Prediction of the prognosis of advanced hepatocellular carcinoma by TERT promoter mutations in circulating tumor DNA

Abstract

Background andAim: Human telomerase reverse transcriptase (TERT) promoter mutations were the most prevalent mutations in patients with hepatocellular carcinoma (HCC). We tried to detect the mutations with plasma circulating tumor DNA (ctDNA) in patients with advanced HCC and elucidated their clinical utility. Methods: Circulating tumor DNA in plasma was extracted from 130 patients with advanced HCC who were treated with systemic chemotherapy (n = 86) or transcatheter arterial chemoembolization (n = 44), and TERT promoter mutations were examined with digital droplet polymerase chain reaction. The correlations between these mutations and the clinical outcome of patients were analyzed. Results: Of the 130 patients examined, 71 patients (54.6%) were positive for TERT promoter mutations in ctDNA, of which 64 patients were À124bp G > A and 10 were À146bp G > A. The presence of TERT promoter mutations was correlated with large intrahepatic tumor size (P = 0.05) and high des-gamma carboxyprothrombin (P = 0.005). Overall survival of the patients with the mutations was significantly shorter than those without them (P < 0.001), and the patients with high (≥ 1%) fractional abundance of the mutant alleles showed shorter survival than those with low (< 1%) fractional abundance. Multivariate analysis revealed that TERT promoter mutation (hazard ratio [HR]: 1.94; 95% confidence interval [CI], 1.18-3.24; P < 0.01), systemic chemotherapy (HR: 2.38; 95% CI, 1.29-4.57; P < 0.01), and vascular invasion (HR: 2.16; 95% CI, 1.22-3.76; P < 0.01) were significant factors for poor overall survival. Conclusions: TERT promoter mutations in ctDNA were associated with short survival and could be a valuable biomarker for predicting the prognosis of patients with advanced HCC.

The Role of Liquid Biopsy in Hepatocellular Carcinoma Prognostication

“…In a cohort of 41 HCC patients and 10 controls, detection of these mutations was associated with shorter recurrence-free survival after liver resection [31]. This was confirmed by other studies identifying TERT prom and TP53 mutations as prognostic factors of poor survival [33,34,36,37]. Targeted-sequencing of various panels of genes further confirmed the prognostic impact of ctDNA detection, associated with worse survival or higher recurrence [30].…”

Current status of ctDNA in precision oncology for hepatocellular carcinoma

“…Frequent occurrences of TERT promoter mutations located at − 124 and − 146 bp relative to the start codon in various cancers, especially alterations in -124C > T, clearly boost transcriptional activity in HCC cell lines [80]. Furthermore, patients with this type of mutation in ctDNA are more prone to have vascular invasion (p = 0.005) and are positively correlated with an advanced TNM stage (p < 0.0001), large intrahepatic tumor size (p = 0.05), high des-gamma carboxyprothrombin value (p = 0.005), and increased mortality [81,82]. Telomerase-targeting compounds, like GRN163L, BIBR1532, or compounds that interfere with RNA, can decrease telomere length, which is expected to be applied in the following treatment, but still needs clinical evaluation [65,66].…”

Genomic Landscape of Liquid Biopsy for Hepatocellular Carcinoma Personalized Medicine

“…Mutations in human telomerase reverse transcriptase (TERT) gene promoter are the most prominent in HCC tumor tissue. A recent study showed that about 55% of 130 HCC patients are positive in ctDNA TERT promoter mutations, and this correlates with large tumor size and high DCP levels, followed by significantly shorter OS (34). Moreover, a triple diagnostic panel consisting of ctDNA TERT promoter mutations (C228T and C250T), miR-122, and AFP showed the best performance in distinguishing HBV-related HCC from non-HCC diseases such as chronic hepatitis B (CHB) and liver cirrhosis (35).…”