Telomerase reverse transcriptase germline mutations and hepatocellular carcinoma in patients with nonalcoholic fatty liver disease

Benedetta Donati, Maria Benedetta Donati, Alessandro Pietrelli, Piero Pingitore, Paola Dongiovanni, Andrea Caddeo, Lucy Walker, Guido Baselli, Serena Pelusi, Chiara Rosso, Ester Vanni, Ann Daly, Rosellina Margherita Mancina, Antonio Grieco, Luca Miele, Stefania Grimaudo, Antonio Craxi, Salvatore Petta, Laura De Luca, Silvia MaierGiorgio Soardo, Elisabetta Bugianesi, Fabio Colli, Renato Romagnoli, Quentin M. Anstee, Helen L. Reeves, Anna Ludovica Fracanzani, Silvia Fargion, Stefano Romeo, Luca Valenti

Risultato della ricerca: Contributo in rivistaArticolo in rivista

20 Citazioni (Scopus)


In an increasing proportion of cases, hepatocellular carcinoma (HCC) develops in patients with nonalcoholic fatty liver disease (NAFLD). Mutations in telomerase reverse transcriptase (hTERT) are associated with familial liver diseases. The aim of this study was to examine telomere length and germline hTERT mutations as associated with NAFLD-HCC. In 40 patients with NAFLD-HCC, 45 with NAFLD-cirrhosis and 64 healthy controls, peripheral blood telomere length was evaluated by qRT-PCR and hTERT coding regions and intron-exon boundaries sequenced. We further analyzed 78 patients affected by primary liver cancer (NAFLD-PLC, 76 with HCC). Enrichment of rare coding mutations (allelic frequency <0.001) was evaluated by Burden test. Functional consequences were estimated in silico and by over-expressing protein variants in HEK-293 cells. We found that telomere length was reduced in individuals with NAFLD-HCC versus those with cirrhosis (P = 0.048) and healthy controls (P = 0.0006), independently of age and sex. We detected an enrichment of hTERT mutations in NAFLD-HCC, that was confirmed when we further considered a larger cohort of NAFLD-PLC, and was more marked in female patients (P = 0.03). No mutations were found in cirrhosis and local controls, and only one in 503 healthy Europeans from the 1000 Genomes Project (allelic frequency = 0.025 vs. <0.001; P = 0.0005). Mutations with predicted functional impact, including the frameshift Glu113Argfs*79 and missense Glu668Asp, cosegregated with liver disease in two families. Three patients carried missense mutations (Ala67Val in homozygosity, Pro193Leu and His296Pro in heterozygosity) in the N-terminal template-binding. domain (P = 0.037 for specific enrichment). Besides Glu668Asp, the Ala67Val variant resulted in reduced intracellular protein levels. In conclusion, we detected an association between shorter telomeres in peripheral blood and rare germline hTERT mutations and NAFLD-HCC.
Lingua originaleEnglish
pagine (da-a)1930-1940
Numero di pagine11
RivistaCancer Medicine
Stato di pubblicazionePubblicato - 2017


  • Aged
  • Aged, 80 and over
  • Alleles
  • Amino Acid Substitution
  • Cancer Research
  • Carcinoma, Hepatocellular
  • Cohort Studies
  • Computational Biology
  • Disease Susceptibility
  • Female
  • Genetic Association Studies
  • Germ-Line Mutation
  • Hepatocellular carcinoma
  • Humans
  • Leukocytes, Mononuclear
  • Liver Neoplasms
  • Male
  • Middle Aged
  • Non-alcoholic Fatty Liver Disease
  • Nonalcoholic fatty liver
  • Oncology
  • Phenotype
  • Radiology, Nuclear Medicine and Imaging
  • Rare germline mutations
  • Sequence Analysis, DNA
  • Severity of Illness Index
  • Telomerase
  • Telomerase reverse transcriptase
  • Telomere
  • Telomere Shortening


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