographically approved
List of papers
1. Altered plasma metabolite levels can be detected years before a glioma diagnosis
Open this publication in new window or tab >>Altered plasma metabolite levels can be detected years before a glioma diagnosis
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2023 (English)In: JCI Insight, ISSN 2379-3708, Vol. 8, no 19, article id e171225Article in journal (Refereed) Published
Abstract [en]

Genetic and metabolic changes in tissue and blood are reported to occur several years before glioma diagnosis. Since gliomas are currently detected late, a liquid biopsy for early detection could affect the quality of life and prognosis of patients. Here, we present a nested case-control study of 550 prediagnostic 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 8 years before diagnosis. Out of these metabolites, a panel of 20 selected metabolites showed strong disease correlation and a consistent progression pattern toward diagnosis in both the NSHDS and EPIC cohorts, and they separated 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 8 years before diagnosis in patients within the NSHDS cohort and up to 2 years before diagnosis in EPIC. Pathway enrichment analysis detected metabolites related to the TCA cycle, Warburg effect, gluconeogenesis, and cysteine, pyruvate, and tyrosine metabolism as the most affected.

Place, publisher, year, edition, pages
American Society For Clinical Investigation, 2023
Keywords
Brain cancer, Metabolism, Oncology
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-215372 (URN)10.1172/jci.insight.171225 (DOI)001085355700001 ()37651185 (PubMedID)2-s2.0-85173580693 (Scopus ID)
Funder
Swedish Research Council, 2017-00650Swedish Research Council, 2019-01566Swedish Cancer Society, CAN2018/390Swedish Cancer Society, 19 0370Cancerforskningsfonden i Norrland, AMP 21-1045Cancerforskningsfonden i Norrland, AMP22-1084Sjöberg Foundation, 2020-01-07-08Public Health Agency of Sweden , 2020-2022World Cancer Research Fund InternationalRegion SkåneRegion Västerbotten
Available from: 2023-10-31 Created: 2023-10-31 Last updated: 2024-10-02Bibliographically approved
2. Blood based metabolic markers of glioma from pre-diagnosis to surgery
Open this publication in new window or tab >>Blood based metabolic markers of glioma from pre-diagnosis to surgery
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2024 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 14, article id 20680Article in journal (Refereed) Published
Abstract [en]

Gliomas are highly complex and metabolically active brain tumors associated with poor prognosis. Recent reports have found altered levels of blood metabolites during early tumor development, suggesting that tumor development could be detected several years before clinical manifestation. In this study, we performed metabolite analyses of blood samples collected from healthy controls and future glioma patients, up to eight years before glioma diagnosis, and on the day of glioma surgery. We discovered that metabolites related to early glioma development were associated with an increased energy turnover, as highlighted by elevated levels of TCA-related metabolites such as fumarate, malate, lactate and pyruvate in pre-diagnostic cases. We also found that metabolites related to glioma progression at surgery were primarily high levels of amino acids and metabolites of amino acid catabolism, with elevated levels of 11 amino acids and two branched-chain alpha-ketoacids, ketoleucine and ketoisoleucine. High amino acid turnover in glioma tumor tissue is currently utilized for PET imaging, diagnosis and delineation of tumor margins. By examining blood-based metabolic progression patterns towards disease onset, we demonstrate that this high amino acid turnover is also detectable in a simple blood sample. These findings provide additional insight of metabolic alterations during glioma development and progression.

Place, publisher, year, edition, pages
Springer Nature, 2024
Keywords
Glioma, Glioblastoma, Blood metabolites, Early detection, Surgery, Liquid biopsy
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-229233 (URN)10.1038/s41598-024-71375-6 (DOI)39237693 (PubMedID)2-s2.0-85203420003 (Scopus ID)
Funder
Swedish Cancer Society, 19 0370PJSwedish Cancer Society, 22 31PJ01HSwedish Cancer Society, 21 1384Pj01HCancerforskningsfonden i Norrland, AMP 18-907Cancerforskningsfonden i Norrland, AMP 21-1045Cancerforskningsfonden i Norrland, AMP 22-1084Cancerforskningsfonden i Norrland, AMP 23-1131Lions Cancerforskningsfond i Norr, LP21-2259Swedish Research Council, 2019-01566Sjöberg Foundation, 2020-01-07-08Familjen Erling-Perssons Stiftelse, 2021 0046
Available from: 2024-09-05 Created: 2024-09-05 Last updated: 2024-10-01Bibliographically approved
3. Diagnostic metabolic markers of glioma in blood for early detection
Open this publication in new window or tab >>Diagnostic metabolic markers of glioma in blood for early detection
(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-230216 (URN)
Note

Alternative title: "Discovery of diagnostic metabolic markers of glioma in blood"

Available from: 2024-10-01 Created: 2024-10-01 Last updated: 2024-10-02

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Jonsson, Sebastian

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