Metabolome-wide association identifies altered metabolites and metabolic pathways in the serum of patients with cholangiocarcinoma
Linsey E. Jackson,
Jennifer L. Tomlinson,
Roberto Alva-Ruiz,
Lindsey A. Gregory,
Seul Kee Byeon,
Amro M. Abdelrahman,
Dong-Gi Mun,
Caroline W. Grant,
Zachary C. Fogarty,
Chen Wang,
Lewis R. Roberts,
Rondell P. Graham,
Mitesh J. Borad,
Sumera I. Ilyas,
Gregory J. Gores,
Akhilesh Pandey,
Arjun P. Athreya,
Rory L. Smoot
Affiliations
Linsey E. Jackson
Center For Clinical and Translational Science, Mayo Clinic, Rochester, MN, USA
Jennifer L. Tomlinson
Department of Surgery, Mayo Clinic, Rochester, MN, USA
Roberto Alva-Ruiz
Department of Surgery, Mayo Clinic, Rochester, MN, USA
Lindsey A. Gregory
Department of Surgery, Mayo Clinic, Rochester, MN, USA
Seul Kee Byeon
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
Amro M. Abdelrahman
Department of Surgery, Mayo Clinic, Rochester, MN, USA
Dong-Gi Mun
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
Caroline W. Grant
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
Zachary C. Fogarty
Department of Computational Biology, Mayo Clinic, Rochester, MN, USA
Chen Wang
Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
Lewis R. Roberts
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
Rondell P. Graham
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
Mitesh J. Borad
Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA; Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA; Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Phoenix, AZ, USA
Sumera I. Ilyas
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA; Department of Immunology, Mayo Clinic, Rochester, MN, USA
Gregory J. Gores
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
Akhilesh Pandey
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; Center For Individualized Medicine, Mayo Clinic, Rochester, MN, USA; Manipal Academy of Higher Education (MAHE), Manipal, India; Corresponding authors. Addresses: Department of Molecular Pharmacology and Experimental Therapeutics, 200 First Street SW, Rochester, MN 55905, USA. Tel.: 507-422-6073 (A.P. Athreya); Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel: 507-293-9564 (A. Pandey); Department of Surgery and Department Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel.: 507-284-1529; Fax: 507 284 5196 (R.L. Smoot)
Arjun P. Athreya
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA; Corresponding authors. Addresses: Department of Molecular Pharmacology and Experimental Therapeutics, 200 First Street SW, Rochester, MN 55905, USA. Tel.: 507-422-6073 (A.P. Athreya); Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel: 507-293-9564 (A. Pandey); Department of Surgery and Department Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel.: 507-284-1529; Fax: 507 284 5196 (R.L. Smoot)
Rory L. Smoot
Department of Surgery, Mayo Clinic, Rochester, MN, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA; Corresponding authors. Addresses: Department of Molecular Pharmacology and Experimental Therapeutics, 200 First Street SW, Rochester, MN 55905, USA. Tel.: 507-422-6073 (A.P. Athreya); Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel: 507-293-9564 (A. Pandey); Department of Surgery and Department Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel.: 507-284-1529; Fax: 507 284 5196 (R.L. Smoot)
Background & Aims: Metabolomic and lipidomic analyses provide an opportunity for novel biological insights. Cholangiocarcinoma (CCA) remains a highly lethal cancer with limited response to systemic, targeted, and immunotherapeutic approaches. Using a global metabolomics and lipidomics platform, this study aimed to discover and characterize metabolomic variations and associated pathway derangements in patients with CCA. Methods: Leveraging a biospecimen collection, including samples from patients with digestive diseases and normal controls, global serum metabolomic and lipidomic profiling was performed on 213 patients with CCA and 98 healthy controls. The CCA cohort of patients included representation of intrahepatic, perihilar, and distal CCA tumours. Metabolome-wide association studies utilizing multivariable linear regression were used to perform case–control comparisons, followed by pathway enrichment analysis, CCA subtype analysis, and disease stage analysis. The impact of biliary obstruction was evaluated by repeating analyses in subsets of patients only with normal bilirubin levels. Results: Of the 420 metabolites that discriminated patients with CCA from controls, decreased abundance of cysteine-glutathione disulfide was most closely associated with CCA. Additional conjugated bile acid species were found in increased abundance even in the absence of clinically relevant biliary obstruction denoted by elevated serum bilirubin levels. Pathway enrichment analysis also revealed alterations in caffeine metabolism and mitochondrial redox-associated pathways in the serum of patients with CCA. Conclusions: The presented metabolomic and lipidomic profiling demonstrated multiple alterations in the serum of patients with CCA. These exploratory data highlight novel metabolic pathways in CCA and support future work in therapeutic targeting of these pathways and the development of a precision biomarker panel for diagnosis. Impact and implications: Cholangiocarcinoma (CCA) is a highly lethal hepatobiliary cancer with limited treatment response, highlighting the need for a better understanding of the disease biology. Using a global metabolomics and lipidomics platform, we characterized distinct changes in the serum of 213 patients with CCA compared with healthy controls. The results of this study elucidate novel metabolic pathways in CCA. These findings benefit stakeholders in both the clinical and research realms by providing a foundation for improved disease diagnostics and identifying novel targets for therapeutic design.
