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

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• 作者：Jean Charles Nault¹ ;   ; ² ; Monique Fabre³ ; Gabrielle Couchy¹ ;   ; ² ; Camilla Pilati¹ ;   ; ² ; Emmanuelle Jeannot¹ ;   ; ² ; Jeanne Tran Van Nhieu⁴ ; Marie-Christine Saint-Paul⁵ ; Anne De Muret⁶ ; Marie-José ; Redon³ ; Catherine Buffet⁷ ; Sylvie Salenave⁸ ; Charles Balabaud⁹ ; Sophie Prevot¹⁰ ; Philippe Labrune¹¹ ; Paulette Bioulac-Sage¹² ; Jean-Yves Scoazec¹³ ; Philippe Chanson⁸ ; Jessica Zucman-Rossi¹ ;   ; ² ;   ; ¹⁴ ;   ; ^{zucman@cephb.fr} ;   ; ^{jessica@inserm-u674.net}
• 刊名：Journal of Hepatology
• 出版年：2012
• 出版时间：January 2012
• 年：2012
• 卷：56
• 期：1
• 页码：184-191
• 全文大小：1411 K

文摘

Background & Aims

Mosaic G-protein alpha-subunit (GNAS)-activating mutations are responsible for the McCune¨CAlbright (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.