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Untargeted Serum Metabolomics Reveals Differential Signatures in Gallstone-Associated and Gallstone-Free Gallbladder Cancer

ABSTRACT:

Gallbladder cancer (GBC) is an aggressive malignancy often associated with gallstones (GBCGS), a condition distinct from gallstone disease (GSD). Both GBC and GBCGS are rare, with unclear pathogenesis and no established biomarker-based solutions. This pilot study aimed to identify distinct metabolic signatures in GBC and GBCGS for early diagnosis and stratification of high-risk GSD patients. A comparative untargeted serum metabolomic profiling was performed across three patient groups: GBC (n1=9), GBCGS (n2=11), and GSD (n3=10). A total of 35,385 mass-features in both positive and negative ionization modes with MS/MS characteristics were detected and annotated into 736 biochemicals.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS12514 | MetaboLights | 2025-12-22

REPOSITORIES: MetaboLights

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Project description:Introduction: Gallbladder cancer (GBC) is a highly aggressive malignancy with limited therapeutic options, particularly in underrepresented populations, including South Africa. Understanding the molecular landscape of GBC may provide novel insights into its pathogenesis and potential therapeutic targets. Molecular changes are known to be associated with GBC, however, there is a paucity of this information especially in African populations. Furthermore, within the tumour microenvironment, different immune cells contribute to GBC progression. We investigated gene expression patterns in GBC tumours and their association with different immune cells in a cohort of South African patients. Methods: RNA sequencing was conducted on 2 normal and 8 gallbladder cancer tissues from South African patients (Ethics: M160640) to identify differentially expressed genes. Bioinformatics tools were used for pathway analysis, while immune cell quantification was performed using the quanTIseq software and presented as median [IQR]. Verification studies were further carried out using real-time PCR on an independent cohort comprising 7 gallstone samples and 26 gallbladder tumour samples. Results: A total of 65 genes were found to be significantly differentially expressed between the gallbladder tumours and gallstone controls. We also identified 37 upregulated and 28 downregulated genes in this cohort. Among the most upregulated genes, MUC16 was confirmed to be significantly overexpressed in tumours. Normal tissues exhibited a significantly higher proportion of dysregulated genes associated with B cells (17.132 [14.866–18.483], p<0.0001) and M1 macrophages (18.943 [1.097–36.790], p<0.0001) compared to tumours. In contrast, tumours showed a greater association with dysregulated genes linked to regulatory T cells (Tregs) (14.373 [9.696–20.162]) relative to normal tissues. Pathway analysis further revealed the upregulation of defective GALNT12, defective GALNT3, defective C1GALT1C1 and termination of O-glycan biosynthesis, highlighting key mechanisms potentially involved in tumour progression. Conclusion: The study has shown the dysregulation of key genes in South African gallbladder cancer patients. Specifically, MUC16 was verified to be significantly elevated in tumour samples. Furthermore, the association of these dysregulated genes with key immune cells in this patient group may further highlight their roles in dysfunctional immune processes linked with tumourigenesis.

			Action	DRS
	GBC1.abf	Other
	GBC10.abf	Other
	GBC2.abf	Other
	GBC3.abf	Other
	GBC4.abf	Other

Dataset Information

Untargeted Serum Metabolomics Reveals Differential Signatures in Gallstone-Associated and Gallstone-Free Gallbladder Cancer

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