title: Genotype-phenotype correlation of CTNNB1 mutations reveals different ß-catenin activity associated with liver tumor progression.
abstract: CTNNB1 mutations activating ß-catenin are frequent somatic events in hepatocellular carcinoma (HCC) and adenoma (HCA), particularly associated with a risk of malignant transformation. We aimed to understand the relationship between CTNNB1 mutation types, tumor phenotype, and level of ß-catenin activation in malignant transformation. To this purpose, CTNNB1 mutation spectrum was analyzed in 220 HCAs, 373 HCCs, and 17 borderline HCA/HCC lesions. ß-catenin activation level was assessed in tumors by quantitative reverse-transcriptase polymerase chain reaction and immunohistochemistry (IHC), in cellulo by TOP-Flash assay. Overall, ß-catenin activity was higher in malignant mutated tumors, compared to adenomas, and this was related to a different spectrum of CTNNB1 mutations in HCCs and HCAs. In benign tumors, we defined three levels of ß-catenin activation related to specific mutations: (1) S45, K335, and N387 mutations led to weak activation; (2) T41 mutations were related to moderate activity; and (3) highly active mutations included exon 3 deletions and amino acid substitutions within the ß-TRCP binding site (D32-S37). Accordingly, in vitro, K335I and N387K mutants showed a lower activity than S33C. Tumors with highly active mutations demonstrated strong/homogeneous glutamine synthase (GS) staining and were associated with malignancy. In contrast, weak mutants demonstrated heterogeneous pattern of GS staining and were more frequent in HCAs except for the S45 mutants identified similarly in 20% of mutated HCAs and HCCs; however, in most of the HCCs, the weak S45 mutant alleles were duplicated, resulting in a final high ß-catenin activity.
  
  
  
  High ß-catenin activity driven by specific CTNNB1 mutations and S45 allele duplication is associated with malignant transformation. Consequently, HCAs with S45 and all high/moderate mutants should be identified with precise IHC criteria or mutation screening. (Hepatology 2016;64:2047-2061).
authors.affiliation: Inserm, UMR-1162, Functional Genomics of Solid Tumors, Equipe labellisée Ligue Contre le Cancer, Paris, France.|University of Paris Descartes, Sorbonne Paris Cité, Labex Immuno-oncology, Paris, France.|University of Paris Diderot, Sorbonne Paris Cité, University Institute of Hematology, Paris, France.|University of Paris 13, Sorbonne Paris Cité, Saint-Denis, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Rebouissou
authors.affiliation: Inserm, UMR-1162, Functional Genomics of Solid Tumors, Equipe labellisée Ligue Contre le Cancer, Paris, France.|University of Paris Descartes, Sorbonne Paris Cité, Labex Immuno-oncology, Paris, France.|University of Paris Diderot, Sorbonne Paris Cité, University Institute of Hematology, Paris, France.|University of Paris 13, Sorbonne Paris Cité, Saint-Denis, France.
authors.forename: Andrea
authors.initials: A
authors.lastname: Franconi
authors.affiliation: Inserm, UMR-1162, Functional Genomics of Solid Tumors, Equipe labellisée Ligue Contre le Cancer, Paris, France.|University of Paris Descartes, Sorbonne Paris Cité, Labex Immuno-oncology, Paris, France.|University of Paris Diderot, Sorbonne Paris Cité, University Institute of Hematology, Paris, France.|University of Paris 13, Sorbonne Paris Cité, Saint-Denis, France.|Public Hospitals of Paris, Department of Pathology, CHU Henri Mondor, Créteil, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Calderaro
authors.affiliation: Inserm, UMR-1162, Functional Genomics of Solid Tumors, Equipe labellisée Ligue Contre le Cancer, Paris, France.|University of Paris Descartes, Sorbonne Paris Cité, Labex Immuno-oncology, Paris, France.|University of Paris Diderot, Sorbonne Paris Cité, University Institute of Hematology, Paris, France.|University of Paris 13, Sorbonne Paris Cité, Saint-Denis, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Letouzé
authors.affiliation: Inserm, UMR-1162, Functional Genomics of Solid Tumors, Equipe labellisée Ligue Contre le Cancer, Paris, France.|University of Paris Descartes, Sorbonne Paris Cité, Labex Immuno-oncology, Paris, France.|University of Paris Diderot, Sorbonne Paris Cité, University Institute of Hematology, Paris, France.|University of Paris 13, Sorbonne Paris Cité, Saint-Denis, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Imbeaud
authors.affiliation: Inserm, UMR-1162, Functional Genomics of Solid Tumors, Equipe labellisée Ligue Contre le Cancer, Paris, France.|University of Paris Descartes, Sorbonne Paris Cité, Labex Immuno-oncology, Paris, France.|University of Paris Diderot, Sorbonne Paris Cité, University Institute of Hematology, Paris, France.|University of Paris 13, Sorbonne Paris Cité, Saint-Denis, France.
authors.forename: Camilla
authors.initials: C
authors.lastname: Pilati
authors.affiliation: Inserm, UMR-1162, Functional Genomics of Solid Tumors, Equipe labellisée Ligue Contre le Cancer, Paris, France.|University of Paris Descartes, Sorbonne Paris Cité, Labex Immuno-oncology, Paris, France.|University of Paris Diderot, Sorbonne Paris Cité, University Institute of Hematology, Paris, France.|University of Paris 13, Sorbonne Paris Cité, Saint-Denis, France.|Public Hospitals of Paris, University hospital of Paris-Seine Saint-Denis, Site Jean Verdier, Cancerology unit, Department of Hepatology, Bondy, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Nault
authors.affiliation: Inserm, UMR-1162, Functional Genomics of Solid Tumors, Equipe labellisée Ligue Contre le Cancer, Paris, France.|University of Paris Descartes, Sorbonne Paris Cité, Labex Immuno-oncology, Paris, France.|University of Paris Diderot, Sorbonne Paris Cité, University Institute of Hematology, Paris, France.|University of Paris 13, Sorbonne Paris Cité, Saint-Denis, France.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Couchy
authors.affiliation: Public Hospitals of Paris, Department of Digestive and Hepatobiliary Surgery, CHU Henri Mondor, Créteil, France.|INSERM U955 Henri Mondor Hospital University of Paris-Est Créteil, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Laurent
authors.affiliation: Inserm, UMR-1053, Bordeaux, France.|University of Bordeaux, Bordeaux, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Balabaud
authors.affiliation: Inserm, UMR-1053, Bordeaux, France.|University of Bordeaux, Bordeaux, France.|Hospital of Bordeaux, Pellegrin Hospital, Department of Pathology, Bordeaux, France.
authors.forename: Paulette
authors.initials: P
authors.lastname: Bioulac-Sage
authors.affiliation: Inserm, UMR-1162, Functional Genomics of Solid Tumors, Equipe labellisée Ligue Contre le Cancer, Paris, France.|University of Paris Descartes, Sorbonne Paris Cité, Labex Immuno-oncology, Paris, France.|University of Paris Diderot, Sorbonne Paris Cité, University Institute of Hematology, Paris, France.|University of Paris 13, Sorbonne Paris Cité, Saint-Denis, France.|Public Hospitals of Paris, European Hospital Georges Pompidou, Paris, France.
authors.forename: Jessica
authors.initials: J
authors.lastname: Zucman-Rossi
mesh_terms: D018248:Adenoma, Liver Cell / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D018450:Disease Progression; D056726:Genetic Association Studies; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D009154:Mutation; D014407:Tumor Cells, Cultured; D051176:beta Catenin / Q000235:genetics* / Q000502:physiology
chemical_list: C495270:CTNNB1 protein, human; D051176:beta Catenin