Molecular perspectives for the treatment of hepatocellular carcinoma.

Major advances have been performed in the understanding of genomic dysregulation of hepatocellular carcinoma. A median of 40 to 60 somatic mutations in coding sequence per tumor was identified including 2 to 6 mutations per tumor in genes driving liver carcinogenesis. The main genetic alterations target the key signaling pathways of liver carcinogenesis : telomere maintenance, cell cycle gene, Wnt/beta-catenin pathway, epigenetic modifier gene, oxidative stress pathway, AKT/mTOR and Ras/Raf MAP kinase pathways. A genotype/phenotype classification between these genetic drivers the tumor and patient's features have been also described and was correlated with transcriptomic profiling. These data will be helpful to identify subgroups of HCC that will respond or resist to systemic treatments already used in clinical practice such as tyrosine kinase inhibitors, anti-VEGFR antibody or checkpoint inhibitors and will be useful to identify new therapeutic targets tested in future clinical trials.

Overexpression and promoter mutation of the TERT gene in malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a very aggressive tumor with no known curative treatment. Better knowledge of the molecular mechanisms of mesothelial carcinogenesis is required to develop new therapeutic strategies. MPM, like all cancer cells, needs to maintain telomere length to prevent senescence. Previous studies suggested that the telomere lengthening mechanism in MPM is based mainly on telomerase activity. For this reason, we focused on the key catalytic enzyme, TERT (telomerase reverse transcriptase), by analyzing its gene expression in MPM and by studying the mechanism underlying its upregulation. We used our large collection of MPM composed of 61 MPM in culture and 71 frozen MPM tumor samples. Evaluation of TERT mRNA expression by quantitative RT-PCR showed overexpression in MPM in culture compared with normal mesothelial cells, and in MPM tumor samples compared with normal pleura. We identified a 'hot spot' of mutations in the TERT gene core promoter in both MPM in culture and in MPM tumor samples with an overall frequency of 15%. Furthermore, data clearly identified mutation in the TERT promoter as a mechanism of TERT mRNA upregulation in MPM. In contrast, gene copy number amplification was not associated with TERT overexpression. Then, we analyzed the clinicopathological, etiological and genetic characteristics of MPM with mutations in the TERT promoter. TERT promoter mutations were more frequent in MPM with sarcomatoid histologic subtype (P<0.01), and they were frequently associated with CDKN2A gene inactivation (P=0.03). In conclusion, a subgroup of MPM presents TERT promoter mutations, which lead to TERT mRNA upregulation. This is the first recurrent gain-of-function oncogenic mutations identified in MPM.