TERT promoter mutations in primary liver tumors.
Next-generation sequencing has drawn the genetic landscape of hepatocellular carcinoma and several signaling pathways are altered at the DNA level in tumors: Wnt/β-catenin, cell cycle regulator, epigenetic modifier, histone methyltransferase, oxidative stress, ras/raf/map kinase and akt/mtor pathways. Hepatocarcinogenesis is a multistep process starting with the exposure to different risk factors, followed by the development of a chronic liver disease and cirrhosis precede in the vast majority of the cases the development of HCC. Several lines of evidence have underlined the pivotal role of telomere maintenance in both cirrhosis and HCC pathogenesis. TERT promoter mutations were identified as the most frequent genetic alterations in hepatocellular carcinoma with an overall frequency around 60%. Moreover, in cirrhosis, TERT promoter mutations are observed at the early steps of hepatocarcinogenesis since they are recurrently identified in low-grade and high-grade dysplastic nodules. In contrast, acquisition of genomic diversity through mutations of classical oncogenes and tumor suppressor genes (TP53, CTNNB1, ARID1A…) occurred only in progressed HCC. In normal liver, a subset of HCC can derived from the malignant transformation of hepatocellular adenoma (HCA). In HCA, CTNNB1 mutations predispose to transformation of HCA in HCC and TERT promoter mutations are required in most of the cases as a second hit for a full malignant transformation. All these findings have refined our knowledge of HCC pathogenesis and have pointed telomerase as a target for tailored therapy in the future.
Inserm, UMR-1162, Génomique fonctionnelle des Tumeurs solides, Équipe Labellisée Ligue Contre le Cancer, 75010 Paris, France; Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine, 75006 Paris, France; Université Paris 13, Sorbonne Paris Cité, UFR SMBH, 93000 Bobigny, France; Université Paris Diderot, 75013 Paris, France; AP-HP, Hôpitaux Universitaires Paris - Seine-Saint-Denis, Site Jean-Verdier, Pôle d'Activité Cancérologique Spécialisée, Service d'Hépatologie, 93143 Bondy, France.
Jean-Charles
JC
Nault
Inserm, UMR-1162, Génomique fonctionnelle des Tumeurs solides, Équipe Labellisée Ligue Contre le Cancer, 75010 Paris, France; Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine, 75006 Paris, France; Université Paris 13, Sorbonne Paris Cité, UFR SMBH, 93000 Bobigny, France; Université Paris Diderot, 75013 Paris, France; Assistance publique-Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, 75015 Paris, France. Electronic address: jessica.zucman-rossi@inserm.fr.
Jessica
J
Zucman-Rossi
D018248:Adenoma, Liver Cell / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics*; D019098:Telomerase / Q000235:genetics*
C509186:TERT protein, human; D019098:Telomerase