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

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 Maier, Giorgio SoardoElisabetta Bugianesi, Fabio Colli, Renato Romagnoli, Quentin M. Anstee, Helen L. Reeves, Anna Ludovica Fracanzani, Silvia Fargion, Stefano Romeo, Luca Valenti

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1930-1940
JournalCancer Medicine
Volume6
Issue number8
DOIs
Publication statusPublished - 2017

Fingerprint

Germ-Line Mutation
Telomerase
Hepatocellular Carcinoma
Telomere
Mutation
Liver Diseases
Fibrosis
Non-alcoholic Fatty Liver Disease
HEK293 Cells
Mutation Rate
Missense Mutation
Liver Neoplasms
Liver Cirrhosis
Computer Simulation
Introns
Exons
Proteins
Genome
Polymerase Chain Reaction

Keywords

  • Hepatocellular carcinoma
  • Nonalcoholic fatty liver
  • Rare germline mutations
  • Telomerase reverse transcriptase
  • Telomere

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

Cite this

Telomerase reverse transcriptase germline mutations and hepatocellular carcinoma in patients with nonalcoholic fatty liver disease. / Donati, Benedetta; Pietrelli, Alessandro; Pingitore, Piero; Dongiovanni, Paola; Caddeo, Andrea; Walker, Lucy; Baselli, Guido; Pelusi, Serena; Rosso, Chiara; Vanni, Ester; Daly, Ann; Mancina, Rosellina Margherita; Grieco, Antonio; Miele, Luca; Grimaudo, Stefania; Craxi, Antonio; Petta, Salvatore; De Luca, Laura; Maier, Silvia; Soardo, Giorgio; Bugianesi, Elisabetta; Colli, Fabio; Romagnoli, Renato; Anstee, Quentin M.; Reeves, Helen L.; Fracanzani, Anna Ludovica; Fargion, Silvia; Romeo, Stefano; Valenti, Luca.

In: Cancer Medicine, Vol. 6, No. 8, 2017, p. 1930-1940.

Research output: Contribution to journalArticle

Donati, B, Pietrelli, A, Pingitore, P, Dongiovanni, P, Caddeo, A, Walker, L, Baselli, G, Pelusi, S, Rosso, C, Vanni, E, Daly, A, Mancina, RM, Grieco, A, Miele, L, Grimaudo, S, Craxi, A, Petta, S, De Luca, L, Maier, S, Soardo, G, Bugianesi, E, Colli, F, Romagnoli, R, Anstee, QM, Reeves, HL, Fracanzani, AL, Fargion, S, Romeo, S & Valenti, L 2017, 'Telomerase reverse transcriptase germline mutations and hepatocellular carcinoma in patients with nonalcoholic fatty liver disease', Cancer Medicine, vol. 6, no. 8, pp. 1930-1940. https://doi.org/10.1002/cam4.1078
Donati, Benedetta ; Pietrelli, Alessandro ; Pingitore, Piero ; Dongiovanni, Paola ; Caddeo, Andrea ; Walker, Lucy ; Baselli, Guido ; Pelusi, Serena ; Rosso, Chiara ; Vanni, Ester ; Daly, Ann ; Mancina, Rosellina Margherita ; Grieco, Antonio ; Miele, Luca ; Grimaudo, Stefania ; Craxi, Antonio ; Petta, Salvatore ; De Luca, Laura ; Maier, Silvia ; Soardo, Giorgio ; Bugianesi, Elisabetta ; Colli, Fabio ; Romagnoli, Renato ; Anstee, Quentin M. ; Reeves, Helen L. ; Fracanzani, Anna Ludovica ; Fargion, Silvia ; Romeo, Stefano ; Valenti, Luca. / Telomerase reverse transcriptase germline mutations and hepatocellular carcinoma in patients with nonalcoholic fatty liver disease. In: Cancer Medicine. 2017 ; Vol. 6, No. 8. pp. 1930-1940.
@article{e31ef4f4a8454f0188196740a510b7fa,
title = "Telomerase reverse transcriptase germline mutations and hepatocellular carcinoma in patients with nonalcoholic fatty liver disease",
abstract = "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.",
keywords = "Hepatocellular carcinoma, Nonalcoholic fatty liver, Rare germline mutations, Telomerase reverse transcriptase, Telomere",
author = "Benedetta Donati and Alessandro Pietrelli and Piero Pingitore and Paola Dongiovanni and Andrea Caddeo and Lucy Walker and Guido Baselli and Serena Pelusi and Chiara Rosso and Ester Vanni and Ann Daly and Mancina, {Rosellina Margherita} and Antonio Grieco and Luca Miele and Stefania Grimaudo and Antonio Craxi and Salvatore Petta and {De Luca}, Laura and Silvia Maier and Giorgio Soardo and Elisabetta Bugianesi and Fabio Colli and Renato Romagnoli and Anstee, {Quentin M.} and Reeves, {Helen L.} and Fracanzani, {Anna Ludovica} and Silvia Fargion and Stefano Romeo and Luca Valenti",
year = "2017",
doi = "10.1002/cam4.1078",
language = "English",
volume = "6",
pages = "1930--1940",
journal = "Cancer Medicine",
issn = "2045-7634",
publisher = "John Wiley and Sons Ltd",
number = "8",

}

TY - JOUR

T1 - Telomerase reverse transcriptase germline mutations and hepatocellular carcinoma in patients with nonalcoholic fatty liver disease

AU - Donati, Benedetta

AU - Pietrelli, Alessandro

AU - Pingitore, Piero

AU - Dongiovanni, Paola

AU - Caddeo, Andrea

AU - Walker, Lucy

AU - Baselli, Guido

AU - Pelusi, Serena

AU - Rosso, Chiara

AU - Vanni, Ester

AU - Daly, Ann

AU - Mancina, Rosellina Margherita

AU - Grieco, Antonio

AU - Miele, Luca

AU - Grimaudo, Stefania

AU - Craxi, Antonio

AU - Petta, Salvatore

AU - De Luca, Laura

AU - Maier, Silvia

AU - Soardo, Giorgio

AU - Bugianesi, Elisabetta

AU - Colli, Fabio

AU - Romagnoli, Renato

AU - Anstee, Quentin M.

AU - Reeves, Helen L.

AU - Fracanzani, Anna Ludovica

AU - Fargion, Silvia

AU - Romeo, Stefano

AU - Valenti, Luca

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Hepatocellular carcinoma

KW - Nonalcoholic fatty liver

KW - Rare germline mutations

KW - Telomerase reverse transcriptase

KW - Telomere

UR - http://www.scopus.com/inward/record.url?scp=85021814485&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85021814485&partnerID=8YFLogxK

U2 - 10.1002/cam4.1078

DO - 10.1002/cam4.1078

M3 - Article

AN - SCOPUS:85021814485

VL - 6

SP - 1930

EP - 1940

JO - Cancer Medicine

JF - Cancer Medicine

SN - 2045-7634

IS - 8

ER -