title: GNAS-activating mutations define a rare subgroup of inflammatory liver tumors characterized by STAT3 activation.
abstract: OBJECTIVE
  Mosaic G-protein alpha-subunit (GNAS)-activating mutations are responsible for the McCune-Albright (MCA) syndrome. This oncogene that activates the adenylate cyclase is also mutated in various tumor types leading to the accumulation of cyclic-AMP. Identification of a hepatocellular adenoma (HCA) in two MCA patients led us to search for GNAS activation in benign and malignant hepatocellular carcinogenesis.
  
  
  METHODS
  GNAS mutations were screened by sequencing 164 HCA, 245 hepatocellular carcinoma (HCC), and 17 fibrolamellar carcinomas. Tumors were characterized by quantitative RT-PCR, gene mutation screening and pathological reviewing. The consequences of wild type and mutant GNAS expression were analyzed in hepatocellular cell lines.
  
  
  RESULTS
  A somatic GNAS-activating mutation was identified in 5 benign tumors and in 2 HCC. In benign tumors, GNAS mutations were exclusive from HNF1A, CTNNB1, and IL6ST mutations whereas one HCC demonstrated both CTNNB1 and GNAS mutations. Quantitative RT-PCR showed an activation of the IL-6 and interferon pathways in GNAS-mutated tumor tissues. Accordingly, pathological reviewing identified in GNAS-mutated tumors an inflammatory phenotype characterized by fibrosis and STAT3 activation. We further demonstrated in HCC cell lines that GNAS mutant expression induced inflammatory response and STAT3 activation.
  
  
  CONCLUSIONS
  We identified for the first time the association between two rare diseases, MCA syndrome and HCA occurrence, but also that somatic GNAS-activating mutations in sporadic benign and malignant liver tumors are characterized by an inflammatory phenotype. These results showed a cross-talk between cyclic-AMP and JAK/STAT pathways in liver tumors and they reinforce the role of STAT3 activation in liver tumorigenesis.
authors.affiliation: Inserm, U674, Génomique fonctionnelle des tumeurs solides, Paris, France.
authors.forename: Jean Charles
authors.initials: JC
authors.lastname: Nault
authors.forename: Monique
authors.initials: M
authors.lastname: Fabre
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Couchy
authors.forename: Camilla
authors.initials: C
authors.lastname: Pilati
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Jeannot
authors.forename: Jeanne
authors.initials: J
authors.lastname: Tran Van Nhieu
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Saint-Paul
authors.forename: Anne
authors.initials: A
authors.lastname: De Muret
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Redon
authors.forename: Catherine
authors.initials: C
authors.lastname: Buffet
authors.forename: Sylvie
authors.initials: S
authors.lastname: Salenave
authors.forename: Charles
authors.initials: C
authors.lastname: Balabaud
authors.forename: Sophie
authors.initials: S
authors.lastname: Prevot
authors.forename: Philippe
authors.initials: P
authors.lastname: Labrune
authors.forename: Paulette
authors.initials: P
authors.lastname: Bioulac-Sage
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Scoazec
authors.forename: Philippe
authors.initials: P
authors.lastname: Chanson
authors.forename: Jessica
authors.initials: J
authors.lastname: Zucman-Rossi
mesh_terms: D018248:Adenoma, Liver Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002864:Chromogranins; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D005359:Fibrous Dysplasia, Polyostotic / Q000235:genetics; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000145:classification / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009154:Mutation; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D002864:Chromogranins; D004273:DNA, Neoplasm; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs