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Background
Liver cancer is ranked sixth in incidence and third most prevalent cause of cancer-related deaths globally [1, 2]. Liver cancer remains a spectrum disease with heterogeneity that encompasses hepatocellular carcinoma (HCC), intrahepatic and extrahepatic cholangiocarcinoma (iCCA and eCCA), and ampullary carcinoma (AC) among others [3, 4]. HCC is the most prevalent and aggressive subtype of liver cancer and remains the major cause of liver cancer-related mortality over decades [5, 6–7]. About 80% of HCC cases are reported in Eastern Asia and sub-Saharan Africa [8]. Chronic hepatitis B and C virus infections, alcohol abuse, aflatoxin B1 exposure, and nonalcoholic fatty liver disease (NAFLD) are the major risk factors for the development of HCC [9]. The impact of conventional risk factors of HCC, like hepatitis B and C viral infections, high alcohol intake, and aflatoxin in HCC developments, are significantly declining, while the effect of NAFLD is emerging [10]. Risk factors for NASH-HCC development can be broadly classified as non-genetic and genetic. There are several non-genetic factors, including obesity, type 2 diabetes, dyslipidemia, sedentary lifestyle, and poor dietery habits, reported to impact NASH–HCC development. The genetic predispositions to NAFL and NASH-HCC have been analysed in recent decades, especially single nucleotide polymorphisms (SNPs) in genes related to cellular proliferation, which includes Telomerase Reverse Transcriptase (TERT) promoter mutations, Catenin Beta 1 (CTNNB1), Tumour Protein 53 (TP53), Activin A Receptor Type 2A (ACVR2A). Among these genes, the TERT promoter region is reported as the most prevalent in NAFL and NASH-HCC patients. Two common SNPs termed C228T and C250T, are located at − 124 bp and − 146 bp upstream of the TERT transcription site.
The most reported consequence of C228T and C250T SNPs is upregulation of TERT gene expression, which stabilises and maintains the length of the telomere’s ends, which in turn prevents cancerous hepatocytes from undergoing conventional apoptosis, hence, constitutively maintains their survival. However, little is known about the actual mechanism (s) through which it upregulates hepatocarcinogenesis in NASH-HCC. Considering the global increase in the prevalence of NASH-HCC, this review presents the current studies on TERT promoter mutations and their impact on NASH-HCC progression in some part of the wold. This review also highlights the TERT promoter mutations correlating with TERT...