Characterization of tumor heterogeneity in beta-catenin mutated hepatocellular adenomas

ABSTRACT: Hepatocellular adenomas (HCA) are rare benign tumours of the liver which have been extensively classified at the clinico-pathological, genetic and proteomic levels. The b-HCA subtype has several types of mutations in the ß-catenin gene (CTNNB1) with very different clinical phenotypes and risks. Recently, we revealed a glutamine synthetase (GS) positive rim in b-HCA exon 3 S45 and b-HCA exon 7/8, indicating protein expression heterogeneity into b-HCA in comparison with the rest of the tumor. A difference in vascularization had been associated with this rim revealed by a diffuse CD34 labeling only at the center of the tumor and not in the rim. In this study, we sought to characterize this tumor heterogeneity in a tumor considered monoclonal. We used laser microdissection to analyze the rim (R) at the molecular level. We cut 1mm² areas of GS+/CD34- rim on serial cuts and we analyzed in parallel, the mutation status of CTNNB1 and the levels of protein expression by mass spectrometry. Comparison of the proteomic profiles of the rim versus the tumor center (T) revealed a sufficiently large protein expression differential to distinguish them by principal component analysis. Forty proteins were significantly differentially expressed between R and T, including a large majority of amino acid and lipid metabolism proteins whose deregulations were comparable to a perivenous expression profile in a normal hepatocyte context. Our results suggest that protein expression in the rim seems not to be dependent on the mutational status of CTNNB1 but rather on the influence of venous drainage. Thanks to laser microdissection coupled with proteomic analysis on fixed tissue, we were able to analyze this tumor heterogeneity and provide elements of biological interpretation.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Liver

DISEASE(S): Hepatocellular Adenoma

SUBMITTER: Dupuy Jean-William  

LAB HEAD: Anne-Aurelie Raymond

PROVIDER: PXD031323 | Pride | 2023-05-02

REPOSITORIES: Pride