Telomerase reverse transcriptase promoter mutation is an early somatic genetic alteration in the transformation of premalignant nodules in hepatocellular carcinoma on cirrhosis

Jean Charles Nault, Julien Calderaro, Luca Di Tommaso, Charles Balabaud, Elie Serge Zafrani, Paulette Bioulac-Sage, Massimo Roncalli, Jessica Zucman-Rossi

Research output: Contribution to journalArticle

113 Citations (Scopus)

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. Conclusion: 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.

Original languageEnglish
Pages (from-to)1983-1992
Number of pages10
JournalHepatology
Volume60
Issue number6
DOIs
Publication statusPublished - Dec 1 2014

Fingerprint

Telomerase
Hepatocellular Carcinoma
Fibrosis
Mutation
Immunohistochemistry
Glypicans
HSP70 Heat-Shock Proteins
Liver
Glutamine
Genes
Carcinogenesis
Biomarkers

ASJC Scopus subject areas

  • Hepatology
  • Medicine(all)

Cite this

Telomerase reverse transcriptase promoter mutation is an early somatic genetic alteration in the transformation of premalignant nodules in hepatocellular carcinoma on cirrhosis. / Nault, Jean Charles; Calderaro, Julien; Di Tommaso, Luca; Balabaud, Charles; Zafrani, Elie Serge; Bioulac-Sage, Paulette; Roncalli, Massimo; Zucman-Rossi, Jessica.

In: Hepatology, Vol. 60, No. 6, 01.12.2014, p. 1983-1992.

Research output: Contribution to journalArticle

Nault, Jean Charles ; Calderaro, Julien ; Di Tommaso, Luca ; Balabaud, Charles ; Zafrani, Elie Serge ; Bioulac-Sage, Paulette ; Roncalli, Massimo ; Zucman-Rossi, Jessica. / Telomerase reverse transcriptase promoter mutation is an early somatic genetic alteration in the transformation of premalignant nodules in hepatocellular carcinoma on cirrhosis. In: Hepatology. 2014 ; Vol. 60, No. 6. pp. 1983-1992.
@article{296bf685f2684d2286c103bffd8d421b,
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. Conclusion: 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.",
author = "Nault, {Jean Charles} and Julien Calderaro and {Di Tommaso}, Luca and Charles Balabaud and Zafrani, {Elie Serge} and Paulette Bioulac-Sage and Massimo Roncalli and Jessica Zucman-Rossi",
year = "2014",
month = "12",
day = "1",
doi = "10.1002/hep.27372",
language = "English",
volume = "60",
pages = "1983--1992",
journal = "Hepatology",
issn = "0270-9139",
publisher = "John Wiley and Sons Inc.",
number = "6",

}

TY - JOUR

T1 - Telomerase reverse transcriptase promoter mutation is an early somatic genetic alteration in the transformation of premalignant nodules in hepatocellular carcinoma on cirrhosis

AU - Nault, Jean Charles

AU - Calderaro, Julien

AU - Di Tommaso, Luca

AU - Balabaud, Charles

AU - Zafrani, Elie Serge

AU - Bioulac-Sage, Paulette

AU - Roncalli, Massimo

AU - Zucman-Rossi, Jessica

PY - 2014/12/1

Y1 - 2014/12/1

N2 - 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. Conclusion: 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.

AB - 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. Conclusion: 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.

UR - http://www.scopus.com/inward/record.url?scp=84911902519&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84911902519&partnerID=8YFLogxK

U2 - 10.1002/hep.27372

DO - 10.1002/hep.27372

M3 - Article

VL - 60

SP - 1983

EP - 1992

JO - Hepatology

JF - Hepatology

SN - 0270-9139

IS - 6

ER -