TERT Promoter Mutation in Serum Cell-Free DNA Is a Diagnostic Marker of Primary Hepatocellular Carcinoma in Patients with Nonalcoholic Fatty Liver Disease

Abstract

<b><i>Introduction:</i></b> It remains unclear whether <i>TERT</i> promoter mutation (TERT C228T) in serum cell-free DNA (cfDNA) is useful for the diagnosis of hepatocellular carcinoma (HCC) in patients with nonalcoholic fatty liver disease (NAFLD). <b><i>Methods:</i></b> In this retrospective study, we analyzed the relationships between TERT C228T in serum cfDNA and levels of AFP and PIVKAII in 57 Japanese patients with histopathologically confirmed NAFLD background, consisting of 36 patients with HCC and 21 without HCC. We also examined the liver-related survival rate and HCC recurrence rate after the initial treatment for HCC. TERT C228T was detected using a highly sensitive method based on wild-type blocking PCR (detection limit in excess of 0.7% mutant-type DNA). <b><i>Results:</i></b> In all of the 57 patients, multivariate analysis identified TERT C228T positive as significant determinant of primary HCC. In the 36 patients with HCC, the percentage of patients positive for TERT C228T was 63.9%. The percentage of patients positive for TERT C228T with normal AFP and PIVKAII was 35.3%. The positive predictive value and specificity for prediction of BCLC stage 0 or A were both high. In 6 patients, TERT C228T was repeatedly negative during follow-up but became positive at the time of HCC diagnosis. Four patients who underwent HCC surgical resection had well-differentiated solitary HCC measuring <30 mm, and all were TERT C228T positive with normal AFP and PIVKAII. TERT C228T status had no influence on the cumulative liver-related survival rate and HCC recurrence rate. <b><i>Conclusions:</i></b> Our results highlight the superiority of TERT C228T in serum cfDNA compared with AFP and PIVKAII in the early diagnosis of primary HCC in NAFLD patients.

Detection of oncogenic mutations in paired circulating tumor DNA and circulating tumor cells in patients with hepatocellular carcinoma

“…These findings are in line with recent findings by others, that have correlated TERT promotor mutation in plasma with macrovascular invasion and overall survival [27 , 28] . The ddPCR technique used in our study for TERT promoter mutation analysis is a relatively easy, fast and affordable assay, that can be used in clinical care for detection of this biomarker, for instance as an additional tool in the early detection of HCC, as was suggested by others [47 , 48] . Previously, ctDNA mutations in early-stage HCC patients have been associated with microvascular invasion and recurrence by others [44 , 45] .…”

Usefulness of Cell‐Free Human Telomerase Reverse Transcriptase Mutant DNA Quantification in Blood for Predicting Hepatocellular Carcinoma Treatment Efficacy

“…( 28 ) At the same time, because hTERT promoter mutation might reflect tumor volume, hTERT promoter mutant DNA could also be used as an early HCC diagnostic marker if a highly sensitive detection system is introduced. ( 29 , 30 ) We hypothesized that changes in mutant DNA levels reflect the amount of tumor necrosis caused by treatment and focused on changes in mutant DNA levels and treatment effects in advanced cancer. In a cross‐sectional analysis of factors associated with the detection of hTERT promoter mutant DNA in the blood before HCC treatment, tumor diameter was extracted as a factor.…”

Non-alcoholic steatohepatitis and risk of hepatocellular carcinoma

“…[ 82 , 83 ] These occur frequently in HCC patients (from 60% to 90%), with a few studies using TERT mutation as a therapeutic target with little success. [ 84 ] However, Akuta et al [ 85 ] have proven the feasibility of TERT promoter mutation ( TERT C228T) in diagnosing primary HCC, which performed better than alpha-fetoprotein (AFP). Liver cancer diagnosis in family members can be correlated with an increased probability of developing HCC, with both inherited and acquired factors promoting carcinogenesis.…”