Telomeres and Telomerase in the Development of Liver Cancer

Abstract

Liver cancer is one of the most common cancer types worldwide and the fourth leading cause of cancer-related death. Liver carcinoma is distinguished by a high heterogeneity in pathogenesis, histopathology and biological behavior. Dysregulated signaling pathways and various gene mutations are frequent in hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), which represent the two most common types of liver tumors. Both tumor types are characterized by telomere shortening and reactivation of telomerase during carcinogenesis. Continuous cell proliferation, e.g., by oncogenic mutations, can cause extensive telomere shortening in the absence of sufficient telomerase activity, leading to dysfunctional telomeres and genome instability by breakage–fusion–bridge cycles, which induce senescence or apoptosis as a tumor suppressor mechanism. Telomerase reactivation is required to stabilize telomere functionality and for tumor cell survival, representing a genetic risk factor for the development of liver cirrhosis and liver carcinoma. Therefore, telomeres and telomerase could be useful targets in hepatocarcinogenesis. Here, we review similarities and differences between HCC and iCCA in telomere biology.

Significance of TERT Genetic Alterations and Telomere Length in Hepatocellular Carcinoma

“…The prevalence of TERT promoter mutations was significantly different according to the underlying liver disease, with the highest frequency in HCV-related HCC (44%) followed by non-viral (38%) and HBV-related HCC (23%). The mutation rates were largely consistent with those in previous studies, which reported mutation frequencies of 50-60% in HCV-related and 25-35% in HBV-related HCCs [9][10][11]. Interestingly, we observed the more apparent association of TERT mutations with the prognosis of non-HBV HCC rather than HBV-related HCCs in the surgical group (Figure S2).…”

Using Hepatocellular Carcinoma Tumor Burden Score to Stratify Prognosis after Liver Transplantation

“…Understanding the biology and pathology of HCC is a challenge due to the cellular and anatomic complexities of the liver and the local immune environment [ 42 ], as well as due to high heterogeneity in pathogenesis, histopathology, and biological behavior [ 43 , 44 ]. There is an emerging body of literature that focuses on the role of tumor biology and microenvironment [ 30 , 45 , 46 ].…”

Current status of ctDNA in precision oncology for hepatocellular carcinoma

“…A mutation in the promoter region of the TERT gene always occurs early during HCC oncogenesis and is regarded as a driver gene for HCC carcinogenesis [78]. The expression of mutational TERT genes results in telomeres extending compensates for eroded telomeric ends and allows for epithelial cell immortalization [79]. 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].…”