Plasma proteome plus site-specific N-glycoprofiling for hepatobiliary carcinomas

Area of Science:

• Biochemistry
• Oncology
• Proteomics

Background:

• Hepatobiliary cancer is a major global health concern, ranking as the third leading cause of cancer mortality worldwide.
• Current diagnostic and prognostic tools for hepatobiliary cancers are insufficient for early detection and monitoring disease progression.
• Plasma N-glycoproteins, largely originating from the hepatobiliary system, represent a promising source for novel biomarker discovery.

Purpose of the Study:

• To identify and validate novel plasma N-glycoprotein biomarkers for hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and combined HCC and CCA (cHCC-CCA).
• To assess the correlation of identified biomarkers with tumor characteristics, including stage, grade, and patient survival outcomes.
• To investigate the role of specific N-glycan structures on protein biomarkers in relation to cancer prognosis.

Main Methods:

• Quantitative proteomic analysis using mass spectrometry to profile plasma N-glycoproteomes from patients with hepatobiliary cancers and controls.
• Differential expression analysis to identify proteins significantly altered in cancer patients.
• Postproteomic site-specific N-glycan analysis to characterize glycoforms and their abundance.

Main Results:

• 57 out of 5358 identified plasma proteins were differentially expressed in hepatobiliary cancers.
• Four proteins—complement C3, apolipoprotein C-III (HCC); galectin-3-binding protein (CCA); and 72 kDa inositol polyphosphate 5-phosphatase (cHCC-CCA)—showed strong correlations with tumor stage, grade, and survival.
• Specific N-glycan structures on complement C3 at Asn85, particularly hybrid glycoforms, were associated with lower tumor recurrence and mortality rates in HCC patients.

Conclusions:

• Plasma N-glycoproteins with distinct N-glycan compositions hold potential as noninvasive biomarkers for evaluating the oncological status of hepatobiliary cancers.
• Complement C3, with specific N-glycan modifications, may serve as a prognostic marker for hepatocellular carcinoma.
• These findings pave the way for developing new diagnostic and prognostic tools to improve patient management in hepatobiliary oncology.