N-Glycosylation Patterns Correlate with Hepatocellular Carcinoma Genetic Subtypes

Abstract

Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths globally, and the incidence rate in the United States is increasing. Studies have identified inter- and intratumor heterogeneity as histologic and/or molecular subtypes/variants associated with response to certain molecular targeted therapies. Spatial HCC tissue profiling of N-linked glycosylation by matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS) may serve as a new method to evaluate the tumor heterogeneity. Previous work has identified significant changes in the N-linked glycosylation of HCC tumors but has not accounted for the heterogeneous genetic and molecular nature of HCC. To determine the correlation between HCC-specific N-glycosylation changes and genetic/molecular tumor features, we profiled HCC tissue samples with MALDI-IMS and correlated the spatial N-glycosylation with a widely used HCC molecular classification (Hoshida subtypes). MALDI-IMS data displayed trends that could approximately distinguish between subtypes, with subtype 1 demonstrating significantly dysregulated N-glycosylation versus adjacent nontumor tissue. Although there were no individual N-glycan structures that could identify specific subtypes, trends emerged regarding the correlation of branched glycan expression to HCC as a whole and fucosylated glycan expression to subtype 1 tumors specifically. Implications: Correlating N-glycosylation to specific subtypes offers the specific detection of subtypes of HCC, which could both enhance early HCC sensitivity and guide targeted clinical therapies.

A Fucosylated Glycopeptide as a Candidate Biomarker for Early Diagnosis of NASH Hepatocellular Carcinoma Using a Stepped HCD Method and PRM Evaluation

“…Serum markers including alpha fetoprotein (AFP) and AFP-L3, a core-fucosylated form of AFP, have been used in clinical settings for early detection monitoring. However, these markers still have inadequate performance characteristics for early detection ( 3 , 4 ). To date, there are data available on several serum proteins as potential biomarkers for HCC detection; however, most existing markers require further validation prior to use in routine clinical practice ( 5 ).…”

Glycoprotein α-Subunit of Glucosidase II (GIIα) is a novel prognostic biomarker correlated with unfavorable outcome of urothelial carcinoma

“…Dr. Anand Mehta. et al demonstrated a correlation of specific sugar structures to specific hepatocellular carcinoma subtypes [ 22 ]. Further studies on the relationship of GANAB-mediated aberrant glycosylation and UC molecular subtypes might be able to explain the heterogeneity of UC.…”

Lectin Drug Conjugates Targeting High Mannose N‐Glycans

“…Disrupting the N-glycosylation biosynthetic pathway using a type I mannosidase inhibitor can increase the abundance of high mannose N-glycans. [19] To test this hypoth- ChemBioChem esis, we utilized TNBC MDA-MB-468 cells, as this cell line presents low levels of high mannose N-glycans, and the kifunensine analogue JDW-II-010 (5) to inhibit type I mannosidase (MAN I) enzymes. [10] When MDA-MB-468 cells were treated with 5 a significant increase in the binding of Cyt-CVNH MB 488 to the cells was observed by flow cytometry (Figure 4A), indicating that 5 increased the abundance of high mannose Nglycans.…”