Discovery of new pathway of tumourigenesis in humans

The first identification of GP130 somatic activating mutations in human tumours was announced today at EASL 2009, the Annual Meeting of the European Association for the Study of Liver Disease in Copenhagen, Denmark.

Identification of recurrent somatic mutation activating GP130 in inflammatory hepatocellular tumours reveals a new pathway of tumourigenesis in humans, according to researchers. This finding reinforces the role of inflammation in hepatocarcinogenesis and particularly in the malignant transformation of hepatocellular adenomas (HCA). Moreover, GP130 mutations will enable the refinement of the molecular classification of hepatocellular tumors in humans.

Inflammatory hepatocellular adenomas (IHCA) are benign liver tumours defined by the presence of inflammatory infiltrates and by an over-expression of inflammatory proteins. IHCA are usually developed in women and their occurrence is frequently associated with obesity and alcohol intake. Recently, somatic mutations were identified that activated GP130 in 60% of IHCA (Rebouissou et al, Nature, 2009), thus defining GP130 as a new oncogene in human tumours. This study aimed to evaluate frequency of GP130 mutations in a wide series of tumours.

Dr Jessica Zucman-Rossi of Inserm U674, Paris, France, who led the study, said: "This exciting advance means we now have a novel means of further investigating the development pathway of hepatocellular tumours as well as a new tool in the classification of hepatocellular tumours. It is an important step forward in our understanding of hepatocarcinogenesis and the future management of this disease."

Researchers in this study screened a series of 400 well-characterised hepatocellular tumours including hepatocellular adenomas, carcinomas, hepatocholangio-carcinoma, fibrolamellar carcinomas and intra-hepatic cholangiocarcinomas. 100 tumours from different organs were also collected. To search for mutations, GP130 exons were screened in all samples and the function of 7 different mutants was analysed in HEP3B.

A somatic mutation was identified in 65% of the IHCA including 24 different small in-frame deletions or duplications. A spectrum of mutations shows that mutations clearly target the IL-6 binding site in GP130. Also demonstrated was the fact that the expression of the most frequent GP130 mutants in HEP3B cells activates STAT3 in absence of IL-6. The researchers searched for possible interaction and cooperation of GP130 activation with other pathways altered in hepatocellular adenoma. HNF1alpha inactivation and gp130 activation were mutually exclusive in HCA (P< 10-4). By contrast, in half of the beta-catenin activating HCA, a GP130-activating mutation was identified. For two IHCA associated with a malignant transformation, both an activating gp130 and beta-catenin mutations were found. Further, analysis of 220 hepatocellular carcinomas revealed rare GP130 alterations in all cases accompanied by beta-catenin-activating mutations, suggesting a cooperative effect of these signalling pathways in the malignant transformation of hepatocytes.