title: Telomerase reverse transcriptase promoter mutation is an early somatic genetic alteration in the transformation of premalignant nodules in hepatocellular carcinoma on cirrhosis.
abstract: Genetic determinants of the early steps of carcinogenesis on cirrhosis are still poorly understood. We aimed to evaluate the occurrence of telomerase reverse transcriptase (TERT) promoter mutations in the transformation of cirrhotic nodules into hepatocellular carcinoma (HCC). We analyzed a series of 268 liver samples, including 96 nodules developed in 58 patients with cirrhosis and 114 additional cirrhosis. All samples were screened for TERT promoter mutations, and in 31 nodules, for 10 genes recurrently mutated in HCC. Immunohistochemistry (IHC) analyses were performed for glypican 3, glutamine synthase, and heat shock protein 70. Six liver pathologists reviewed all the samples. Among The 96 nodules, 88 were firmly diagnosed as low-grade dysplastic nodules (LGDNs; 32 cases), high-grade dysplastic nodules (HGDNs; 16 cases), early HCC (eHCC; 23 cases), or small and progressed HCC in 17 cases. The agreement between the initial diagnosis from pathological report and the final expert consensus report was moderate for the diagnosis of benign versus malignant nodules (weighted kappa = 0.530). TERT promoter mutations were highly related to the step-wise hepatocarcinogenesis because mutations were identified in 6% of LGDNs, 19% of HGDNs, 61% of eHCCs, and 42% of small and progressed HCC. TERT promoter mutation is the most frequent molecular alteration in eHCC given that the IHC criteria for diagnosis of malignancy were found in only 39% of the cases. TERT promoter mutation was also the earliest genetic alteration because mutations in 10 other genes were only identified in 28% of the small and progressed HCC.
  
  
  CONCLUSIONS
  Frequency of TERT promoter mutations rapidly increases during the different steps of the transformation of premalignant lesions into HCC on cirrhosis. Consequently, somatic TERT promoter mutation is a new biomarker predictive of transformation of premalignant lesions into HCC.
authors.affiliation: Inserm, UMR-1162, Génomique fonctionnelle des Tumeurs solides, IUH, Paris, France; Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France; Université Paris 13, Sorbonne Paris Cité, UFR SMBH, Bobigny, France; Université Paris Diderot, Paris, France; APHP, Hôpitaux Universitaires Paris-Seine Saint-Denis, Site Jean Verdier, Pôle d'Activité Cancérologique Spécialisée, Service d'Hépatologie, Bondy, France.
authors.forename: Jean Charles
authors.initials: JC
authors.lastname: Nault
authors.forename: Julien
authors.initials: J
authors.lastname: Calderaro
authors.forename: Luca
authors.initials: L
authors.lastname: Di Tommaso
authors.forename: Charles
authors.initials: C
authors.lastname: Balabaud
authors.forename: Elie Serge
authors.initials: ES
authors.lastname: Zafrani
authors.forename: Paulette
authors.initials: P
authors.lastname: Bioulac-Sage
authors.forename: Massimo
authors.initials: M
authors.lastname: Roncalli
authors.forename: Jessica
authors.initials: J
authors.lastname: Zucman-Rossi
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000209:etiology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008103:Liver Cirrhosis / Q000150:complications*; D008113:Liver Neoplasms / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011230:Precancerous Conditions / Q000235:genetics*; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D019098:Telomerase