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RESEARCH PRODUCT
Telomerase reverse transcriptase germline mutations and hepatocellular carcinoma in patients with nonalcoholic fatty liver disease
Ann K. DalyLuca MieleAlessandro PietrelliStefano RomeoStefano RomeoAntonio GriecoS. MaierBenedetta DonatiPiero PingitoreHelen L. ReevesHelen L. ReevesRenato RomagnoliChiara RossoGuido BaselliLaura De LucaAnna Ludovica FracanzaniElisabetta BugianesiSilvia FargionAntonio CraxìSalvatore PettaStefania GrimaudoPaola DongiovanniLuca ValentiLucy J. WalkerAndrea CaddeoSerena PelusiRosellina Margherita MancinaFabio ColliQuentin M. AnsteeQuentin M. AnsteeGiorgio SoardoEster Vannisubject
MaleCancer ResearchHepatocellular carcinomaSeverity of Illness IndexGermlineLoss of heterozygosityCohort StudiesLiver disease0302 clinical medicineNon-alcoholic Fatty Liver DiseaseNuclear Medicine and ImagingNonalcoholic fatty liver disease80 and overLeukocytesTelomeraseTelomere ShorteningOriginal ResearchCancer BiologyAged 80 and overHepatocellular carcinoma; Nonalcoholic fatty liver; Rare germline mutations; Telomerase reverse transcriptase; Telomere; Oncology; Radiology Nuclear Medicine and Imaging; Cancer ResearchtelomereLiver Neoplasmstelomerase reverse transcriptaseMiddle Aged3. Good healthPhenotypeOncology030220 oncology & carcinogenesisHepatocellular carcinoma030211 gastroenterology & hepatologyFemaleDisease SusceptibilityRadiologySequence AnalysisRare germline mutationCarcinoma HepatocellularMononuclearBiology03 medical and health sciencesGermline mutationHepatocellular carcinoma; Nonalcoholic fatty liver; Rare germline mutations; Telomerase reverse transcriptase; Telomere; Aged; Aged 80 and over; Alleles; Amino Acid Substitution; Carcinoma Hepatocellular; Cohort Studies; Computational Biology; Disease Susceptibility; Female; Genetic Association Studies; Humans; Leukocytes Mononuclear; Liver Neoplasms; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Phenotype; Sequence Analysis DNA; Severity of Illness Index; Telomerase; Telomere; Telomere Shortening; Germ-Line Mutationmedicinenonalcoholic fatty liverHumansRadiology Nuclear Medicine and imagingTelomerase reverse transcriptaseAllelesGenetic Association StudiesGerm-Line MutationAgedrare germline mutationsCarcinomaComputational BiologyHepatocellularDNASequence Analysis DNAmedicine.diseasedigestive system diseasesTelomereAmino Acid SubstitutionCancer researchLeukocytes Mononucleardescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2017-07-01 | Cancer Medicine |