GNAS-activating mutations define a rare subgroup of inflammatory liver tumors characterized by STAT3 activation. - Université Paris Cité Accéder directement au contenu
Article Dans Une Revue Journal of Hepatology Année : 2012

GNAS-activating mutations define a rare subgroup of inflammatory liver tumors characterized by STAT3 activation.

Monique Fabre
  • Fonction : Auteur
Marie-Christine Saint-Paul
  • Fonction : Auteur
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Anne de Muret
  • Fonction : Auteur
Marie-José Redon
  • Fonction : Auteur
Sylvie Salenave
  • Fonction : Auteur

Résumé

BACKGROUND & AIMS: 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.

Domaines

Cancer

Dates et versions

hal-00724895 , version 1 (23-08-2012)

Identifiants

Citer

Jean Charles Nault, Monique Fabre, Gabrielle Couchy, Camilla Pilati, Emmanuelle Jeannot, et al.. GNAS-activating mutations define a rare subgroup of inflammatory liver tumors characterized by STAT3 activation.. Journal of Hepatology, 2012, 56 (1), pp.184-91. ⟨10.1016/j.jhep.2011.07.018⟩. ⟨hal-00724895⟩
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